Beta-adrenergic control of coronary circulation during handgrip exercise and isolated metaboreflex activation in postmenopausal women

Beta-adrenergic control of coronary circulation during handgrip exercise and isolated metaboreflex activation in postmenopausal women | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Beta-adrenergic control of coronary circulation during handgrip exercise and isolated metaboreflex activation in postmenopausal women Eliza Prodel, Maitê Gondim, Pedro Augusto de Carvalho Mira, Antonio Claudio Lucas da Nobrega This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9475086/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Menopause represents the process during which oestrogen and progesterone synthesis and release cease, leading to the diminished protective cardiovascular effect of reproductive female hormones. Therefore, it is crucial to understand the physiological mechanisms related to the coronary circulation during menopause. The aim of this investigation is to test the effect of the β-adrenergic blockade on coronary circulation in postmenopausal women during exercise and metaboreflex activation. In healthy young (YW: n = 12) and postmenopausal (PMW: n = 5) women, coronary blood velocity (CBV), coronary conductance index (CCI) and rate pressure product (RPP) were measured at rest, during handgrip exercise (Grip) and post-exercise circulatory occlusion, i.e. isolated metaboreflex activation (Metabo), under control condition and after β-adrenergic blockade. Overall, CBV was higher in YW compared to PMW, Grip increased CBV only in YW, and during Metabo, CBV returned to resting levels in YW. Under the blockade, CBV did not increase in YW. In PMW, neither Grip nor the Metabo changed CBV. CCI decreased during Grip and Metabo in YW, which, under the blockade, decreased to lower levels. The RPP increased during Grip and Metabo in both groups of women, the β-blockade decreased RPP in young women along the protocol, and no effect of the blockade was observed in PMW. In conclusion, coronary circulation is decreased after menopause, and the increased metabolism does not stimulate an increase in coronary circulation in post menopausal women. Additionally, vasodilation during sympathetic stimulation depends on the β-adrenergic receptor in young women, while in postmenopausal women the β-adrenergic receptor effect is blunted. Coronary blood velocity exercise menopause Figures Figure 1 Introduction Cardiovascular diseases are still the major cause of mortality worldwide [ 1 ] [ 2 ], and myocardial infarction represents a major risk of death [ 3 ]. The myocardium do not tolerate ischemic conditions and therefore, coronary circulation is strictly maintained according to metabolic demand via redundant physiological mechanisms (e.g., myogenic, metabolic and neural) [ 4 ]. The failure to control the coronary blood flow and supply myocardial oxygen demand might result in tissue damage [ 4 ]. Ageing, even when healthy, also increases the risk of the development of cardiovascular disease and myocardial infarction [ 5 ]. Young women are at lower cardiovascular risk compared with young men [ 6 ], however, after menopause, the cardiovascular risk in women increases to a higher level compared to age-matched men [ 7 ]. Menopause is the process during which synthesis and release of oestrogen and progesterone cease 8, leading to a diminished protective cardiovascular effect of reproductive female hormones [ 8 ]. Therefore, it is crucial to understand the physiological mechanisms related to the coronary circulation during menopause. The neural control of coronary circulation depends on the interaction of α-adrenergic receptor vasoconstriction with β2-adrenergic receptor vasodilation, especially during stress [ 4 ]. In young men, coronary circulation increases during handgrip exercise, and β-adrenergic blockade decreases vascular conductance and restrains blood flow, even with increased myocardium metabolic demand [ 9 ]. During trigeminal nerve stimulation, a reflex-related decrease in heart rate is observed; hence was applied as a physiological approach to decrease myocardial metabolic demand. Yet, β-blockade also restrained the increase of coronary blood velocity in young men and women [ 10 ]. Menopause seems to disrupt coronary circulatory control; handgrip exercise and isolated metaboreflex activation did not stimulate an increase in blood velocity in postmenopausal women as observed in young women[ 11 ]. Furthermore, α-adrenergic blockade does not change coronary circulation in women after menopause; however, in young women, α-adrenergic receptor restrains coronary circulation, measured by blood flow velocity, during sympathetic stimulation [ 12 ]. In young women, β-adrenergic receptor stimulation diminishes the vasoconstrictor effect of sympathetic stimulation, which is not observed in young men or postmenopausal women [ 13 ]. Accordingly, β2-adrenergic agonists dilate women's vasculature via nitric oxide release [ 14 ]. The explanation relies on the interaction of oestrogen with the β-adrenergic receptor on the arterioles, by which oestrogen increases nitric oxide released during β2-adrenergic stimulation. However, the role of the β-adrenergic receptor in controlling the coronary circulation in women after menopause is not fully known. Importantly, it could be one of the mechanisms to explain the increased ischemic events in older women. Therefore, the aim of this investigation was to test the effect of the β-adrenergic blockade on coronary circulation in postmenopausal women during exercise and metaboreflex activation. Methods Participants The Fluminense Federal University ethics committee (2.362.515) granted approval for all experimental procedures, which were performed in accordance with the Declaration of Helsinki. This protocol was conducted before the COVID-19 pandemic lockdown. Before participating, all women received comprehensive verbal and written information about the protocol and provided written consent. The study enrolled 19 participants, consisting of 10 young women (YW) and 5 postmenopausal women (PMW), all of whom were apparently healthy and had no history or symptoms of any diseases. The young women were tested during the early follicular phase of their menstrual cycle or during the low-hormone phase of oral contraceptive use (n = 4) to minimize the cardiovascular effects of hormonal variation across the menstrual cycle. Menopause was defined as the absence of menstruation for at least one year, and the postmenopausal women had never undergone hormonal replacement therapy. None of the participants was taking prescribed or over-the-counter medication. Participants were instructed to refrain from consuming caffeine, alcohol, any medication, including primary dysmenorrhea therapy, or exercising for 24 hours prior to the experimental session. The experimental protocol was conducted 2 hours after the participants consumed a light meal, and the temperature in the room was maintained between 22°C and 24°C. Physiological measurements In this study, heart rate (HR, bpm) was continuously monitored using a standard lead II electrocardiogram (Powerlab; ADInstruments, Bella Vista, Australia). Systolic and diastolic blood pressure (SBP and DBP, mmHg) were measured beat-to-beat via photoplethysmography from the middle finger of the left hand (Finometer Pro; Finapres Medical Systems, Arnhem, The Netherlands). The signals were sampled at 1000 Hz and integrated over time for offline analysis (Powerlab, LabChart; ADInstruments, Bella Vista, Australia). Mean arterial pressure (MAP, mmHg) was calculated by integrating the arterial blood pressure waveform over a cardiac cycle (Finometer Pro; Finapres Medical Systems, Arnhem, The Netherlands). Stroke volume (SV, ml) was derived from the blood pressure waveform using the modelflow® method [ 15 ] (Finometer Pro; Finapres Medical Systems, Arnhem, The Netherlands), and the cardiac output (CO, l·min-1) was calculated as SV×HR. Transthoracic duplex ultrasound (Vivid 7, GE Medical, USA) was used to assess coronary perfusion with a multifrequency sector transducer (3S) set at an image depth of 8 to 10 cm and a sample volume of 2.5 mm. Coronary mean blood velocity (CBV, cm·s-1) was measured on the left anterior coronary artery (LCA) on the parasternal short axis (E.P.). The Doppler tracking of blood velocity was obtained during the diastolic portion of each cardiac cycle manually by the same trained investigator [ 9 ]. The values were averaged from 10 cardiac cycles during the last 30 seconds of each protocol phase, and the coronary conductance index (CCI, cm·s-1·mmHg-1) was calculated as (CCI = CBV ÷ DBP). This non-invasive method has been validated and widely used as a surrogate for coronary circulation assessment in conscious humans [ 9 ]. The CBV measurement consistency was previously published by this group [ 9 – 11 ]. The rate-pressure product (RPP, bpm·mmHg) was calculated as (RPP = HR x SBP) to estimate the myocardial metabolic demand [ 16 ]. Brachial blood pressure was measured in the left arm using the oscillometer method (Omron, Dalian co, HEM-7113, Japan), and the values were used to correct the absolute values of the finger blood pressure. The β-adrenergic blockade was induced through oral administration of the non-selective β-adrenergic receptor antagonist propranolol. Participants weighing less than 60 kg received 80 mg (n = 5), whereas those weighing more than 60 kg received 120 mg (n = 12), resulting in a mean group dose of 1.6 ± 0.2 mg·kg⁻¹ (mean ± SD). Approximately 40 minutes after administration, all participants showed a marked reduction in resting heart rate (> 10 bpm), confirming effective β-blockade [ 9 ]. Experimental Protocol The experimental protocol consisted of two visits to the laboratory. During the first visit, participants underwent a familiarisation session. During the second visit, participants underwent two conditions: a control condition and a β-adrenergic receptor blockade condition. The control condition was always conducted before the blockade to avoid the carry-over effects of the drug administered. Upon arrival at the laboratory, participants had their weight and height measured. They were then placed in a semi-recumbent position with back support set at 45° and were instrumented with an electrocardiogram, photoplethysmography on the middle finger of the left hand, and a cuff on the left arm for brachial blood pressure measurements. The maximal voluntary contraction (MVC) was measured with an electronic handgrip dynamometer placed in the right hand and was determined as an average of 3 maximal efforts. Afterwards, participants sat quietly for at least 10 minutes until the variables were at baseline levels. This was followed by 3 minutes of static handgrip exercise at 40% of MVC, and then post-exercise muscle ischemia for 3 minutes, which isolated the metabolites produced during the exercise. The post-exercise muscle ischemia was achieved by rapid inflation of an arm cuff (E20; Hokanson, Bellevue, WA) placed proximally in the right arm to a supra-systolic pressure of 250 mmHg, two seconds before exercise cessation. After the cuff release, participants recovered for 3 minutes. A scale from 1 to 10 was used to acquire a rating of perceived effort during the handgrip exercise and a rating of perceived discomfort [ 17 ] during the isolated metaboreflex activation. Statistical analysis During each protocol phase, variables were averaged over the last 30 seconds, and delta values were calculated from baseline resting values. The resulting means and standard deviations are presented. Statistical analyses were achieved using IBM's SPSS Statistics V20.0 software. The Shapiro-Wilk test was used to test for normal distribution of the data. Student's t-tests were used to compare participant characteristics. A three-way ANOVA with repeated measures for time and condition was used to test for main effects of time (rest, exercise, and metaboreflex or baseline and CPT), condition (control and blockade), and group (YW and PMW) and their interactions. When significant interactions were found, multiple comparisons were performed using the Bonferroni post hoc adjustment. A significance level of P ≤ 0.05 was used, with a α-value of 0.05 assumed. Graphs were created using GraphPad Prism 8 software from San Diego, CA, USA. Results Demography of the participants is presented in Table 1; overall, younger women and postmenopausal women were statistically similar in body mass index, and maximum voluntary contraction. As expected, a significant difference was observed in age between groups. At rest, under control conditions, and after the blockade, young women showed similar heart rate and lower systolic and diastolic blood pressures (Table 2). Handgrip exercise increased heart rate in young women and blood pressure in both groups during the control condition. Under the blockade during exercise, heart rate increased in both groups, and young women showed a higher increase in heart rate, and postmenopausal women showed an exaggerated increase in systolic blood pressure (Table 2). During isolated metaboreflex activation, heart rate returned to resting levels in young and postmenopausal women. The isolated metaboreflex activation kept blood pressure steadily elevated in both groups, during the control condition and under the β-blocked (Table 2). Only during isolated metaboreflex activation, stroke volume increased in young women, before and after blockade. In post menopausal women, the stroke volume did not change along the protocol, during the control condition and under β-blocker, and stroke volume was similar between the groups, before and after the β-blocked (Table 2). However, cardiac output was similar between the young and postmenopausal women at rest in both conditions, and increased during handgrip exercise only in the young group, and the β-blocker did not change cardiac output behaviour (Table 2). The isolated metaboreflex activation kept cardiac output elevated compared to rest, but at lower levels compared to handgrip exercise, in young women, and β-adrenergic blockade reduced cardiac output throughout the protocol. In postmenopausal women, handgrip exercise and isolated metaboreflex activation did not change cardiac output before and under blockade. The β-adrenergic blocker kept the cardiac output consistently lower in postmenopausal women compared to young women (Table 2). Before the blockade, coronary blood velocity was higher in young compared to postmenopausal women (Fig. 1), handgrip exercise increased coronary blood velocity only in young women, and during isolated metaboreflex activation, the coronary blood velocity returned to resting levels in young women. Under the blockade, coronary blood velocity did not increase in young women (Fig. 1). In postmenopausal women, neither handgrip exercise nor the isolated metaboreflex activation changed coronary blood velocity. During exercise and metaboreflex activation, the coronary conductance index decreased in young women, and the β-blocker induced a higher decrease in the coronary conductance index during exercise and metaboreflex activation. While, in menopausal women, the coronary conductance index decreased during exercise similarly before and after the blockade (Fig. 1). The rate-pressure product increased during handgrip exercise and isolated metaboreflex activation in both groups of women, and β-blockade decreased the rate-pressure product in young women, and no effect of the blockade was observed in menopausal women (Table 1). Discussion The primary results of this work were that young women depend on β-adrenergic stimulation to control the increase in coronary circulation during handgrip exercise. Postmenopausal women showed reduced coronary circulation, while the coronary rate-pressure product increased. Further, post menopausal women presented chronotropic incompetence and exaggerated blood pressure response during exercise and isolated metaboreflex activation. Ultimately, postmenopausal women presented reduced sensitivity to β-adrenergic stimulation. The myocardium has a high oxidative metabolism, and oxygen delivery is regulated by redundant physiological mechanisms (e.g., myogenic, metabolic and neural) [ 4 ]. Classically, the neural control of coronary circulation relies on the aftermath of α-adrenergic vasoconstriction and β-adrenergic vasodilation during sympathetic stimulation [ 18 , 19 ]. Our results showed that menopausal women presented lower coronary blood flow velocity, and handgrip exercise did not increase blood flow velocity. The coronary arterioles exhibit a high capacity of oxygen extraction [ 20 ], which could explain why an increased metabolism did not increase coronary blood velocity. Additionally, we could speculate that decreased blood supply causes the chronotropic incompetence observed in this study, and decreased heart rate during maximal exercise as observed in menopausal women compared to younger women [ 21 ]. In this study, we observed an exaggerated increase in blood pressure in menopausal women during exercise and metaboreflex activation when compared to younger women. The exercise pressor reflex is fundamental to sustaining blood pressure during exercise and ensuring oxygen delivery to active muscles [ 22 ]. Afferent feedback from the mechanical and metabolic-sensitive fibres from skeletal muscles to the cardiovascular centres in the brainstem stimulates sympathetic activation and consequently increases blood pressure and redistribution of cardiac output [ 22 ]. However, a dysfunctional exercise pressure reflex could be part of the mechanism to drive exaggerated blood pressure response [ 23 ]. For instance, evidence shows that ageing increases the risk of exaggerated blood pressure stress response in women and men, isolated metaboreflex activation [ 24 ]. We found a blunted effect of β-adrenergic blockade on coronary blood velocity and diastolic blood pressure in postmenopausal women. In fact, it was observed that on muscle vasculature, β-adrenergic blockade vasodilation is blunted with ageing in women [ 25 ]. This can explain the lack of increase in coronary blood velocity and the exaggerated increase in blood pressure during exercise and metaboreflex activation. Experimental Considerations Considering that we use static handgrip exercise, our results cannot be extrapolated to dynamic exercises that use larger muscle mass. Also, the results of this study only apply to women during healthy ageing; therefore, patients with any diagnosis would have different mechanisms supporting coronary oxygen supply. Additionally, postmenopausal women in this group of participants were not under hormonal therapy, which might change the mechanisms controlling coronary circulation. The number of participants in this study is low, but considering our inclusion criteria, the results provide novel insights and point to future directions for a deeper understanding of the underlying physiological mechanisms and for mitigating risk. We used photoplethysmography to measure beat-to-beat blood pressure and derive cardiac output, but it has been reported that photoplethysmography shows good agreement with Doppler echocardiography measurements [ 26 ]. We used transthoracic Doppler ultrasound, so the coronary diameter could not be measured due to the limited resolution of the technique. Yet, previous studies reported that coronary blood velocity is closely related to coronary blood flow [ 27 , 28 ]. Women who were using oral hormonal contraceptive pills were included in this study, but were tested during the placebo phase of the contraceptive pill. Conclusion The evidence found in this study leads us to the conclusion that coronary circulation is decreased, and the increased metabolism does not stimulate an increase in coronary circulation after menopause. Additionally, vasodilation during sympathetic stimulation depends on the β-adrenergic receptor in young women, while in postmenopausal women, the β-adrenergic receptor effect is blunted. Declarations Author contributions EP and ACLN contributed to the study's conception and design. Data analysis was performed by MLG. Material preparation and data collection were performed by EPC, MLG, and PAM. The first draft of the manuscript was written by EP. All authors commented on previous versions of the manuscript and read and approved the final version of this manuscript. Acknowledgements The authors appreciate the time and effort of all women who volunteered to participate in this study. Professor Edmundo Drummond Alves Jr. and Jonas Lírio Gurgel facilitated contact with the participants from the PrevQuedas program. We would also like to thank all funding agencies, CAPES, CNPq, FAPERJ, and FINEP, for their financial support. 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Supplementary Files Tables1.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 15 May, 2026 Reviewers invited by journal 27 Apr, 2026 Editor assigned by journal 25 Apr, 2026 First submitted to journal 20 Apr, 2026 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-9475086","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":630339139,"identity":"9da5d71a-a0af-431b-a33f-f7afd1934594","order_by":0,"name":"Eliza Prodel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIie3RsQrCMBCA4QuFTlezplD0FQIFXYq+ihJwrEOhOMZFlz5A+jaBglPp3FFwdSi4uGmrS7fETTD/dsPHHRyAy/Wz+RBRIBcAhLU1wVB6/EvC9UDAglAIzl2XJxi3wr/vI0gX0kBCORGlarY4b4VX1ghZpA2Ea4y94Fj1ZFcRibBRpsNWH/LEWAnPjnB4E42c2RKmJ4KoRiCrrwNhGTMRKoMKunw5pad+y6FIUiOB2W00kMIMYHj4qIeNcLlcrn/rBew3MlwmB2duAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-2700-0409","institution":"Universidade Federal Rural do Rio de Janeiro","correspondingAuthor":true,"prefix":"","firstName":"Eliza","middleName":"","lastName":"Prodel","suffix":""},{"id":630339140,"identity":"853e8152-98e3-4d3b-9ac2-4c51e4d0e1e6","order_by":1,"name":"Maitê Gondim","email":"","orcid":"","institution":"Universidade Federal Fluminense","correspondingAuthor":false,"prefix":"","firstName":"Maitê","middleName":"","lastName":"Gondim","suffix":""},{"id":630339141,"identity":"269498e0-2589-4c06-843d-393e3bf5a7b9","order_by":2,"name":"Pedro Augusto de Carvalho Mira","email":"","orcid":"","institution":"Ebserh: Empresa Brasileira de Servicos Hospitalares","correspondingAuthor":false,"prefix":"","firstName":"Pedro","middleName":"Augusto de Carvalho","lastName":"Mira","suffix":""},{"id":630339142,"identity":"c2c80c19-dd12-4af7-b203-87dc806217ce","order_by":3,"name":"Antonio Claudio Lucas da Nobrega","email":"","orcid":"","institution":"Universidade Federal Fluminense","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Claudio Lucas da","lastName":"Nobrega","suffix":""}],"badges":[],"createdAt":"2026-04-20 17:07:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9475086/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9475086/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108624064,"identity":"c34af905-5fb6-4860-be8b-d3229a2596bb","added_by":"auto","created_at":"2026-05-06 15:15:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":71168,"visible":true,"origin":"","legend":"\u003cp\u003e\u0026nbsp;Legend not included with this version.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9475086/v1/fe4972546405c6a7049c5a62.png"},{"id":108804895,"identity":"5cc2e5c7-8670-4a6a-a2da-91801865467b","added_by":"auto","created_at":"2026-05-08 15:24:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":225269,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9475086/v1/ec80a49f-2fdc-4dca-aa6b-f6475f57e18f.pdf"},{"id":108624065,"identity":"b7cfae92-dc8f-42de-b6d7-9e0e3db1db59","added_by":"auto","created_at":"2026-05-06 15:15:44","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15282,"visible":true,"origin":"","legend":"","description":"","filename":"Tables1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9475086/v1/7fbf8bd095b69166caa66b94.xlsx"}],"financialInterests":"","formattedTitle":"Beta-adrenergic control of coronary circulation during handgrip exercise and isolated metaboreflex activation in postmenopausal women","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiovascular diseases are still the major cause of mortality worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], and myocardial infarction represents a major risk of death [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The myocardium do not tolerate ischemic conditions and therefore, coronary circulation is strictly maintained according to metabolic demand via redundant physiological mechanisms (e.g., myogenic, metabolic and neural) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The failure to control the coronary blood flow and supply myocardial oxygen demand might result in tissue damage [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAgeing, even when healthy, also increases the risk of the development of cardiovascular disease and myocardial infarction [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Young women are at lower cardiovascular risk compared with young men [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], however, after menopause, the cardiovascular risk in women increases to a higher level compared to age-matched men [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Menopause is the process during which synthesis and release of oestrogen and progesterone cease 8, leading to a diminished protective cardiovascular effect of reproductive female hormones [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, it is crucial to understand the physiological mechanisms related to the coronary circulation during menopause.\u003c/p\u003e \u003cp\u003eThe neural control of coronary circulation depends on the interaction of α-adrenergic receptor vasoconstriction with β2-adrenergic receptor vasodilation, especially during stress [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In young men, coronary circulation increases during handgrip exercise, and β-adrenergic blockade decreases vascular conductance and restrains blood flow, even with increased myocardium metabolic demand [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. During trigeminal nerve stimulation, a reflex-related decrease in heart rate is observed; hence was applied as a physiological approach to decrease myocardial metabolic demand. Yet, β-blockade also restrained the increase of coronary blood velocity in young men and women [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Menopause seems to disrupt coronary circulatory control; handgrip exercise and isolated metaboreflex activation did not stimulate an increase in blood velocity in postmenopausal women as observed in young women[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, α-adrenergic blockade does not change coronary circulation in women after menopause; however, in young women, α-adrenergic receptor restrains coronary circulation, measured by blood flow velocity, during sympathetic stimulation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn young women, β-adrenergic receptor stimulation diminishes the vasoconstrictor effect of sympathetic stimulation, which is not observed in young men or postmenopausal women [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Accordingly, β2-adrenergic agonists dilate women's vasculature via nitric oxide release [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The explanation relies on the interaction of oestrogen with the β-adrenergic receptor on the arterioles, by which oestrogen increases nitric oxide released during β2-adrenergic stimulation. However, the role of the β-adrenergic receptor in controlling the coronary circulation in women after menopause is not fully known. Importantly, it could be one of the mechanisms to explain the increased ischemic events in older women.\u003c/p\u003e \u003cp\u003eTherefore, the aim of this investigation was to test the effect of the β-adrenergic blockade on coronary circulation in postmenopausal women during exercise and metaboreflex activation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003e The Fluminense Federal University ethics committee (2.362.515) granted approval for all experimental procedures, which were performed in accordance with the Declaration of Helsinki. This protocol was conducted before the COVID-19 pandemic lockdown. Before participating, all women received comprehensive verbal and written information about the protocol and provided written consent. The study enrolled 19 participants, consisting of 10 young women (YW) and 5 postmenopausal women (PMW), all of whom were apparently healthy and had no history or symptoms of any diseases. The young women were tested during the early follicular phase of their menstrual cycle or during the low-hormone phase of oral contraceptive use (n\u0026thinsp;=\u0026thinsp;4) to minimize the cardiovascular effects of hormonal variation across the menstrual cycle. Menopause was defined as the absence of menstruation for at least one year, and the postmenopausal women had never undergone hormonal replacement therapy. None of the participants was taking prescribed or over-the-counter medication. Participants were instructed to refrain from consuming caffeine, alcohol, any medication, including primary dysmenorrhea therapy, or exercising for 24 hours prior to the experimental session. The experimental protocol was conducted 2 hours after the participants consumed a light meal, and the temperature in the room was maintained between 22\u0026deg;C and 24\u0026deg;C.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePhysiological measurements\u003c/h3\u003e\n\u003cp\u003eIn this study, heart rate (HR, bpm) was continuously monitored using a standard lead II electrocardiogram (Powerlab; ADInstruments, Bella Vista, Australia). Systolic and diastolic blood pressure (SBP and DBP, mmHg) were measured beat-to-beat via photoplethysmography from the middle finger of the left hand (Finometer Pro; Finapres Medical Systems, Arnhem, The Netherlands). The signals were sampled at 1000 Hz and integrated over time for offline analysis (Powerlab, LabChart; ADInstruments, Bella Vista, Australia). Mean arterial pressure (MAP, mmHg) was calculated by integrating the arterial blood pressure waveform over a cardiac cycle (Finometer Pro; Finapres Medical Systems, Arnhem, The Netherlands). Stroke volume (SV, ml) was derived from the blood pressure waveform using the modelflow\u0026reg; method [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] (Finometer Pro; Finapres Medical Systems, Arnhem, The Netherlands), and the cardiac output (CO, l\u0026middot;min-1) was calculated as SV\u0026times;HR. Transthoracic duplex ultrasound (Vivid 7, GE Medical, USA) was used to assess coronary perfusion with a multifrequency sector transducer (3S) set at an image depth of 8 to 10 cm and a sample volume of 2.5 mm. Coronary mean blood velocity (CBV, cm\u0026middot;s-1) was measured on the left anterior coronary artery (LCA) on the parasternal short axis (E.P.). The Doppler tracking of blood velocity was obtained during the diastolic portion of each cardiac cycle manually by the same trained investigator [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The values were averaged from 10 cardiac cycles during the last 30 seconds of each protocol phase, and the coronary conductance index (CCI, cm\u0026middot;s-1\u0026middot;mmHg-1) was calculated as (CCI\u0026thinsp;=\u0026thinsp;CBV\u0026thinsp;\u0026divide;\u0026thinsp;DBP). This non-invasive method has been validated and widely used as a surrogate for coronary circulation assessment in conscious humans [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The CBV measurement consistency was previously published by this group [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The rate-pressure product (RPP, bpm\u0026middot;mmHg) was calculated as (RPP\u0026thinsp;=\u0026thinsp;HR x SBP) to estimate the myocardial metabolic demand [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Brachial blood pressure was measured in the left arm using the oscillometer method (Omron, Dalian co, HEM-7113, Japan), and the values were used to correct the absolute values of the finger blood pressure.\u003c/p\u003e \u003cp\u003eThe β-adrenergic blockade was induced through oral administration of the non-selective β-adrenergic receptor antagonist propranolol. Participants weighing less than 60 kg received 80 mg (n\u0026thinsp;=\u0026thinsp;5), whereas those weighing more than 60 kg received 120 mg (n\u0026thinsp;=\u0026thinsp;12), resulting in a mean group dose of 1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 mg\u0026middot;kg⁻\u0026sup1; (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD). Approximately 40 minutes after administration, all participants showed a marked reduction in resting heart rate (\u0026gt;\u0026thinsp;10 bpm), confirming effective β-blockade [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eExperimental Protocol\u003c/h3\u003e\n\u003cp\u003eThe experimental protocol consisted of two visits to the laboratory. During the first visit, participants underwent a familiarisation session. During the second visit, participants underwent two conditions: a control condition and a β-adrenergic receptor blockade condition. The control condition was always conducted before the blockade to avoid the carry-over effects of the drug administered.\u003c/p\u003e \u003cp\u003eUpon arrival at the laboratory, participants had their weight and height measured. They were then placed in a semi-recumbent position with back support set at 45\u0026deg; and were instrumented with an electrocardiogram, photoplethysmography on the middle finger of the left hand, and a cuff on the left arm for brachial blood pressure measurements. The maximal voluntary contraction (MVC) was measured with an electronic handgrip dynamometer placed in the right hand and was determined as an average of 3 maximal efforts. Afterwards, participants sat quietly for at least 10 minutes until the variables were at baseline levels. This was followed by 3 minutes of static handgrip exercise at 40% of MVC, and then post-exercise muscle ischemia for 3 minutes, which isolated the metabolites produced during the exercise. The post-exercise muscle ischemia was achieved by rapid inflation of an arm cuff (E20; Hokanson, Bellevue, WA) placed proximally in the right arm to a supra-systolic pressure of 250 mmHg, two seconds before exercise cessation. After the cuff release, participants recovered for 3 minutes. A scale from 1 to 10 was used to acquire a rating of perceived effort during the handgrip exercise and a rating of perceived discomfort [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] during the isolated metaboreflex activation.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDuring each protocol phase, variables were averaged over the last 30 seconds, and delta values were calculated from baseline resting values. The resulting means and standard deviations are presented. Statistical analyses were achieved using IBM's SPSS Statistics V20.0 software. The Shapiro-Wilk test was used to test for normal distribution of the data. Student's t-tests were used to compare participant characteristics. A three-way ANOVA with repeated measures for time and condition was used to test for main effects of time (rest, exercise, and metaboreflex or baseline and CPT), condition (control and blockade), and group (YW and PMW) and their interactions. When significant interactions were found, multiple comparisons were performed using the Bonferroni post hoc adjustment. A significance level of P\u0026thinsp;\u0026le;\u0026thinsp;0.05 was used, with a α-value of 0.05 assumed. Graphs were created using GraphPad Prism 8 software from San Diego, CA, USA.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eDemography of the participants is presented in Table\u0026nbsp;1; overall, younger women and postmenopausal women were statistically similar in body mass index, and maximum voluntary contraction. As expected, a significant difference was observed in age between groups.\u003c/p\u003e \u003cp\u003eAt rest, under control conditions, and after the blockade, young women showed similar heart rate and lower systolic and diastolic blood pressures (Table\u0026nbsp;2). Handgrip exercise increased heart rate in young women and blood pressure in both groups during the control condition. Under the blockade during exercise, heart rate increased in both groups, and young women showed a higher increase in heart rate, and postmenopausal women showed an exaggerated increase in systolic blood pressure (Table\u0026nbsp;2). During isolated metaboreflex activation, heart rate returned to resting levels in young and postmenopausal women. The isolated metaboreflex activation kept blood pressure steadily elevated in both groups, during the control condition and under the β-blocked (Table\u0026nbsp;2). Only during isolated metaboreflex activation, stroke volume increased in young women, before and after blockade. In post menopausal women, the stroke volume did not change along the protocol, during the control condition and under β-blocker, and stroke volume was similar between the groups, before and after the β-blocked (Table\u0026nbsp;2). However, cardiac output was similar between the young and postmenopausal women at rest in both conditions, and increased during handgrip exercise only in the young group, and the β-blocker did not change cardiac output behaviour (Table\u0026nbsp;2). The isolated metaboreflex activation kept cardiac output elevated compared to rest, but at lower levels compared to handgrip exercise, in young women, and β-adrenergic blockade reduced cardiac output throughout the protocol. In postmenopausal women, handgrip exercise and isolated metaboreflex activation did not change cardiac output before and under blockade. The β-adrenergic blocker kept the cardiac output consistently lower in postmenopausal women compared to young women (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eBefore the blockade, coronary blood velocity was higher in young compared to postmenopausal women (Fig.\u0026nbsp;1), handgrip exercise increased coronary blood velocity only in young women, and during isolated metaboreflex activation, the coronary blood velocity returned to resting levels in young women. Under the blockade, coronary blood velocity did not increase in young women (Fig.\u0026nbsp;1). In postmenopausal women, neither handgrip exercise nor the isolated metaboreflex activation changed coronary blood velocity. During exercise and metaboreflex activation, the coronary conductance index decreased in young women, and the β-blocker induced a higher decrease in the coronary conductance index during exercise and metaboreflex activation. While, in menopausal women, the coronary conductance index decreased during exercise similarly before and after the blockade (Fig.\u0026nbsp;1). The rate-pressure product increased during handgrip exercise and isolated metaboreflex activation in both groups of women, and β-blockade decreased the rate-pressure product in young women, and no effect of the blockade was observed in menopausal women (Table\u0026nbsp;1).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe primary results of this work were that young women depend on β-adrenergic stimulation to control the increase in coronary circulation during handgrip exercise. Postmenopausal women showed reduced coronary circulation, while the coronary rate-pressure product increased. Further, post menopausal women presented chronotropic incompetence and exaggerated blood pressure response during exercise and isolated metaboreflex activation. Ultimately, postmenopausal women presented reduced sensitivity to β-adrenergic stimulation.\u003c/p\u003e \u003cp\u003eThe myocardium has a high oxidative metabolism, and oxygen delivery is regulated by redundant physiological mechanisms (e.g., myogenic, metabolic and neural) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Classically, the neural control of coronary circulation relies on the aftermath of α-adrenergic vasoconstriction and β-adrenergic vasodilation during sympathetic stimulation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Our results showed that menopausal women presented lower coronary blood flow velocity, and handgrip exercise did not increase blood flow velocity. The coronary arterioles exhibit a high capacity of oxygen extraction [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which could explain why an increased metabolism did not increase coronary blood velocity. Additionally, we could speculate that decreased blood supply causes the chronotropic incompetence observed in this study, and decreased heart rate during maximal exercise as observed in menopausal women compared to younger women [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we observed an exaggerated increase in blood pressure in menopausal women during exercise and metaboreflex activation when compared to younger women. The exercise pressor reflex is fundamental to sustaining blood pressure during exercise and ensuring oxygen delivery to active muscles [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Afferent feedback from the mechanical and metabolic-sensitive fibres from skeletal muscles to the cardiovascular centres in the brainstem stimulates sympathetic activation and consequently increases blood pressure and redistribution of cardiac output [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, a dysfunctional exercise pressure reflex could be part of the mechanism to drive exaggerated blood pressure response [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For instance, evidence shows that ageing increases the risk of exaggerated blood pressure stress response in women and men, isolated metaboreflex activation [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe found a blunted effect of β-adrenergic blockade on coronary blood velocity and diastolic blood pressure in postmenopausal women. In fact, it was observed that on muscle vasculature, β-adrenergic blockade vasodilation is blunted with ageing in women [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This can explain the lack of increase in coronary blood velocity and the exaggerated increase in blood pressure during exercise and metaboreflex activation.\u003c/p\u003e\n\u003ch3\u003eExperimental Considerations\u003c/h3\u003e\n\u003cp\u003eConsidering that we use static handgrip exercise, our results cannot be extrapolated to dynamic exercises that use larger muscle mass. Also, the results of this study only apply to women during healthy ageing; therefore, patients with any diagnosis would have different mechanisms supporting coronary oxygen supply. Additionally, postmenopausal women in this group of participants were not under hormonal therapy, which might change the mechanisms controlling coronary circulation. The number of participants in this study is low, but considering our inclusion criteria, the results provide novel insights and point to future directions for a deeper understanding of the underlying physiological mechanisms and for mitigating risk.\u003c/p\u003e \u003cp\u003eWe used photoplethysmography to measure beat-to-beat blood pressure and derive cardiac output, but it has been reported that photoplethysmography shows good agreement with Doppler echocardiography measurements [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. We used transthoracic Doppler ultrasound, so the coronary diameter could not be measured due to the limited resolution of the technique. Yet, previous studies reported that coronary blood velocity is closely related to coronary blood flow [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Women who were using oral hormonal contraceptive pills were included in this study, but were tested during the placebo phase of the contraceptive pill.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe evidence found in this study leads us to the conclusion that coronary circulation is decreased, and the increased metabolism does not stimulate an increase in coronary circulation after menopause. Additionally, vasodilation during sympathetic stimulation depends on the β-adrenergic receptor in young women, while in postmenopausal women, the β-adrenergic receptor effect is blunted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eEP and ACLN contributed to the study's conception and design. Data analysis was performed by MLG. Material preparation and data collection were performed by EPC, MLG, and PAM. The first draft of the manuscript was written by EP. All authors commented on previous versions of the manuscript and read and approved the final version of this manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors appreciate the time and effort of all women who volunteered to participate in this study. Professor Edmundo Drummond Alves Jr. and Jonas L\u0026iacute;rio Gurgel facilitated contact with the participants from the \u003cem\u003ePrevQuedas\u003c/em\u003e program. We would also like to thank all funding agencies, CAPES, CNPq, FAPERJ, and FINEP, for their financial support.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eResearch data associated with this paper will be available upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWoodruff RC, Tong X, Khan SS et al (2024) Trends in Cardiovascular Disease Mortality Rates and Excess Deaths, 2010\u0026ndash;2022. 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Circulation 72:82\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/01.CIR.72.1.82\u003c/span\u003e\u003cspan address=\"10.1161/01.CIR.72.1.82\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\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":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Coronary blood velocity, exercise, menopause","lastPublishedDoi":"10.21203/rs.3.rs-9475086/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9475086/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMenopause represents the process during which oestrogen and progesterone synthesis and release cease, leading to the diminished protective cardiovascular effect of reproductive female hormones. Therefore, it is crucial to understand the physiological mechanisms related to the coronary circulation during menopause. The aim of this investigation is to test the effect of the β-adrenergic blockade on coronary circulation in postmenopausal women during exercise and metaboreflex activation. In healthy young (YW: n\u0026thinsp;=\u0026thinsp;12) and postmenopausal (PMW: n\u0026thinsp;=\u0026thinsp;5) women, coronary blood velocity (CBV), coronary conductance index (CCI) and rate pressure product (RPP) were measured at rest, during handgrip exercise (Grip) and post-exercise circulatory occlusion, i.e. isolated metaboreflex activation (Metabo), under control condition and after β-adrenergic blockade. Overall, CBV was higher in YW compared to PMW, Grip increased CBV only in YW, and during Metabo, CBV returned to resting levels in YW. Under the blockade, CBV did not increase in YW. In PMW, neither Grip nor the Metabo changed CBV. CCI decreased during Grip and Metabo in YW, which, under the blockade, decreased to lower levels. The RPP increased during Grip and Metabo in both groups of women, the β-blockade decreased RPP in young women along the protocol, and no effect of the blockade was observed in PMW. In conclusion, coronary circulation is decreased after menopause, and the increased metabolism does not stimulate an increase in coronary circulation in post menopausal women. Additionally, vasodilation during sympathetic stimulation depends on the β-adrenergic receptor in young women, while in postmenopausal women the β-adrenergic receptor effect is blunted.\u003c/p\u003e","manuscriptTitle":"Beta-adrenergic control of coronary circulation during handgrip exercise and isolated metaboreflex activation in postmenopausal women","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-06 15:15:40","doi":"10.21203/rs.3.rs-9475086/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-05-16T00:06:34+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-27T12:34:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-25T08:28:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Autonomic Research","date":"2026-04-20T13:07:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5854b7f8-63e8-4ac9-8017-5937b290fe7d","owner":[],"postedDate":"May 6th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"","date":"2026-05-16T00:06:34+00:00","index":0,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T15:15:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-06 15:15:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9475086","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9475086","identity":"rs-9475086","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}