Expression of adrenergic and cholinergic receptors on peripheral blood leucocytes of adolescents with primary hypertension

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Methods: 49 yet untreated adolescents with PH in a mean age of 15.2 ±1.9 years, and 47 healthy, normotensive adolescents, matched both for sex and age (mean age of 14.7 ±1.0 years) were included in the study. The percentage of positive cells (PPC) and mean fluorescence intensity (MFI) of PBL and monocytes was analyzed. Results: in hypertensive adolescents PBL and monocytes presented greater PPC and MFI of AR and α7nAChR in comparison with normotensive group. Carotid intima-media thickness and carotid wall cross sectional area correlated with extracellular MIF of α1AR (r = 0.438 and r = 0.602, respectively; p<0.05), left ventricular mass index with extracellular MFI of α7nAChR (r = 0.340; p<0.05) and PPC of α1AR (r = 0.340; p<0.05). Stroke volume, and total peripheral resistance correlated with extracellular MIF of β2AR (r = 0,283, and r = -0.221, respectively; all p<0.05). Serum uric acid levels correlated with AR and α7nAChRexpression. However, hsCRP did not correlate with AR and α7nAChR expression. Conclusions: adolescents with PH show significant alterations in the expression of adrenergic and cholinergic receptors in PBL. These changes correlate with hypertension mediated organ damage, hemodynamic and metabolic parameters typical of childhood hypertension. Health sciences/Diseases/Cardiovascular diseases/Hypertension Health sciences/Diseases primary hypertension adolescents adrenergic receptors immune system Figures Figure 1 Figure 2 Summary table What is known about the topic The role of the immune system in the pathogenesis of essential hypertension has been proven both in experimental models and clinical observations Sympathetic nervous system activation is a significant disturbance in the initial stages of the pathogenesis of primary hypertension in adolescents. Changes in the expression of adrenergic receptors on immune cells of experimental animals with hypertension suggest an interrelationship between the activation of the sympathetic and immune systems in the pathogenesis of hypertension. What this study adds This is the first study to evaluate the expression of adrenergic and nicotinic receptors on peripheral blood leukocytes in adolescents with untreated primary hypertension and in age and gender matched normotensive control group. Hypertensive adolescents show significant changes in the expression of adrenergic and nicotinic receptors on peripheral blood leukocytes, and the disturbed pattern of receptor expression correlates with markers of hypertension mediated organ damage and hemodynamic changes typical for early stage of primary hypertension. Introduction Primary hypertension (PH) develops already in the developmental age, and although it is practically not recognized in the youngest children, during adolescence there is a sharp increase in the recognition of this form of hypertension [1]. This is correlated with a significant rise of systolic blood pressure in boys, which explains the predominance of boys among adolescents with PH. Adolescents with PH demonstrate a typical hemodynamic phenotype that includes isolated systolic hypertension as the predominant type of hypertension and features indicative of sympathetic nervous system (SNS) activation: higher stroke volume (SV), higher left ventricular contraction velocity, faster heart rate (HR), and disturbances in circadian blood pressure rhythms indicative of prolonged sympathetic activation [2–5]. This is accompanied by disturbances in body composition, metabolic disorders typical of metabolic syndrome, and activation of both the innate and adaptive immune systems [6–8]. In adolescents with PH, these disorders are interconnected. Sympathetic receptors, both alpha and beta, are present on immunocompetent cells, including peripheral blood leukocytes (PBL). Thus, we assumed that adolescents with PH have a significant change in the expression of adrenergic receptors (AR) and alfa7-nicotinic acetylcholine receptor (α7nAChR) compared to their normotensive peers. The aim of the study was to assess the intracellular and membrane expression of AR and α7nAChR on PBL in untreated adolescents with PH and to compare them with an age- and sex-matched group of normotensive peers. The second aim was to assess the relationship between AR and α7nAChR expression on PBL and hypertension mediated end-organ damage (HMOD), hemodynamic and metabolic parameters typically associated with PH. Patients and control group. The patients description and methodology were provided previously [9]. In short, out of 275 children and adolescents referred to our clinic due to elevated office blood pressure, 49 (40 males) yet untreated adolescents with a mean age of 15.2 ± 1.9 years, in whom secondary hypertension was excluded after a full diagnostic process, were included in the study. PH was diagnosed following the recent guidelines and confirmed by 24-hour ambulatory blood pressure monitoring. The exclusion criteria included the presence of any significant chronic disease (except for PH), including diabetes and chronic kidney disease, any acute illness plus infections in the six weeks preceding enrolment, cigarette smoking, and incomplete data. None of the patients received antihypertensive therapy before enrolment in the study. The control group consisted of 47 (35 males) healthy, normotensive adolescents, matched both for sex and age (mean age of 14.7 ± 1.0 years), and recruited voluntarily from schools. The exclusion criteria included the presence of any chronic disease, use of drugs, any acute illness plus infections in the six weeks preceding enrolment, cigarette smoking, and/or incomplete data. All subjects included to the study and their parents gave informed consents. The study was approved by Bioethical Committee at The Children’s Memorial Health Institute ((No. 121/KBE/2013). Methods Hypertension-mediated organ damage assessment In all patients and subjects of the control group, carotid intima-media thickness (cIMT), left ventricular mass index (LVMI), pulse wave velocity (PWV) and pulse wave analysis (PWA) were assessed. Echocardiography (ECHO), cIMT, PWA, and PWV were assessed by investigators who knew clinical diagnosis but were not aware of final diagnosis confirming or excluding arterial hypertension and final classification of hypertension severity. cIMT measurements The cIMT and carotid wall cross-sectional area (WCSA) were evaluated by ultrasound following the methodology described previously [9,10]. cIMT-SDS above 1.65 was taken as a cut-off for the 95 th percentile for age and sex. The echocardiographic LVMI assessment ECHO measurements were performed following the American Society of Echocardiography guidelines. To standardize the left ventricular mass with height, LVMI was calculated following de Simone’s formula. Left ventricular hypertrophy (LVH) was defined as an LVMI value above the 95th percentile for age and sex based on reference data and severe LVH as LVMI ≥51 g/m 2.7 [11]. Relative wall thickness (RWT), a marker of concentric remodeling, was calculated as the sum of the interventricular septum and posterior wall thickness measured in diastole and divided by internal ventricular diameter in diastole. PWV and PWA assessment PWV and PWA were measured non-invasively with oscillometric method using Vicorder® (SMT Medical) system device, which has been cross-validated against applanation tonometry system (Sphygmocor) and invasive measurements of central blood pressure. It was found to be a reliable and simple alternative to tonometry, and has also been validated in children[12,13]. The Vicorder system provides a simple and quick non-invasive oscillometric method of obtaining PWV measured between carotid and femoral artery. Measurements were performed in the supine position after 5 minutes of rest. The PWV cuffs were placed on the neck of the patient (30-mm plethysmographic partial inflatable sensor) and the right thigh (a 100-mm wide cuff). Both cuffs were automatically inflated to 65mmHg and the corresponding oscillometric signal from each cuff was digitally analyzed by means of the latest patented technique to accurately extract, in real time, the pulse time delay and the consequent PWV. The approximate transit distance of the pulse wave was estimated based on the measurement of the distance between the carotid artery and the femoral artery, which was found to be accurate and reproducible. The PWV in m/s (absolute values obtained the device) were subsequently converted to z-scores based on pediatric normative data[14,15]. Transfer function was applied to the waweform of brachial artery in order to obtain aortic swaveform, which enables calculation of various parameters of arterial system characteristics including central systolic blood pressure (cSBP), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) using company proprietary algorithm. The formula also calculated augmentation pressure (AugPress) and augmentation index (AugInd) as parameters describing the contribution of the return wave for cSBP and central pulse pressure (cPP). AugInd determines the percentage of AugPress in cPP. In both PWV and PWA, the first few measured waves were omitted; if the following (at least 5) pulse waves were of good quality the 10-15 consecutive pulse waves (heart beats) were taken into the analysis. Assessment of expression of AR and α7nAChR receptors on PBL The developed protocol involved the collection of blood samples into tubes containing an anticoagulant (EDTA) and a cellular surface antigen-stabilizing agent (Life Technologies, Carlsbad, CA, USA). Samples were stored at 4°C for up to 96 hours prior to processing. Both intracellular and extracellular receptor expression were assessed. Samples were stained in two independent tubes with directly conjugated antibodies for identification of peripheral blood mononuclear cell populations (lymphocytes, monocytes, granulocytes). Both tubes were stained with PE-anti-human CD3, APC-anti-human CD14, APC-Cy7-anti-human CD4, and BV421-anti-human CD45 antibodies (BD Biosciences). Subsequently, cells were fixed, permeabilized, and co-stained using an indirect method with primary antibodies against human α1A-adrenergic receptor (α1-AR) in the first tube and α7-nicotinic acetylcholine receptor (α7nAChR) in the second tube (Santa Cruz Biotechnology). These were followed by incubation with appropriate secondary antibodies conjugated to fluorescent dyes: donkey anti-goat PerCP for the first tube and either goat anti-rabbit PE for the second tube (Santa Cruz Biotechnology). Additionally, the first tube received a directly FITC-conjugated anti-human β2-adrenergic receptor (β2AR) antibody (Santa Cruz Biotechnology). Extracellular receptor expression was evaluated using the same protocol, omitting the fixation and permeabilization steps. Prepared cells were analyzed using a flow cytometer (FACS Canto II, BD Biosciences). Instrument setup was performed with BD Cytometer Setup and Tracking beads. Data acquisition was carried out with BD FACSDiva software version 6.1.3 (BD Biosciences). Compensation settings were established using compensation tubes and BD CompBead antibody-capturing particles, applying the compensation setup tool within BD FACSDiva software. Fluorescence-minus-one (FMO) and isotype antibody controls were employed to accurately define populations exhibiting fluorescence above background levels. Neutrophil and monocyte populations were initially gated based on morphological parameters (side scatter, SSC) and receptor expression (CD14), with debris and platelets excluded. Doublets and aggregates were eliminated by selecting singlet cells on a forward scatter area versus height (FSC-A/FSC-H) plot. Results were expressed as the percentage of positive cells (PPC) and mean fluorescence intensity (MFI), and analyzed using FlowJo software version 7.5.5 (Tree Star Inc.) Statistical analysis Descriptive statistics provided means and standard deviations (SD) for normally distributed continuous variables, medians with interquartile ranges (IQR) in case of normally distributed variables, and proportions for categorical variables. Normality in the data was assessed by examination of histogram, skewness and kurtosis and Kolmogorov-Smirnoff test. In the case of non-normal distribution medians and quantile 1 (Q1) and quantile 3 (Q3) are presented. Group differences were assessed with the Mann-Whitney U test. A p-value below 0.05 deemed statistically significant Pearson’s and Spearman’s correlation coefficients, as appropriate, were calculated to determine relationships between variables. Age- and sex-specific BMI standard deviation scores (SDS) were calculated relative to Polish 2010 reference data [19]. Differences in categorical variables were evaluated with the chi-square test. Data were analysed with the use of Statistica PL statistical software. Results There were no differences in age and gender between the study and control groups. PH patients were heavier and had a higher both absolute and standardized BMI values which were within the range of values corresponding to overweight. By definition, subjects from PH group had higher blood pressure values. Comparison of HMOD markers showed that PH patients had higher LVMi, WCSA, PWV and cBP values (Table 1). Analysis of the expression of AR and α7nAChR on PBL, measured as PPC and MFI, showed that adolescents with PH have greater intra- and extra cellular expression of α7nAChR on all PBL. However, monocytes did not express extracellular AR and α7nAChR and only expression of intracellular receptors was available for analysis. In monocytes increased expression of intracellular α7nAChR and β2AR was found. In general, intra- and extracellular expression of β2AR, α1-A AR expression was generally higher compared to the control group (Table 2). However, differences in expression of βAR were not so uniform as in case of α1-A AR. In patients with PH there were some significant correlations between markers of HMOD and expression of AR and α7nAChR on PBL (Table 3). Specifically, cIMT-SDS correlated with extracellular α1-A AR MFI (r = 0.381, p = 0.008). Similarly, WCSA-SDS values correlated with MFI of extracellular α1-A AR (r = 0.556, p = 0.001), extracellular α7nAChR (r = 0.322, p = 0.001) and PPC of intracellular α1-A AR (r = 0.405; p = 0.04) (Table 3). LVMi correlated with PPC of extracellular α1-A AR (r = 0.340, p = 0.001) and MFI of extracellular α7nAChR (r = 0.359, p = 0.001). Among the hemodynamic variables, we observed weak correlations of heart rate, stroke volume, total peripheral resistance and cardiac output with AR and α7nAChR expression (Table 3). Of biochemical variables only serum uric acid levels correlated with AR and α7nAChR expression on PBL (Table 3) The next step in the analysis was to assess differences in receptor expression depending on the presence or absence of HMOD. We defined subclinical hypertensive arterial disease as values of cIMT, WCSA and PWV greater than 1.67 SDS of the median normal range, and left ventricular hypertrophy as LVMi greater than 42 g/m of height 2.7 . Although the groups differed significantly in terms of cIMT, WCSA, PWV and LVMi values, the analysis revealed differences only in the expression of single receptors. Subjects with elevated cIMT did not differ in receptor expression from those with normal cIMT. Individuals with evidence of common carotid artery remodeling, expressed as elevated WCSA, had significantly higher MFI values for extracellular α1 receptors (7.4 ±4 vs 3.3±1.2; p = 0.008) and higher PPC values for cholinergic receptors in monocytes (99.1 ±1.4 vs 87 ±29; p = 0.01). Left ventricular hypertrophy was associated with higher MFI values for intracellular β2 receptors (625 ±457 vs 386 ±149; p = 0.03) (Figure 3). Discussion The main result of our study is different expression of both intra- and extracellular adrenergic and cholinergic receptors in PBL of yet untreated adolescents with PH in comparison with normotensive peers. Both αAR and α7nAChR expression was increased both intra- and extracellularly and expressed as PPC and MFI. However, for βAR the differences were not as pronounced and we also observed lower expression in PH patients. In addition, we also found moderate, statistically significant correlations between the expression of some receptors and HMOD markers and hemodynamic parameters such as HR, SV and TPR. The involvement of the autonomic nervous system (ANS) in the pathogenesis of PH is usually considered as an effect on cardiac function and peripheral resistance. However, the ANS has a much broader role in the regulation of homeostasis and also includes the control of the inflammatory response. In describing the pathogenesis of PH, the term neuro-immune axis is used to describe the relationship between adrenergic activation and the immune system[16]. The parasympathetic nervous system (PNS) is believed to have anti-inflammatory effects and SNS is pro-inflammatory[17,18]. There are data showing that αAR mediate stimulatory effects and βAR mediate more inhibitory effects on immune cells. The classical paradigm assumes that there is a balance between the activity of the SNS and immune systems. This balance is modulated by PNS and activation of α7nAChR has anti-inflammatory effects, particularly on monocytes and macrophages. Monocytes circulate in the blood and after activation and entry into tissues, they transform into macrophages. Experimental studies over the last two decades have shown an important role of macrophages in the pathogenesis of PH[16]. SNS exerts its effects through direct stimulation of sympathetic nerves innervating lymphatic organs, such as the spleen, and forming the so-called neuroimmune synapse, as well as by the non-neuronal way, by the direct effect of catecholamines in the blood, which act on AR. The major lymphatic organs where immune cells mature are innervated by both the SNS and PNS. Moreover, immune cells present AR and react with SNS mediators. It is thought to correspond to that observed in peripheral vasculature regulating vascular resistance. Activation of PBL, including monocytes, by SNS causes the secretion of cytokines and increases the ability to adhere to the endothelium and rolling. This contributes to the intensification of inflammatory changes in the vessel wall. Both experimental studies and clinical observations indicate the role of immune activation in the pathogenesis of hypertension[8]. Children with PH, although they present a fairly typical set of metabolic and body composition abnormalities typical of metabolic syndrome, are generally not exposed to other cardiovascular risk factors such as atherosclerosis, diabetes, cigarette smoking or aging-related inflammatory activation, which affect adults. Therefore, studies in this age group are not confounded by the influence of other additional factors modulating both the activity of the ANS and the immune system. Second, pediatric studies give the opportunity to observe pathophysiological mechanisms not affected by treatment. Pediatric studies have shown both the activation of the innate immune response, its association with HMOD, and significant changes in the maturation of T lymphocytes and regulatory T cells in adolescents with PH compared to their normotensive peers[8]. There is also a lot of evidence indicating the activation of the adrenergic system in PH and there is ample evidence to suggest that hyperkinetic circulation is observed in adolescents and young adults with PH. It is considered to be typical of the first phase of PH with increased SV and apparently normal TPR[4,19]. Therefore, it is important to consider the age of the patients studied. AR and α7nAChR belong to the family of G protein coupled receptors (GPCRs). Their expression is regulated by GPCR kinase (GRK). AR activation triggers the GRK mechanism, which, on the one hand, enables the expression of the receptor stimulation effect and, on the other hand, triggers the process of desensitization and reduction of the membrane expression of the receptor[20]. Differences in AR expression in adolescents with PH compared to normotensive peers is difficult to explain. We found greater extra- and intracellular expression of both α1 and β2AR and in general greater expression of α7nAChR in hypertensive children. Previously published studies analyzing distribution of AR on PBL included adults, and the study on so-called young adults included people on average 15 years older than the group described in our study. In the early studies done in 1980-ties and using different methods to assess AR expression, it was found that expression of βAR on PBL of hypertensive adults was lower in comparison with normotensive subjects. This phenomenon may be caused by desensitization of receptors and their shift from the membrane to the interior of the cell[21]. In other studies AR expression was assessed as mRNA expression. These studies showed increased expression of α1AR mRNA in peripheral blood mononuclear cells from young adults with hypertension[22]. In another study of young adults with hypertension and in the normotensive group and using the same technique it was shown not only that the expression of β1AR mRNA was higher in the hypertensive group but also that it correlated with diastolic blood pressure. Additionally, the expression of GRK3 mRNA was negatively correlated with blood pressure values[23]. In contrast to the effect of β1AR and GRK3, in a population-based study of African-Americans, expression of GRK2 and GRK5, which desensitize βAR (both β1 and β2) and abolish its vasodilatory effect, was greater in individuals with systolic blood pressure above 130 mmHg[24]. Middeke et al. in a study published in 1983 showed that β2 receptor expression was higher in hypertensives but only when whole cells were assessed. However, no differences were found in membrane extracts. Furthermore, β2 receptor expression in whole cells, i.e. intracellular, correlated with mean blood pressure values. This study, although performed using a different methodology, indicates the importance of AR internalization in pathogenesis of PH[25]. Disturbance of the balance between the effects of βAR 1 and 2 stimulation causes various hemodynamic disorders. Stimulation of β1AR causes increase in cardiac contractility, and stimulation of β2AR leads to vasodilatation. In our study, the membrane expression of the β2AR was slightly lower in patients with PH compared to their normotensive peers. This may correspond to early changes corresponding to the process of β receptor desensitization. However, a longitudinal study is necessary to prove this. In our study hypertensive patients presented typical hemodynamic phenotype of early phase of PH with increased SV, CO and apparently normal TPR. We found significant although moderate correlations between hemodynamic parameters and AR. Such relationships are consistent with the effect of stimulation of the appropriate AR. Increased α7nAChR expression may indicate underactivity of PNS. As mentioned above, parasympathetic activation via the α7nAChR is associated with the inhibition of the inflammatory response. However, in experimental studies, stimulation of α7nAChR with nicotine has been shown to cause proinflammatory activation of monocytes and increase the percentage of the M1 subpopulation in SHR rats. In contrast, in normotensive Wistar-Kyoto rats, the same stimulation with nicotine causes a decrease of inflammatory activation of monocytes and an increase in the percentage of the anti-inflammatory M2 subpopulation. This phenomenon suggests a primary disturbance at the receptor level in experimental animals modeling PH[26]. However, in our study we did not investigate the effects of AR and α7nAChR stimulation. So far, no studies on the expression of AR and cholinergic receptors in children with PH have been published. Therefore, it is difficult to refer to the results of other studies. The cross-sectional nature of our study does not allow for the assessment of the expression of the tested receptors during treatment. In previous prospective interventional studies, we have shown that standard antihypertensive treatment not only reduces blood pressure and HMOD regression, but also reduces inflammatory activity[27]. Moreover, the expression of genes of the renin-angiotensin-aldosterone system and adipokines on the surface of PBL was changed, correlated with PH stage and normalized with treatment[28]. Although there is a lack of studies on the expression of AR and cholinergic receptors in humans with PH, there are isolated reports on α7nAChR expression in pregnant women with preeclampsia[29]. Unlike in our study, they were shown to have lower extracellular expression of α7nAChR on PBL than nonpregnant and normotensive pregnant women. Such differences in results may indicate that the ANS response is different depending on the nature of hypertension: differs between PH and secondary forms of hypertension. We found significant correlations between serum uric acid levels and AR and α7nAChR expression. A tendency toward higher uric acid concentrations is typical for adolescents with PH, and serum uric acid concentrations were significantly higher in the hypertensive group. Therefore, the observed associations between uric acid concentrations may reflect only general differences in AR and α7nAChR expression between groups. We did not demonstrate differences between groups in inflammatory activation assessed by hsCRP concentration. However, it should be noted that, unlike adults with PH, we cannot expect equally pronounced inflammatory features in adolescents in the early stages of PH. Limitations and strengths of the study The main limitation of our study is its cross-sectional nature, which does not allow for the assessment of changes in AR expression over time and under the influence of treatment. Second, we assessed only a narrow aspect of the disorder, not taking into account the relationship with T cell subpopulations and did not assess GRK activity. We also did not assess the concentrations of catecholamines and their metabolites in plasma. However, there are strengths of our study. First, to the best of our knowledge, this is the first pediatric study to assess AR expression in the early stage of PH. Other previously published studies concerned adult groups, with a wide age range. Therefore, our study provides information on AR expression in the early stages of hypertensive disease that has not been published so far. Secondly, in our patients and control group we performed the same set of tests assessing both basic cardiovascular risk factors and HMOD markers. Third, PH patients were examined immediately after PH diagnosis, before any treatment was initiated. Perspectives The assessment of the early stages of PH and cardiovascular disease development is still poorly understood. Although there are relatively many reports on metabolic disorders and their association with HMOD, few studies address the assessment of disorders at the cellular level. The relationship between ANS and the immune system and HMOD and hemodynamic disorders in PH is practically undescribed, especially in patients with early stage of PH. The relatively low invasiveness of the tests used in our study allows for the design of studies on a larger group, taking into account gender and, most importantly, a prospective study. Such studies should take into account different types of treatment, both non-pharmacological and the effects of different groups of drugs. Conclusions Adolescents with PH show significant changes in the expression of SNS and PNS receptors in peripheral blood leukocytes. These changes are correlated with HMOD and hemodynamic parameters typical of the early stages of PH development. The challenge remains to assess the evolution of these disturbances and changes under the influence of treatment. Declarations The data contained in the manuscript have not been published before Funding: The work was supported by research grant No. 2013/11/B/NZ4/03832 awarded by the National Research Center. Conflict of interest: NONE References Obrycki Ł, Skoczyński K, Sikorski M, Koziej J, Mitoraj K, Pilip J, et al. 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Downregulation of α7 nicotinic acetylcholine receptors in peripheral blood monocytes is associated with enhanced inflammation in preeclampsia. BMC Pregnancy Childbirth 2019; 19:188. Tables Table 1 Demographic and laboratory data Demographic, clinical and laboratory values in hypertensive patients and subjects from control group. Variable Hypertensive patients (n = 49) Control group (n = 47) P Age (years) 15.2 ± 1.9 14.7 ± 1.0 n.s. Gender (males/females) 40/9 35/12 n.s. Height (cm) 172 ± 10 170 ± 10 n.s. Weight (kg) 76 ± 18 58 ± 12 n.s. BMI (kg/m 2 ) 25.3 ± 5.2 19.8 ± 3.8 0.0001 BMI-SDS 1.1 ± 0.9 -0.1 ± 1.1 0.0001 SBP (mmHg) 134 ± 10 116 ± 8 0.00001 DBP (mmHg) 71 ± 9 64 ± 6 0.00001 Central SBP (mmHg) 120 ± 9 105 ± 7 0.00001 cIMT (mm) 0.44 ± 0.04 0.43 ± 0.04 n.s. WCSA (mm 2 ) 7.2 ± 0.9 6.6 ± 0.7 0.03 LVMi (g/height m 2.7 ) 36.0 ± 7.5 31.6 ± 6.1 0.0002 Pulse Wave Velocity (m/s) 6.0 ± 0.7 5.6 ± 0.7 0.0009 Cardiac Output (l/min) 6.5 ± 1.9 5.2 ± 1.6 0.0001 Stroke Volume (ml) 85 ± 22 68 ± 18 0.0001 Total peripheral resistance (TPU) 0.956 ± 0.30 1.03 ± 0.31 n.s. Heart Rate (beats/min) 77 ± 10 77 ± 13 n.s. Serum cholesterol (mg/dl) 152 ± 31 180 ± 31 0.0003 HDL-cholesterol (mg/dl) 52 ± 18 61 ± 14 0.002 LDL-cholesterol (mg/dl) 81 ± 24 103 ± 32 0.001 Triglicerydes (mg/dl) 94 ± 51 83 ± 27 n.s. Highly sensitive C reactive protein (mg/l) 0.43 ± 0.2 0.39 ± 0.14 n.s. Uric acid (mg/dl) 5.9 ± 1.3 3.7 ± 0.6 0.0001 Table 2 Comparison of expression of adrenergic receptors and α7nAChR in patients wit primary hypertension and in subjects from control group. Receptors expression was measured as mean fluorescence intensity (MFI) and percentage of positive cells (%). variable Primary hypertension N = 49 median [Q1 Q3] Control group N = 47 median [Q1 Q3] P Intracellular neutrophil β2 adrenergic receptor [%] 97.92 [97.09 99.51] 99.22 [97.57 99.68] 0.1189 Intracellular neutrophil alfa1A-adrenergic receptor [%] 52.7 [28.23 96.66] 24.01 [18.12 37.65] 0.0017 Intracellular neutrophil α7nAChR alfa7-nicotinic acetylcholine receptor [%] 98.27 [97.52 99.04] 98.1 [96.62 98.57] 0.1504 Intracellular neutrophil β2 -adrenergic receptor [MFI] 340.6 [247.41 466.15] 350.8 [221.2 518.3] 0.9038 Intracellular neutrophil alfa1A-adrenergic receptor [MFI] 16.09 [9.05 23.89] 10.42 [9.44 11.44] 0.0267 Intracellular neutrophil α7nAChR alfa7-nicotinic acetylcholine receptor [MFI] 306.2 [174.97 753.55] 263.31 [187.04 343.78] 0.2617 Extracellular neutrophil beta2-adrenergic receptor [%] 97.4 [90.2 99.14] 99.4 [93.56 175.57] 0.0039 Extracellular neutrophil alfa1A-adrenergic receptor [%] 43.88 [23.81 59.46] 8.62 [4.45 16.73] < 0.0001 Extracellular neutrophil α7nAChR alfa7-nicotinic acetylcholine receptor [%] 58.95 [46.16 80.59] 44.38 [29.6 64.66] 0.0021 Extracellular neutrophil beta2-adrenergic receptor [MFI] 15.28 [11.94 21] 12.07 [10.41 14.56] 0.0019 Extracellular neutrophil alfa1A-adrenergic receptor [MFI] 3.95 [3.32 4.76] 2.38 [2.25 2.68] < 0.0001 Extracellular neutrophil α7nAChR alfa7-nicotinic acetylcholine receptor [MFI] 32.48 [24.77 41.04] 11.04 [9.18 13.29] < 0.0001 Intracellular monocytes β2 beta 2-adrenergic receptor [%] 99.61 [99.19 99.82] 99.16 [97.41 99.7] 0.0160 Intracellular monocytes alfa1A-adrenergic receptor [%] 39.88 [3.96 96.19] 32.05 [13.35 66.5] 0.6442 Intracellular monocytes α7nAChR alfa7-nicotinic acetylcholine receptor [%] 99.65 [98.44 99.83] 96.84 [83.5 97.87] < 0.0001 Intracellular monocytes beta2-adrenergic receptor ) [MFI] 88.46 [66.35 126.32] 81.3 [56.78 110.19] 0.0782 Intracellular monocytes alfa1A-adrenergic receptor [MFI] 20.74 [9.8 28.66] 15.6 [14.22 19.96] 0.7856 Intracellular monocytes α7nAChR [MFI] 299.21 [197.05 816.06] 182.99 [89.66 371.89] 0.0013 Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Under Review Version 1 posted Review # 1 received at journal 29 Mar, 2026 Reviewer # 1 agreed at journal 17 Mar, 2026 Reviewers invited by journal 21 Jan, 2026 Editor assigned by journal 06 Jan, 2026 Submission checks completed at journal 06 Jan, 2026 First submitted to journal 30 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8484629","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":578092000,"identity":"16f30a2e-aabc-46c3-b83f-5252c811c65b","order_by":0,"name":"Mieczyslaw 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12:37:06","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":115473,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8484629/v1/04dd611d8b80e249ea692a94.html"},{"id":100982436,"identity":"fa5660f5-e517-4451-a4ef-973e787332b7","added_by":"auto","created_at":"2026-01-23 12:37:06","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":315734,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between common carotid wall cross sectional area and mean fluorescence intensity (MFI) of extracellular α1 adrenergic receptor (r = 0.645, p = 0.0001).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8484629/v1/236b5ade1bd2911bf8234b94.jpeg"},{"id":100982472,"identity":"49f7c199-9768-470b-9c25-273c24a8f776","added_by":"auto","created_at":"2026-01-23 12:37:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55222,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between heart rate (beats/minute) and percent of positive cells (PPC) with extracellular α7 nicotinic acetylcholine receptor (ACHalpha7) (r = 0.388; p = 0.0001).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8484629/v1/a2c34286a42752d7eddaf276.png"},{"id":101203311,"identity":"35c8cccb-fb07-4749-bb80-c8c7c84e8f8f","added_by":"auto","created_at":"2026-01-27 09:39:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1143006,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8484629/v1/21aa3526-a743-4ce6-bd57-df64ff11292f.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Expression of adrenergic and cholinergic receptors on peripheral blood leucocytes of adolescents with primary hypertension","fulltext":[{"header":"Summary table","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eWhat is known about the topic\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eThe role of the immune system in the pathogenesis of essential hypertension has been proven both in experimental models and clinical observations\u003c/li\u003e\n \u003cli\u003eSympathetic nervous system activation is a significant disturbance in the initial stages of the pathogenesis of primary hypertension in adolescents.\u003c/li\u003e\n \u003cli\u003eChanges in the expression of adrenergic receptors on immune cells of experimental animals with hypertension suggest an interrelationship between the activation of the sympathetic and immune systems in the pathogenesis of hypertension.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 100%;\"\u003e\n \u003cp\u003eWhat this study adds\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eThis is the first study to evaluate the expression of adrenergic and nicotinic receptors on peripheral blood leukocytes in adolescents with untreated primary hypertension and in age and gender matched normotensive control group.\u003c/li\u003e\n \u003cli\u003eHypertensive adolescents show significant changes in the expression of adrenergic and nicotinic receptors on peripheral blood leukocytes, and the disturbed pattern of receptor expression correlates with markers of hypertension mediated organ damage and hemodynamic changes typical for early stage of primary hypertension.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\u003cp\u003ePrimary hypertension (PH) develops already in the developmental age, and although it is practically not recognized in the youngest children, during adolescence there is a sharp increase in the recognition of this form of hypertension [1]. This is correlated with a significant rise of systolic blood pressure in boys, which explains the predominance of boys among adolescents with PH. \u0026nbsp;Adolescents with PH demonstrate a typical hemodynamic phenotype that includes isolated systolic hypertension as the predominant type of hypertension and features indicative of sympathetic nervous system (SNS) activation: higher stroke volume (SV), higher left ventricular contraction velocity, faster heart rate (HR), and disturbances in circadian blood pressure rhythms indicative of prolonged sympathetic activation [2–5]. This is accompanied by disturbances in body composition, metabolic disorders typical of metabolic syndrome, and activation of both the innate and adaptive immune systems [6–8]. In adolescents with PH, these disorders are interconnected. Sympathetic receptors, both alpha and beta, are present on immunocompetent cells, including peripheral blood leukocytes (PBL). Thus, we assumed that adolescents with PH have a significant change in the expression of adrenergic receptors (AR) and alfa7-nicotinic acetylcholine receptor (α7nAChR) compared to their normotensive peers. The aim of the study was to assess the intracellular and membrane expression of AR and α7nAChR on PBL in untreated adolescents with PH and to compare them with an age- and sex-matched group of normotensive peers. The second aim was to assess the relationship between AR and α7nAChR expression on PBL and hypertension mediated end-organ damage (HMOD), hemodynamic and metabolic parameters typically associated with PH.\u003c/p\u003e\n\u003cp\u003ePatients and control group.\u003c/p\u003e\n\u003cp\u003eThe patients description and methodology were provided previously [9]. In short, out of 275 children and adolescents referred to our clinic due to elevated office blood pressure, 49 (40 males) yet untreated adolescents with a mean age of 15.2 ± 1.9 years, in whom secondary hypertension was excluded after a full diagnostic process, were included in the study. PH was diagnosed following the recent guidelines and confirmed by 24-hour ambulatory blood pressure monitoring. The exclusion criteria included the presence of any significant chronic disease (except for PH), including diabetes and chronic kidney disease, any acute illness plus infections in the six weeks preceding enrolment, cigarette smoking, and incomplete data. None of the patients received antihypertensive therapy before enrolment in the study.\u003c/p\u003e\n\u003cp\u003eThe control group consisted of 47 (35 males) healthy, normotensive adolescents, matched both for sex and age (mean age of 14.7 ± 1.0 years),\u0026nbsp;and recruited voluntarily from schools. The exclusion criteria included the presence of any chronic disease, use of drugs, any acute illness plus infections in the six weeks preceding enrolment, cigarette smoking, and/or incomplete data.\u003c/p\u003e\n\u003cp\u003eAll subjects included to the study and their parents gave informed consents. The study was approved by Bioethical Committee at The Children’s Memorial Health Institute ((No. 121/KBE/2013).\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eHypertension-mediated organ damage assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn all patients and subjects of the control group, carotid intima-media thickness (cIMT), left ventricular mass index (LVMI), pulse wave velocity (PWV) and pulse wave analysis (PWA) were assessed. Echocardiography (ECHO), cIMT, PWA, and PWV were assessed by investigators who knew clinical diagnosis but were not aware of final diagnosis confirming or excluding arterial hypertension and final classification of hypertension severity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ecIMT measurements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cIMT and carotid wall cross-sectional area (WCSA) were evaluated by ultrasound following the methodology described previously [9,10]. cIMT-SDS above 1.65 was taken as a cut-off for the 95\u003csup\u003eth\u003c/sup\u003e percentile for age and sex.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe echocardiographic LVMI assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eECHO measurements were performed following the American Society of Echocardiography guidelines. To standardize the left ventricular mass with height, LVMI was calculated following de Simone’s formula. Left ventricular hypertrophy (LVH) was defined as an LVMI value above the 95th percentile for age and sex based on reference data and severe LVH as LVMI ≥51 g/m\u003csup\u003e2.7\u003c/sup\u003e [11]. Relative wall thickness (RWT), a marker of concentric remodeling, was calculated as the sum of the interventricular septum and posterior wall thickness measured in diastole and divided by internal ventricular diameter in diastole.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePWV and PWA assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePWV and PWA were measured non-invasively with oscillometric method using Vicorder® (SMT Medical) system device, which has been cross-validated against applanation tonometry system (Sphygmocor) and invasive measurements of central blood pressure. It was found to be a reliable and simple alternative to tonometry, and has also been validated in children[12,13]. The Vicorder system provides a simple and quick non-invasive oscillometric method of obtaining PWV measured between carotid and femoral artery. Measurements were performed in the supine position after 5 minutes of rest. The PWV cuffs were placed on the neck of the patient (30-mm plethysmographic partial inflatable sensor) and the right thigh (a 100-mm wide cuff). Both cuffs were automatically inflated to 65mmHg and the corresponding oscillometric signal from each cuff was digitally analyzed by means of the latest patented technique to accurately extract, in real time, the pulse time delay and the consequent PWV. The approximate transit distance of the pulse wave was estimated based on the measurement of the distance between the carotid artery and the femoral artery, which was found to be accurate and reproducible. The PWV in m/s (absolute values obtained the device) were subsequently converted to z-scores based on pediatric normative data[14,15].\u003c/p\u003e\n\u003cp\u003eTransfer function was applied to the waweform of brachial artery in order to obtain aortic swaveform, which enables calculation of various parameters of arterial system characteristics including central systolic blood pressure (cSBP), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) using company proprietary algorithm. The formula also calculated augmentation pressure (AugPress) and augmentation index (AugInd) as parameters describing the contribution of the return wave for cSBP and central pulse pressure (cPP). AugInd determines the percentage of AugPress in cPP. In both PWV and PWA, the first few measured waves were omitted; if the following (at least 5) pulse waves were of good quality the 10-15 consecutive pulse waves (heart beats) were taken into the analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of expression of AR and α7nAChR receptors on PBL\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe developed protocol involved the collection of blood samples into tubes containing an anticoagulant (EDTA) and a cellular surface antigen-stabilizing agent (Life Technologies, Carlsbad, CA, USA). Samples were stored at 4°C for up to 96 hours prior to processing. Both intracellular and extracellular receptor expression were assessed.\u003c/p\u003e\n\u003cp\u003eSamples were stained in two independent tubes with directly conjugated antibodies for identification of peripheral blood mononuclear cell populations (lymphocytes, monocytes, granulocytes). Both tubes were stained with PE-anti-human CD3, APC-anti-human CD14, APC-Cy7-anti-human CD4, and BV421-anti-human CD45 antibodies (BD Biosciences).\u003c/p\u003e\n\u003cp\u003eSubsequently, cells were fixed, permeabilized, and co-stained using an indirect method with primary antibodies against human α1A-adrenergic receptor (α1-AR) in the first tube and α7-nicotinic acetylcholine receptor (α7nAChR) in the second tube (Santa Cruz Biotechnology). These were followed by incubation with appropriate secondary antibodies conjugated to fluorescent dyes: donkey anti-goat PerCP for the first tube and either goat anti-rabbit PE for the second tube (Santa Cruz Biotechnology). Additionally, the first tube received a directly FITC-conjugated anti-human β2-adrenergic receptor (β2AR) antibody (Santa Cruz Biotechnology).\u003c/p\u003e\n\u003cp\u003eExtracellular receptor expression was evaluated using the same protocol, omitting the fixation and permeabilization steps.\u003c/p\u003e\n\u003cp\u003ePrepared cells were analyzed using a flow cytometer (FACS Canto II, BD Biosciences). Instrument setup was performed with BD Cytometer Setup and Tracking beads. Data acquisition was carried out with BD FACSDiva software version 6.1.3 (BD Biosciences). Compensation settings were established using compensation tubes and BD CompBead antibody-capturing particles, applying the compensation setup tool within BD FACSDiva software. Fluorescence-minus-one (FMO) and isotype antibody controls were employed to accurately define populations exhibiting fluorescence above background levels.\u003c/p\u003e\n\u003cp\u003eNeutrophil and monocyte populations were initially gated based on morphological parameters (side scatter, SSC) and receptor expression (CD14), with debris and platelets excluded. Doublets and aggregates were eliminated by selecting singlet cells on a forward scatter area versus height (FSC-A/FSC-H) plot. Results were expressed as the percentage of positive cells (PPC) and mean fluorescence intensity (MFI), and analyzed using FlowJo software version 7.5.5 (Tree Star Inc.)\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eDescriptive statistics provided means and standard deviations (SD) for normally distributed continuous variables, medians with interquartile ranges (IQR) in case of normally distributed variables, and proportions for categorical variables. Normality in the data was assessed by examination of histogram, skewness and kurtosis and Kolmogorov-Smirnoff test. In the case of non-normal distribution medians and quantile 1 (Q1) and quantile 3 (Q3) are presented. Group differences were assessed with the Mann-Whitney U test. A p-value below 0.05 deemed statistically significant\u003c/p\u003e\n\u003cp\u003ePearson’s and Spearman’s correlation coefficients, as appropriate, were calculated to determine relationships between variables. Age- and sex-specific BMI standard deviation scores (SDS) were calculated relative to Polish 2010 reference data [19].\u003c/p\u003e\n\u003cp\u003eDifferences in categorical variables were evaluated with the chi-square test. Data were analysed with the use of Statistica PL statistical software.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThere were no differences in age and gender between the study and control groups. PH patients were heavier and had a higher both absolute and standardized BMI values which were within the range of values corresponding to overweight.\u003c/p\u003e\n\u003cp\u003eBy definition, subjects from PH group had higher blood pressure values. Comparison of HMOD markers showed that PH patients had higher LVMi, WCSA, PWV and cBP values (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalysis of the expression of AR and α7nAChR on PBL, measured as PPC and MFI, showed that adolescents with PH have greater intra- and extra cellular expression of α7nAChR on all PBL. However, monocytes did not express extracellular AR and α7nAChR and only expression of intracellular receptors was available for analysis. In monocytes increased expression of intracellular α7nAChR and β2AR was found. In general, intra- and extracellular expression of β2AR, α1-A AR expression was generally higher compared to the control group (Table 2). However, differences in expression of βAR were not so uniform as in case of α1-A AR.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn patients with PH there were some significant correlations between markers of HMOD and expression of AR and α7nAChR on PBL (Table 3). Specifically, cIMT-SDS correlated with extracellular α1-A AR MFI (r = 0.381, p = 0.008). Similarly, WCSA-SDS values correlated with MFI of extracellular α1-A AR (r = 0.556, p = 0.001), extracellular α7nAChR (r = 0.322, p = 0.001) and PPC of intracellular α1-A AR (r = 0.405; p = 0.04) (Table 3). LVMi correlated with PPC of extracellular α1-A AR (r = 0.340, p = 0.001) and MFI of extracellular α7nAChR (r = 0.359, p = 0.001).\u003c/p\u003e\n\u003cp\u003eAmong the hemodynamic variables, we observed weak correlations of heart rate, stroke volume, total peripheral resistance and cardiac output with AR and α7nAChR expression (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOf biochemical variables only serum uric acid levels correlated with AR and α7nAChR expression on PBL (Table 3)\u003c/p\u003e\n\u003cp\u003eThe next step in the analysis was to assess differences in receptor expression depending on the presence or absence of HMOD. We defined subclinical hypertensive arterial disease as values of cIMT, WCSA and PWV greater than 1.67 SDS of the median normal range, and left ventricular hypertrophy as LVMi greater than 42 g/m of height\u003csup\u003e2.7\u003c/sup\u003e. Although the groups differed significantly in terms of cIMT, WCSA, PWV and LVMi values, the analysis revealed differences only in the expression of single receptors. Subjects with elevated cIMT did not differ in receptor expression from those with normal cIMT. Individuals with evidence of common carotid artery remodeling, expressed as elevated WCSA, had significantly higher MFI values for extracellular α1 receptors (7.4 ±4 vs 3.3±1.2; p = 0.008) and higher PPC values for cholinergic receptors in monocytes (99.1 ±1.4 vs 87 ±29; p = 0.01). Left ventricular hypertrophy was associated with higher MFI values for intracellular β2 receptors (625 ±457 vs 386 ±149; p = 0.03) (Figure 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main result of our study is different expression of both intra- and extracellular adrenergic and cholinergic receptors in PBL of yet untreated adolescents with PH in comparison with normotensive peers. Both αAR and\u0026nbsp;α7nAChR expression was increased both intra- and extracellularly and expressed as PPC and MFI. However, for βAR the differences were not as pronounced and we also observed lower expression in PH patients.\u003c/p\u003e\n\u003cp\u003eIn addition, we also found moderate, statistically significant correlations between the expression of some receptors and HMOD markers and hemodynamic parameters such as HR, SV and TPR.\u003c/p\u003e\n\u003cp\u003eThe involvement of the autonomic nervous system (ANS) in the pathogenesis of PH is usually considered as an effect on cardiac function and peripheral resistance. However, the ANS has a much broader role in the regulation of homeostasis and also includes the control of the inflammatory response. In describing the pathogenesis of PH, the term neuro-immune axis is used to describe the relationship between adrenergic activation and the immune system[16]. The parasympathetic nervous system (PNS) is believed to have anti-inflammatory effects and SNS is pro-inflammatory[17,18]. There are data showing that αAR mediate stimulatory effects and βAR mediate more inhibitory effects on immune cells. The classical paradigm assumes that there is a balance between the activity of the SNS and immune systems. This balance is modulated by PNS and activation of α7nAChR has anti-inflammatory effects, particularly on monocytes and macrophages. Monocytes circulate in the blood and after activation and entry into tissues, they transform into macrophages. Experimental studies over the last two decades have shown an important role of macrophages in the pathogenesis of PH[16].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSNS exerts its effects through direct stimulation of sympathetic nerves innervating lymphatic organs, such as the spleen, and forming the so-called neuroimmune synapse, as well as by the non-neuronal way, by the direct effect of catecholamines in the blood, which act on AR. The major lymphatic organs where immune cells mature are innervated by both the SNS and PNS. Moreover, immune cells present AR and react with SNS mediators. It is thought to correspond to that observed in peripheral vasculature regulating vascular resistance. Activation of PBL, including monocytes, by SNS causes the secretion of cytokines and increases the ability to adhere to the endothelium and rolling. This contributes to the intensification of inflammatory changes in the vessel wall.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBoth experimental studies and clinical observations indicate the role of immune activation in the pathogenesis of hypertension[8]. Children with PH, although they present a fairly typical set of metabolic and body composition abnormalities typical of metabolic syndrome, are generally not exposed to other cardiovascular risk factors such as atherosclerosis, diabetes, cigarette smoking or aging-related inflammatory activation, which affect adults. Therefore, studies in this age group are not confounded by the influence of other additional factors modulating both the activity of the ANS and the immune system. Second, pediatric studies give the opportunity to observe pathophysiological mechanisms not affected by treatment. Pediatric studies have shown both the activation of the innate immune response, its association with HMOD, and significant changes in the maturation of T lymphocytes and regulatory T cells in adolescents with PH compared to their normotensive peers[8].\u003c/p\u003e\n\u003cp\u003eThere is also a lot of evidence indicating the activation of the adrenergic system in PH and there is ample evidence to suggest that hyperkinetic circulation is observed in adolescents and young adults with PH. It is considered to be typical of the first phase of PH with increased SV and apparently normal TPR[4,19]. Therefore, it is important to consider the age of the patients studied.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAR and α7nAChR belong to the family of G protein coupled receptors (GPCRs). Their expression is regulated by GPCR kinase (GRK). AR activation triggers the GRK mechanism, which, on the one hand, enables the expression of the receptor stimulation effect and, on the other hand, triggers the process of desensitization and reduction of the membrane expression of the receptor[20]. Differences in AR expression in adolescents with PH compared to normotensive peers is difficult to explain. We found greater extra- and intracellular expression of both α1 and β2AR and in general greater expression of α7nAChR in hypertensive children. Previously published studies analyzing distribution of AR on PBL included adults, and the study on so-called young adults included people on average 15 years older than the group described in our study. In the early studies done in 1980-ties and using different methods to assess AR expression, it was found that expression of βAR on PBL of hypertensive adults was lower in comparison with normotensive subjects. \u0026nbsp;This phenomenon may be caused by desensitization of receptors and their shift from the membrane to the interior of the cell[21]. In other studies AR expression was assessed as mRNA expression. These studies showed increased expression of α1AR mRNA in peripheral blood mononuclear cells from young adults with hypertension[22]. In another study of young adults with hypertension and in the normotensive group and using the same technique it was shown not only that the expression of β1AR mRNA was higher in the hypertensive group but also that it correlated with diastolic blood pressure. Additionally, the expression of GRK3 mRNA was negatively correlated with blood pressure values[23]. In contrast to the effect of β1AR and GRK3, in a population-based study of African-Americans, expression of GRK2 and GRK5, which desensitize βAR (both β1 and β2) and abolish its vasodilatory effect, was greater in individuals with systolic blood pressure above 130 mmHg[24]. Middeke et al. in a study published in 1983 showed that β2 receptor expression was higher in hypertensives but only when whole cells were assessed. However, no differences were found in membrane extracts. Furthermore, β2 receptor expression in whole cells, i.e. intracellular, correlated with mean blood pressure values. This study, although performed using a different methodology, indicates the importance of AR internalization in pathogenesis of PH[25]. Disturbance of the balance between the effects of βAR 1 and 2 stimulation causes various hemodynamic disorders. Stimulation of β1AR causes increase in cardiac contractility, and stimulation of β2AR leads to vasodilatation. In our study, the membrane expression of the β2AR was slightly lower in patients with PH compared to their normotensive peers. This may correspond to early changes corresponding to the process of β receptor desensitization. However, a longitudinal study is necessary to prove this.\u003c/p\u003e\n\u003cp\u003eIn our study hypertensive patients presented typical hemodynamic phenotype of early phase of PH with increased SV, CO and apparently normal TPR. We found significant although moderate correlations between hemodynamic parameters and AR. Such relationships are consistent with the effect of stimulation of the appropriate AR.\u003c/p\u003e\n\u003cp\u003eIncreased α7nAChR expression may indicate underactivity of PNS. As mentioned above, parasympathetic activation via the\u0026nbsp;α7nAChR is associated with the inhibition of the inflammatory response. However, in experimental studies, stimulation of\u0026nbsp;α7nAChR with nicotine has been shown to cause proinflammatory activation of monocytes and increase the percentage of the M1 subpopulation in SHR rats. In contrast, in normotensive Wistar-Kyoto rats, the same stimulation with nicotine causes a decrease of inflammatory activation of monocytes and an increase in the percentage of the anti-inflammatory M2 subpopulation. This phenomenon suggests a primary disturbance at the receptor level in experimental animals modeling PH[26]. However, in our study we did not investigate the effects of AR and α7nAChR stimulation.\u003c/p\u003e\n\u003cp\u003eSo far, no studies on the expression of AR and cholinergic receptors in children with PH have been published. Therefore, it is difficult to refer to the results of other studies. The cross-sectional nature of our study does not allow for the assessment of the expression of the tested receptors during treatment. In previous prospective interventional studies, we have shown that standard antihypertensive treatment not only reduces blood pressure and HMOD regression, but also reduces inflammatory activity[27]. Moreover, the expression of genes of the renin-angiotensin-aldosterone system and adipokines on the surface of PBL was changed, correlated with PH stage and normalized with treatment[28]. \u0026nbsp;Although there is a lack of studies on the expression of AR and cholinergic receptors in humans with PH, there are isolated reports on α7nAChR expression in pregnant women with preeclampsia[29]. Unlike in our study, they were shown to have lower extracellular expression of α7nAChR on PBL than nonpregnant and normotensive pregnant women. Such differences in results may indicate that the ANS response is different depending on the nature of hypertension: differs between PH and secondary forms of hypertension.\u003c/p\u003e\n\u003cp\u003eWe found significant correlations between serum uric acid levels and AR and α7nAChR expression. A tendency toward higher uric acid concentrations is typical for adolescents with PH, and serum uric acid concentrations were significantly higher in the hypertensive group. Therefore, the observed associations between uric acid concentrations may reflect only general differences in AR and α7nAChR expression between groups. We did not demonstrate differences between groups in inflammatory activation assessed by hsCRP concentration. However, it should be noted that, unlike adults with PH, we cannot expect equally pronounced inflammatory features in adolescents in the early stages of PH.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLimitations and strengths of the study\u003c/p\u003e\n\u003cp\u003eThe main limitation of our study is its cross-sectional nature, which does not allow for the assessment of changes in AR expression over time and under the influence of treatment. Second, we assessed only a narrow aspect of the disorder, not taking into account the relationship with T cell subpopulations and did not assess GRK activity. We also did not assess the concentrations of catecholamines and their metabolites in plasma.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, there are strengths of our study. First, to the best of our knowledge, this is the first pediatric study to assess AR expression in the early stage of PH. Other previously published studies concerned adult groups, with a wide age range.\u0026nbsp;Therefore, our study provides information on AR expression in the early stages of hypertensive disease that has not been published so far. Secondly, in our patients and control group we performed the same set of tests assessing both basic cardiovascular risk factors and HMOD markers. Third, PH patients were examined immediately after PH diagnosis, before any treatment was initiated.\u003c/p\u003e\n\u003cp\u003ePerspectives\u003c/p\u003e\n\u003cp\u003eThe assessment of the early stages of PH and cardiovascular disease development is still poorly understood. Although there are relatively many reports on metabolic disorders and their association with HMOD, few studies address the assessment of disorders at the cellular level. The relationship between ANS and the immune system and HMOD and hemodynamic disorders in PH is practically undescribed, especially in patients with early stage of PH. The relatively low invasiveness of the tests used in our study allows for the design of studies on a larger group, taking into account gender and, most importantly, a prospective study. Such studies should take into account different types of treatment, both non-pharmacological and the effects of different groups of drugs.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAdolescents with PH show significant changes in the expression of SNS and PNS receptors in peripheral blood leukocytes. These changes are correlated with HMOD and hemodynamic parameters typical of the early stages of PH development. The challenge remains to assess the evolution of these disturbances and changes under the influence of treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe data contained in the manuscript have not been published before\u003c/p\u003e\n\u003cp\u003eFunding: The work was supported by research grant No. 2013/11/B/NZ4/03832 awarded by the National Research Center.\u003c/p\u003e\n\u003cp\u003eConflict of interest: NONE\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eObrycki Ł, Skoczyński K, Sikorski M, Koziej J, Mitoraj K, Pilip J, \u003cem\u003eet al.\u003c/em\u003e Current etiology of hypertension in European children - factors associated with primary hypertension. \u003cem\u003ePediatr Nephrol\u003c/em\u003e Published Online First: 20 May 2025. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00467-025-06761-x\u003c/span\u003e\u003cspan address=\"10.1007/s00467-025-06761-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiemirska A, Litwin M, Feber J, Jurkiewicz E. 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Desensitization and redistribution of beta-adrenergic receptors on human mononuclear leukocytes. \u003cem\u003eAm J Physiol\u003c/em\u003e 1986; 250:E583-590.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOliver E, Mont\u0026oacute; F, Rovira E, Valldecabres C, Muedra V, D\u0026rsquo;Ocon P. Changes in the expression of α1B-adrenoceptor in peripheral mononuclear cells correlates with blood pressure and plasmatic homocysteine. \u003cem\u003eBiomed Pharmacother\u003c/em\u003e 2017; 88:721\u0026ndash;727.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOliver E, Rovira E, Mont\u0026oacute; F, Valldecabres C, Julve R, Muedra V, \u003cem\u003eet al.\u003c/em\u003e beta-Adrenoceptor and GRK3 expression in human lymphocytes is related to blood pressure and urinary albumin excretion. \u003cem\u003eJ Hypertens\u003c/em\u003e 2010; 28:1281\u0026ndash;1289.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohn HI, Xi Y, Pesant S, Harris DM, Hyslop T, Falkner B, \u003cem\u003eet al.\u003c/em\u003e G protein-coupled receptor kinase 2 expression and activity are associated with blood pressure in black Americans. \u003cem\u003eHypertension\u003c/em\u003e 2009; 54:71\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiddeke M, Remien J, Block LH, Kirzinger S, Landrock A, Holzgreve H. Beta 2-adrenoceptor density on membranes and on intact mononuclear cells in essential hypertension. \u003cem\u003eRes Exp Med (Berl)\u003c/em\u003e 1983; 183:227\u0026ndash;232.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarwani SC, Ratcliff J, Sutterwala FS, Ballas ZK, Meyerholz DK, Chapleau MW, \u003cem\u003eet al.\u003c/em\u003e Nicotine Mediates CD161a\u0026thinsp;+\u0026thinsp;Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat. \u003cem\u003eCirculation Research\u003c/em\u003e 2016; 119:1101\u0026ndash;1115.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLitwin M, Niemirska A, Sladowska-Kozlowska J, Wierzbicka A, Janas R, Wawer ZT, \u003cem\u003eet al.\u003c/em\u003e Regression of target organ damage in children and adolescents with primary hypertension. \u003cem\u003ePediatr Nephrol\u003c/em\u003e 2010; 25:2489\u0026ndash;2499.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLitwin M, Michałkiewicz J, Trojanek J, Niemirska A, Wierzbicka A, Szalecki M. Altered genes profile of renin-angiotensin system, immune system, and adipokines receptors in leukocytes of children with primary hypertension. \u003cem\u003eHypertension\u003c/em\u003e 2013; 61:431\u0026ndash;436.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu H, Shi Q, Mo Y, Wu L, Gu J, Xu Y. Downregulation of α7 nicotinic acetylcholine receptors in peripheral blood monocytes is associated with enhanced inflammation in preeclampsia. \u003cem\u003eBMC Pregnancy Childbirth\u003c/em\u003e 2019; 19:188.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eDemographic and laboratory data\u003c/span\u003e Demographic, clinical and laboratory values in hypertensive patients and subjects from control group.\u003c/div\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eVariable\u003c/div\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHypertensive patients (n\u0026thinsp;=\u0026thinsp;49)\u003c/div\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eControl group (n\u0026thinsp;=\u0026thinsp;47)\u003c/div\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eP\u003c/div\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eAge (years)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e15.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e14.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eGender (males/females)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e40/9\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e35/12\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHeight (cm)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e172\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e170\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eWeight (kg)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e76\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e58\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e25.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eBMI-SDS\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e-0.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSBP (mmHg)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e134\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e116\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.00001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eDBP (mmHg)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e71\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e64\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.00001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCentral SBP (mmHg)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e120\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e105\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.00001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ecIMT (mm)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eWCSA (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e7.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.03\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eLVMi (g/height m\u003csup\u003e2.7\u003c/sup\u003e)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e36.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e31.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0002\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePulse Wave Velocity (m/s)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0009\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eCardiac Output (l/min)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eStroke Volume (ml)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e85\u0026thinsp;\u0026plusmn;\u0026thinsp;22\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e68\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eTotal peripheral resistance (TPU)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.956\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHeart Rate (beats/min)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e77\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e77\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eSerum cholesterol (mg/dl)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e152\u0026thinsp;\u0026plusmn;\u0026thinsp;31\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e180\u0026thinsp;\u0026plusmn;\u0026thinsp;31\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0003\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHDL-cholesterol (mg/dl)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.002\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eLDL-cholesterol (mg/dl)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e81\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e103\u0026thinsp;\u0026plusmn;\u0026thinsp;32\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eTriglicerydes (mg/dl)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e94\u0026thinsp;\u0026plusmn;\u0026thinsp;51\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e83\u0026thinsp;\u0026plusmn;\u0026thinsp;27\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eHighly sensitive C reactive protein (mg/l)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003en.s.\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eUric acid (mg/dl)\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eComparison of expression of adrenergic receptors and \u0026alpha;7nAChR in patients wit primary hypertension and in subjects from control group. Receptors expression was measured as mean fluorescence intensity (MFI) and percentage of positive cells (%).\u003c/div\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003evariable\u003c/div\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003ePrimary hypertension\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003eN\u0026thinsp;=\u0026thinsp;49\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003emedian [Q1 Q3]\u003c/div\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eControl group\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003eN\u0026thinsp;=\u0026thinsp;47\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003emedian [Q1 Q3]\u003c/div\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eP\u003c/div\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular neutrophil \u0026beta;2 adrenergic receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e97.92 [97.09 99.51]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e99.22 [97.57 99.68]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.1189\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular neutrophil alfa1A-adrenergic receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e52.7 [28.23 96.66]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e24.01 [18.12 37.65]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0017\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular neutrophil \u0026alpha;7nAChR alfa7-nicotinic acetylcholine receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e98.27 [97.52 99.04]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e98.1 [96.62 98.57]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.1504\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular neutrophil \u0026beta;2 -adrenergic receptor\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003e[MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e340.6 [247.41 466.15]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e350.8 [221.2 518.3]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.9038\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular neutrophil alfa1A-adrenergic receptor\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003e[MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e16.09 [9.05 23.89]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e10.42 [9.44 11.44]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0267\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular neutrophil \u0026alpha;7nAChR alfa7-nicotinic acetylcholine receptor [MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e306.2 [174.97 753.55]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e263.31 [187.04 343.78]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.2617\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eExtracellular neutrophil beta2-adrenergic receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e97.4 [90.2 99.14]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e99.4 [93.56 175.57]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0039\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eExtracellular neutrophil alfa1A-adrenergic receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e43.88 [23.81 59.46]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e8.62 [4.45 16.73]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eExtracellular neutrophil \u0026alpha;7nAChR\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003ealfa7-nicotinic acetylcholine receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e58.95 [46.16 80.59]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e44.38 [29.6 64.66]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0021\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eExtracellular neutrophil beta2-adrenergic receptor\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003e[MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e15.28 [11.94 21]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e12.07 [10.41 14.56]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0019\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eExtracellular neutrophil alfa1A-adrenergic receptor [MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e3.95 [3.32 4.76]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e2.38 [2.25 2.68]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eExtracellular neutrophil \u0026alpha;7nAChR\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003ealfa7-nicotinic acetylcholine receptor\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003e[MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e32.48 [24.77 41.04]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e11.04 [9.18 13.29]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular monocytes \u0026beta;2 beta 2-adrenergic receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e99.61 [99.19 99.82]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e99.16 [97.41 99.7]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0160\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular monocytes alfa1A-adrenergic receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e39.88 [3.96 96.19]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e32.05 [13.35 66.5]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.6442\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular monocytes \u0026alpha;7nAChR alfa7-nicotinic acetylcholine receptor [%]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e99.65 [98.44 99.83]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e96.84 [83.5 97.87]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.0001\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular monocytes beta2-adrenergic receptor ) [MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e88.46 [66.35 126.32]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e81.3 [56.78 110.19]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0782\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular monocytes alfa1A-adrenergic receptor [MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e20.74 [9.8 28.66]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e15.6 [14.22 19.96]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.7856\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cdiv class=\"SimplePara\"\u003eIntracellular monocytes \u0026alpha;7nAChR\u003c/div\u003e\n\u003cdiv class=\"SimplePara\"\u003e[MFI]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e299.21 [197.05 816.06]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e182.99 [89.66 371.89]\u003c/div\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cdiv class=\"SimplePara\"\u003e0.0013\u003c/div\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-human-hypertension","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jhh","sideBox":"Learn more about [Journal of Human Hypertension](http://www.nature.com/jhh/)","snPcode":"41371","submissionUrl":"https://mts-jhh.nature.com/cgi-bin/main.plex","title":"Journal of Human Hypertension","twitterHandle":"@jhhypertension","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"primary hypertension, adolescents, adrenergic receptors, immune system","lastPublishedDoi":"10.21203/rs.3.rs-8484629/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8484629/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe assessed the expression of adrenergic (AR) and cholinergic α7 nicotinic acetylcholine receptor (α7nAChR) in peripheral blood leucocytes (PBL) in untreated adolescents with primary hypertension (PH).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: 49 yet untreated adolescents with PH in a mean age of 15.2 ±1.9 years, and 47 healthy, normotensive adolescents, matched both for sex and age (mean age of 14.7 ±1.0 years) were included in the study. The percentage of positive cells (PPC) and mean fluorescence intensity (MFI) of PBL and monocytes was analyzed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: in hypertensive adolescents PBL and monocytes presented greater PPC and MFI of AR and α7nAChR in comparison with normotensive group. \u0026nbsp;Carotid intima-media thickness and carotid wall cross sectional area correlated with extracellular MIF of α1AR (r = 0.438 and r = 0.602, respectively; p\u0026lt;0.05), left ventricular mass index with extracellular MFI of α7nAChR (r = 0.340; p\u0026lt;0.05) and PPC of α1AR (r = 0.340; p\u0026lt;0.05). Stroke volume, and total peripheral resistance correlated with extracellular MIF of β2AR (r = 0,283, and r = -0.221, respectively; all p\u0026lt;0.05). Serum uric acid levels correlated with AR and α7nAChRexpression. However, hsCRP did not correlate with AR and α7nAChR expression.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusions: adolescents with PH show significant alterations in the expression of adrenergic and cholinergic receptors in PBL. These changes correlate with hypertension mediated organ damage, hemodynamic and metabolic parameters typical of childhood hypertension.\u003c/p\u003e","manuscriptTitle":"Expression of adrenergic and cholinergic receptors on peripheral blood leucocytes of adolescents with primary hypertension","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-23 12:37:01","doi":"10.21203/rs.3.rs-8484629/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-29T10:57:15+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-17T12:40:05+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-01-21T11:35:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-06T16:07:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-06T14:40:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Human Hypertension","date":"2025-12-30T23:39:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-human-hypertension","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jhh","sideBox":"Learn more about [Journal of Human Hypertension](http://www.nature.com/jhh/)","snPcode":"41371","submissionUrl":"https://mts-jhh.nature.com/cgi-bin/main.plex","title":"Journal of Human Hypertension","twitterHandle":"@jhhypertension","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"51616f2b-30a2-489b-8342-2edf5b6cf067","owner":[],"postedDate":"January 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61508251,"name":"Health sciences/Diseases/Cardiovascular diseases/Hypertension"},{"id":61508252,"name":"Health sciences/Diseases"}],"tags":[],"updatedAt":"2026-01-23T12:37:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-23 12:37:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8484629","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8484629","identity":"rs-8484629","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}