Effects of Acute Grape Seed Extract Supplementation on Muscle Metaboreflex in Healthy Young Individuals

Effects of Acute Grape Seed Extract Supplementation on Muscle Metaboreflex in Healthy Young Individuals | 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 Effects of Acute Grape Seed Extract Supplementation on Muscle Metaboreflex in Healthy Young Individuals Alvin Apilado, William Boyer, Trevor Gillum, Sean Sullivan, Andrew Harveson, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4349992/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Aug, 2025 Read the published version in Sport Sciences for Health → Version 1 posted 9 You are reading this latest preprint version Abstract Studies demonstrated that grape seed extract (GSE) increases the production of nitric oxide (NO) and reduces central sympathetic output. However, limited data have reported regarding the potential beneficial effects of this extract on blood pressure (BP) to increased sympathetic activity induced by the muscle metaboreflex (MMR) activation. Accordingly, the aim of this study was to determine whether GSE supplementation could reduce the BP in response to static exercise and post exercise muscular ischemia (PEMI) in normotensive young adults. In 12 healthy subjects (7 male and 5 female, 24.6 ± 3.4 year), we compared acute effect of both GSE (600 mg) and placebo (PL: 600 mg) on changes from rest in systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) during static exercise (SE) and PEMI. Subjects completed 2 min of SE at 30% of maximal voluntary contraction (MVC) followed by 2 min of PEMI. MAP was significantly increased during SE and MMR in both conditions, but the rise was significantly attenuated following GSE supplementation compared to PL supplementation (20 ± 2 mmHg vs. 25 ± 2 mmHg). CO was significantly increased during SE and MMR in both conditions, but the rise was significantly higher in GSE treatment than PL treatment. TPR was significantly increased in both conditions, but the rise was significantly higher following PL treatment compared to GSE treatment (SE: 3.1 ± 0.5 mmHg/L/min vs. 0.9 ± 0.6 mmHg/L/min; MMR: 2.7 ± 0.4 mmHg/L/min vs. 1.4 ± 0.4 mmHg/L/min). Our findings suggest that GSE is effective in reducing BP response mediated by the MMR activation. The current study may have potential clinical significance that this extract at least partially buffers an exaggerated BP response evoked during exercise in hypertensive individuals. grape seed extract cardiac output static exercise muscle metaboreflex Figures Figure 1 Figure 2 Introduction In conditions of inadequate oxygen supply induced by a mismatch between blood flow and metabolic demand, the exercise pressor reflex (EPR) adjusts the circulation to increase oxygen delivery to the contracting skeletal muscles (Kaufman & Hayes, 2002 ; O'Leary et al., 1999 ). It is well documented that the reflex evokes increases in sympathetic activity to the heart and skeletal muscles, resulting in increases in blood pressure (BP), heart rate (HR), and total peripheral resistance (TPR) via peripheral vasoconstriction (Grotle et al., 2020 ; McCloskey & Mitchell, 1972 ; Mitchell et al., 1983 ). The afferent arm of the reflex consists of group III and IV skeletal muscle afferents (Kaufman et al., 1983 ). The group III afferents are activated mainly by mechanical stimuli at the onset of muscle contraction and group IV afferents respond predominantly to accumulated metabolites during exercise (Kaufman et al., 1983 ; O'Leary et al., 1999 ). The cardiovascular adjustments induced by the mechanically sensitive and metabolically sensitive components are known as the muscle mechanorelfex and muscle metaboreflex (MMR), respectively. Although the EPR plays an important role in regulating cardiovascular responses to exercise, there is abnormal physiological responses in individuals with hypertension, obesity, heart failure, and peripheral artery disease (Hammond et al., 2001 ; Lee et al., 2020 ; Mitchell, 2017 ; Muller et al., 2012 ). Particularly, exaggerated BP response to exercise is a prognostic indicator of cardiovascular disease risks such as hypertension, myocardial infarction, and stroke in individuals in an absence of coronary disease (Laukkanen & Kurl, 2012 ; Nakashima et al., 2004 ). Even though pathophysiology of exercise-induced hypertension response has not been fully elucidated, plausible mechanisms to explain this phenomenon is associated with an exaggerated increase in sympathetic activity, endothelial dysfunction, arterial stiffness, and increased angiotensin II concentration (Delaney et al., 2010 ; Kim et al., 2020 ; Qin & Li, 2020 ; Tzemos et al., 2015 ). Accordingly, early treatment may be warranted to prevent cardiovascular adverse events. Dietary intervention using nutritional supplements may be a potential approach for managing excessive sympathetic activity. An increase in nitric oxide (NO) bioavailability via dietary supplementation alters efferent sympathetic outflow. For example, a previous study demonstrated that acute dietary supplementation with beetroot juice reduced muscle sympathetic outflow at rest and during exercise in normotensive individuals (Notay et al., 2017 ). Findings suggest that dietary therapy may represent a target to reduce central sympathetic overactivation induced by the MMR during exercise. An extract of grape seed has been manufactured via hydrolysis of specific enzymes, and the manufacturing process results in a grape seed extract (GSE) highly purified and rich in polyphenolic compounds (Meganatural BP; Polyphenolics, Madera, CA) (Shrikhande et al., 2011 ). Studies has demonstrated that the extract lowers BP via an increase in peripheral vasodilation and this health effect is related to the activation of endothelial nitric oxide synthase (eNOS) and, in turn, production of nitric oxide (NO) (Quiñones et al., 2014 ). This GSE consists of total phenolics (90–93%), gallic acid (≥ 2%), and catechins and epicatechins (≥ 5%). The ingredients of phenolic compounds are 9% monomers, 69% oligomers, and 22% polymers as measured by high-performance liquid chromatography (HPL-C). However, even though the NO is known to reduce central sympathetic output and peripheral vasoconstriction, potential beneficial effects of this extract on exercising BP response evoked by the MMR in human subjects have not been revealed. Thus, this study was hypothesized that dietary supplementation with GSE reduces the BP response to the MMR in healthy young individuals. Methods 12 healthy, recreationally active participants (7 males, 5 females) aged between 18 and 30 years volunteered to participate in the study. All participants were informed of any potential risks that may or may not occur during their participation, along with being provided a written consent for them to read and sign. A health history was provided using the Physical Activity Readiness Questionnaire (PAR-Q) survey to determine the eligibility for this study. Prior to any study procedures, the participants completed the PAR-Q survey and signed an informed consent form. Exclusion criteria was as followed: taking medications that affected cardiovascular responses to exercise, musculoskeletal diseases, and cardiovascular diseases. All participants were asked to refrain from smoking, exercising, and ingesting caffeine and/or alcohol 24 hours prior to their lab visit. The current study was approved by the California Baptist University Institutional Review Board (107-2122-EXP). This study was registered in Clinicaltrials.gov (NCT05945771). Experimental Procedures At first visit, the baseline data such as height (m) and weight (kg) were measured. Both measurements were used to calculate the body mass index (BMI) of the participant by using the following equation: kg/m 2 . The participants sat on a chair and quietly rested for at least 5 minutes with their back supported on a chair and both feet on the floor. After 5 minutes, resting BP was measured by a sphygmomanometer and BP cuff placed on the participant’s dominant arm. Next, to determine the relative exercise intensity of static handgrip exercise (SHE), maximal voluntary contraction (MVC) of the dominant forearm was performed via the handgrip dynamometer test twice at maximal effort for < 1s; the peak value was used as their MVC. The static exercise was performed at 30% of MVC (Kim et al., 2014 ). Upon the start of the second and third visit, the participant quietly rested for 20 minutes before undergoing the SHE. The participant used their dominant hand to exert the amount of force that was to be determined based on their first visit’s relative exercise intensity while seated for 3–5 minutes. They performed SHE by using the dominant hand at 30% MVC with visual feedback of the force via a mark on the display. Participants completed 3 min of static exercise followed by 2 min of post exercise muscular ischemia (PEMI). To isolate only the effect of the MMR, the dominant arm was occluded at 200 mmHg via an inflatable occlusion cuff for 2 min. Measurement of Hemodynamic Responses A noninvasive device was continuously used to measure HR, stroke volume (SV) and cardiac output (CO) via impedance cardiography at rest, and during static exercise and PEMI (Physio Flow, Manatec Biomedical, France)(Naylor et al., 2020 ; Shariffi et al., 2022 ). To measure both HR and SV, two electrodes were placed on the left side of the neck, two electrodes were placed on the chest to measure the electrocardiography (ECG), and two electrodes were placed on the xiphoid process. This device was known to have good reliability and validity at rest and during submaximal steady-state exercise in individuals (Charloux et al., 2000 ; Gordon et al., 2018 ). SBP and DBP were measured from the participant’s non-dominant arm at the last 30 seconds of each stage. Mean arterial BP (MAP) was calculated using the following formula: MAP = [(SBP – DBP) x 1/3] + DBP. CO was measured using the following equation: CO = SV x HR. Total peripheral resistance (TPR) was measured using the following equation: TPR = MAP/CO. Supplementations All participants were randomly assigned via a double-blind, cross-over design to evaluate the effects of acute GSE supplementation on the MMR. All participants were randomly assigned and instructed to take GSE (300 mg, 2 capsules) or placebo (PL) (300 mg, 2 capsules containing starch) 2 hours before their laboratory visit. Both treatments looked identical to uphold the blinded aspect of the study between the participant and instructor. Each trial was separated by a 72-hour washout period, but no longer than 7 days. Statistical Analysis All variables were presented as mean ± SE. During SHE and the MMR, the peak 20-s average response for each variable were assessed just prior to the end of both contraction and PEMI. A two-way repeated measures ANOVA and Tukey’s post hoc test was used to compare the effects of GSE supplementation on hemodynamic responses (supplementations x conditions). Significant level was set at P < 0.05. To calculate the sample size, a power test was used to assess the appropriate sample size of any statistically significant change in BP before and after supplementations (power = 0.80) and it revealed the necessity for 10 participants. Effect size (ES) was calculated by Cohen’s D formula as the mean difference (between GSE and PL) divided by the pooled standard deviation. Results The characteristics of the participants were presented in Table 1. By study design, all participants had normal blood pressure and body mass index (Table 1). Figure 1 indicates the absolute peak 20-s average changes from rest in SBP, DBP, and MAP in response to 3 min of SHE and 2 min of MMR activation after supplementation with GSE and PL. A repeated-measures two-way analysis of variance indicated a significant interactive effect (condition x supplement) in both SBP and DBP. The MMR and SHE substantially increased SBP after either GSE or PL supplement ( P < 0.001), but the increase in SBP was significantly attenuated after GSE supplementation ( P = 0.050, P = 0.011, respectively). The rise in DBP were significantly increased following PL treatment during only SHE compared to GSE treatment ( P = 0.005). A condition effect and a supplementation effect were observed for the changes in MAP ( P < 0.001, P = 0.009, respectively). The MAP was significantly increased after PL supplementation during SHE and MMR activation compared to the GSE supplementation. Figure 2 indicates the absolute peak 20-s average changes from rest in HR, SV, CO and TPR in response to 3 min of SHE and 2 min of MMR activation after supplementation with GSE and PL. A condition effect and a supplementation effect were observed for the changes in HR and CO (HR: P < 0.001, P = 0.030, respectively; CO: P < 0.001, P = 0.021, respectively). The HR and CO were significantly increased after GSE supplementation during static exercise and MMR activation compared to the PL supplementation. A condition effect was observed for the changes in SV ( P = 0.002). SV was significantly decreased during static exercise in both conditions compared to the MMR activation. A repeated-measures two-way analysis of variance indicated a significant interactive effect (condition x supplement) in TPR. The static exercise and MMR substantially increased TPR after either GSE or PL supplement, but the increase in TPR was significantly attenuated after GSE supplementation ( P < 0.001, P = 0.008, respectively). Discussion The main finding from this study was that acute GSE supplementation substantially affected BP in response to SHE and MMR activation. SHE and MMR activation increased MAP in both GSE and PL conditions, but the increase was attenuated following the GSE supplementation. CO was significantly increased during static exercise and MMR activation with significant differences between two conditions. SHE had an increase in TPR in both conditions, but GSE supplementation had a lower increase compared to PL. Thus, the reduced MAP response occurred in concert with significant decreases in peripheral vascular constriction. Based on observations from the study, dietary supplementation with GSE decreased MAP to SHE and this reduction may be due to attenuated strength of the MMR. GSE Supplementation During Static Exercise This current study found that supplementation with GSE attenuated MAP responses to static exercise in the healthy young participants due to reduction in TPR (ES = 1.1) despite a larger increase in CO (ES = 0.98) compared to PL condition. The contribution of peripheral vasoconstriction plays a key role in regulating BP response to exercise. One potential explanation contributing to the depressed pressor response to SHE may be due to an improvement in endothelial function via increased production of NO (Kim et al., 2018 ). This phenomenon has been observed in in human normotensive and prehypertensives during dynamic exercise (Dillon et al., 2020 ; Shariffi et al., 2022 ). Collectively, findings indicate that GSE supplementation can attenuate BP response to exercise via an increase in vascular conductance. However, what is not clear, was whether this depressed reflex was due to changes in MMR or muscle mechanoreflex (components of EPR), or some combination of the two. GSE Supplementation During Muscle Metaboreflex PEMI has been used previously in humans to stimulate thin-fiber metaboreceptors in skeletal muscle (Kim et al., 2014 ; Michikami et al., 2002 ; Nishiyasu et al., 1998 ). The assumption underlying the use of muscular ischemia induced immediately following exercise was that this maneuver stimulates muscle afferents that contribute to the EPR. PEMI was an excellent non-invasive technique resulting in reflex-induced elevations in BP that were independent of concurrent effects of mechanoreceptor stimulation and central command that occur during exercise in humnas (Eldridge et al., 1981 ; Waldrop et al., 1996 ). Accordingly, this present study performed PEMI to only isolate the role of muscle metaboreceptors on exercise-induced BP response and then assessed whether GSE supplementation attenuated an increase in BP mediated by the MMR. The study demonstrated that MMR substantially increased MAP in both conditions, but the increase was much lower in GSE condition compared to PL. The reflex also increased TPR in both conditions with less increase in GSE condition. After GSE supplementation, a larger increase in CO occurred with MMR activation yet the pressor response was significantly lower. The lower pressor response may occur because with less contribution of an increase in CO (ES = 0.81), increase in peripheral vascular constriction was depressed (ES = 0.92) compared to PL. The MMR increases the pressor response via an increase in CO with little change in peripheral vascular conductance (Kim et al., 2005 ). However, GSE supplementation attenuates the reflex-induced pressor response through reduction in TPR despite an increase in CO. Effects of GSE Supplementation on Peripheral Vasoconstriction Previous studies reported that static exercise-induced MMR activation increased muscle sympathetic nerve activity (MSNA) in human subjects (Hansen et al., 1994 ; Jellema et al., 1999 ). It would be assumed that GSE supplementation can contribute to a reduction in MSNA to contracting skeletal muscles and in turn decrease peripheral vasoconstriction, since an increase in NO production via dietary supplementation has been known to decrease MSNA (Notay et al., 2017 ). However, the findings of the present study need to be viewed within the context of limitations because the MSNA in response to MMR activation was not recorded. Another study assessed the effects of GSE supplementation on exercising BP and peripheral vasoconstriction in prehypertensive individuals and reported that the supplement decreased exercise-induced BP response via reduction in peripheral vasoconstriction due, partially, to endothelium-dependent vasodilation. These findings indicate that GSE supplementation plays an important role in decreasing BP to MMR activation via increased peripheral vascular conductance mediated by possibly improved endothelial function (Kim et al., 2018 ). Limitations of the Study The current study was limited by the fact that MSNA was not measured to determine the effects of GSE on peripheral vasoconstriction during static exercise and PEMI. It has been reported that an increase in NO production induced by dietary supplementation decreased MSNA during exercise in normotensive individuals (Notay et al., 2017 ) and NO plays an important role in altering sympathetic vasoconstriction in the exercising skeletal muscle (Chavoshan et al., 2002 ). Furthermore, evidence indicated that endothelium-dependent flow-mediated vasodilation makes a small contribution to peripheral vascular conductance during MMR activation (Senador et al., 2017 ). Thus, increased NO bioavailability may play a key role in modulating sympathoexcitation observed during MMR activation. However, the inability to measure MSNA in response to MMR activation in the current study limits to conclude whether GSE supplementation decreases peripheral vasoconstriction via reduction in sympathetic output or an increase in the production of NO. It has established that blood pressure fluctuates during the phases of the menstrual cycle (Choi et al., 2013 ). Accordingly, this study was conducted during late follicular menstrual phases with 3-day washout periods to minimize effects of the menstrual cycle on resting BP. We found that there were no differences in resting BP between two conditions. In conclusion, the current study demonstrated that acute GSE supplementation reduced the increases in MAP in normotensive young adults during SHE and PEMI. Depressed MAP responses occurred by decreased peripheral vasoconstriction despite an increase in CO. Thus, attenuated BP responses to SHE can likely derive from altered strength of MMR. 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The Korean journal of physiology & pharmacology: official journal of the Korean Physiological Society and the Korean Society of Pharmacology, 17(6), 499–503. Ghimire K., Altmann H.M., Straub A.C., Isenberg J.S. 2017. Nitric oxide: what’s new to NO? Am J Physiol Cell Physiol 312: C254-C262 Hietanen E. 1984. Cardiovascular responses to static exercise. Scandinavian journal of work, environment & health, 10(6 Spec No), 397–402. Hureau, T. J., Weavil, J. C., Thurston, T. S., Wan, H. Y., Gifford, J. R., Jessop, J. E., Buys, M. J., Richardson, R. S., & Amann, M. (2019). Pharmacological attenuation of group III/IV muscle afferents improves endurance performance when oxygen delivery to locomotor muscles is preserved. Journal of applied physiology (Bethesda, Md.: 1985), 127(5), 1257–1266. Maeda S., Iemitsu M., Miyauchi T., Kuno S., Matsuda M., Tanaka H. 2005. Aortic stiffness and aerobic exercise: mechanistic insight from microarray analyses. Med Sci Sports Exerc 37: 1710–1716. Murohara T., Asahara T. 2002. Nitric oxide and angiogenesis in cardiovascular disease. Antioxid Redox Signal 4: 825–831. Murphy, R. M., Watt, M. J., & Febbraio, M. A. (2020). Metabolic communication during exercise. Nature metabolism, 2(9), 805–816. Romero, S. A., Minson, C. T., & Halliwill, J. R. 2017. The cardiovascular system after exercise. Journal of applied physiology (Bethesda, Md.: 1985), 122(4), 925–932. Tables Table 1. Physical characteristics of the subjects Variables Subjects (n=12) Height (cm) 169.6 ± 11.3 Weight (kg) 70.3 ± 13.3 Age (yrs) 24.6 ± 3.4 BMI (kg/m 2 ) 24.3 ± 3.6 Resting SBP (mmHg) 112.9 ± 3.9 Resting DBP (mmHg) 72.1 ± 5.1 Resting HR (bpm) 68.7 ± 8.4 Values are expressed as means ± standard error. BMI: body mass index; SBP: systolic blood Pressure; DBP: diastolic blood pressure, HR: heart rate. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Aug, 2025 Read the published version in Sport Sciences for Health → Version 1 posted Editorial decision: Revision requested 31 Oct, 2024 Reviews received at journal 02 Oct, 2024 Reviews received at journal 30 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviewers agreed at journal 07 Sep, 2024 Reviewers invited by journal 06 Sep, 2024 Submission checks completed at journal 02 May, 2024 Editor assigned by journal 02 May, 2024 First submitted to journal 30 Apr, 2024 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. 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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-4349992","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":299621988,"identity":"3620a352-10f6-41f6-b275-5064bad936c3","order_by":0,"name":"Alvin Apilado","email":"","orcid":"","institution":"California Baptist University","correspondingAuthor":false,"prefix":"","firstName":"Alvin","middleName":"","lastName":"Apilado","suffix":""},{"id":299621989,"identity":"9856dbd9-f4da-48e6-9249-e2be1856dfdd","order_by":1,"name":"William Boyer","email":"","orcid":"","institution":"California Baptist University","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Boyer","suffix":""},{"id":299621990,"identity":"6d4067a8-a6c5-48d6-a873-9a561391de55","order_by":2,"name":"Trevor Gillum","email":"","orcid":"","institution":"California Baptist University","correspondingAuthor":false,"prefix":"","firstName":"Trevor","middleName":"","lastName":"Gillum","suffix":""},{"id":299621991,"identity":"b9ba8c35-5a73-4db2-9dc9-f7db9d011b35","order_by":3,"name":"Sean Sullivan","email":"","orcid":"","institution":"California Baptist University","correspondingAuthor":false,"prefix":"","firstName":"Sean","middleName":"","lastName":"Sullivan","suffix":""},{"id":299621992,"identity":"73d7ac42-9415-4b98-ba3b-d9913263c006","order_by":4,"name":"Andrew Harveson","email":"","orcid":"","institution":"California Baptist University","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Harveson","suffix":""},{"id":299621993,"identity":"c9858954-43e8-442f-bd8f-0410b7231ecf","order_by":5,"name":"Albert Lira","email":"","orcid":"","institution":"California Baptist University","correspondingAuthor":false,"prefix":"","firstName":"Albert","middleName":"","lastName":"Lira","suffix":""},{"id":299621994,"identity":"81918859-769b-478f-afc6-224d50574020","order_by":6,"name":"Jong-Kyung Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYBACxgY2hgMMFQwMfBIgrgEDgsSv5QwDAxtIywEDBgmCWoBqgfraYFoYiNDC3N6WeOjmPDt5NunmZ48/FNTVMbA3b5PA67CeYwcO525LNmyTOWZucMDgsAQDz7Ey/FpmpDcAtRxgbJNIMJM4YHBAgkEix4wILXMO2LdJpH8DaqmTYJB/Q0hLGtBhDQcS20CGHzBgBtrCQ0BLz7GEwznHkpPbZM6UG5wxOCzZxpNWbIFPi2F7m/HnnBo7237p9m0PKv7U8fOzH954A6+WBgSbDYnEA+SR2AQVj4JRMApGwQgFAEVkSZEyUR34AAAAAElFTkSuQmCC","orcid":"","institution":"California Baptist University","correspondingAuthor":true,"prefix":"","firstName":"Jong-Kyung","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2024-04-30 15:08:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4349992/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4349992/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11332-025-01499-3","type":"published","date":"2025-08-04T15:57:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56282781,"identity":"0c0f0b56-e082-4e29-8c15-aaf7706516ac","added_by":"auto","created_at":"2024-05-10 21:36:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":11853,"visible":true,"origin":"","legend":"\u003cp\u003ePeak 20-s average changes from rest in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) during static exercise and muscle metaboreflex in normotensive individuals. Black circle: GSE; open circle: PL. *\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, vs. PL\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4349992/v1/65ffe6519d09173e3d980457.png"},{"id":56282765,"identity":"8e990784-5aa3-4900-aed6-8ede56bc5d45","added_by":"auto","created_at":"2024-05-10 21:35:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120324,"visible":true,"origin":"","legend":"\u003cp\u003ePeak 20-s average changes from rest in systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) during static exercise and muscle metaboreflex in normotensive individuals. Symbols and bar same as Figure 1.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4349992/v1/2089725e5fd6ec97bc19a4d3.png"},{"id":88814134,"identity":"02aa5fd4-a3af-470a-b388-44ff78420eba","added_by":"auto","created_at":"2025-08-11 16:07:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":764230,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4349992/v1/c322d3ec-ad5f-43c0-8576-40e28af8aa65.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Acute Grape Seed Extract Supplementation on Muscle Metaboreflex in Healthy Young Individuals","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn conditions of inadequate oxygen supply induced by a mismatch between blood flow and metabolic demand, the exercise pressor reflex (EPR) adjusts the circulation to increase oxygen delivery to the contracting skeletal muscles (Kaufman \u0026amp; Hayes, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; O'Leary et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). It is well documented that the reflex evokes increases in sympathetic activity to the heart and skeletal muscles, resulting in increases in blood pressure (BP), heart rate (HR), and total peripheral resistance (TPR) via peripheral vasoconstriction (Grotle et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; McCloskey \u0026amp; Mitchell, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e1972\u003c/span\u003e; Mitchell et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e1983\u003c/span\u003e). The afferent arm of the reflex consists of group III and IV skeletal muscle afferents (Kaufman et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e1983\u003c/span\u003e). The group III afferents are activated mainly by mechanical stimuli at the onset of muscle contraction and group IV afferents respond predominantly to accumulated metabolites during exercise (Kaufman et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e1983\u003c/span\u003e; O'Leary et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). The cardiovascular adjustments induced by the mechanically sensitive and metabolically sensitive components are known as the muscle mechanorelfex and muscle metaboreflex (MMR), respectively.\u003c/p\u003e \u003cp\u003eAlthough the EPR plays an important role in regulating cardiovascular responses to exercise, there is abnormal physiological responses in individuals with hypertension, obesity, heart failure, and peripheral artery disease (Hammond et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Lee et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Mitchell, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Muller et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Particularly, exaggerated BP response to exercise is a prognostic indicator of cardiovascular disease risks such as hypertension, myocardial infarction, and stroke in individuals in an absence of coronary disease (Laukkanen \u0026amp; Kurl, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Nakashima et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Even though pathophysiology of exercise-induced hypertension response has not been fully elucidated, plausible mechanisms to explain this phenomenon is associated with an exaggerated increase in sympathetic activity, endothelial dysfunction, arterial stiffness, and increased angiotensin II concentration (Delaney et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Kim et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Qin \u0026amp; Li, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Tzemos et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Accordingly, early treatment may be warranted to prevent cardiovascular adverse events.\u003c/p\u003e \u003cp\u003eDietary intervention using nutritional supplements may be a potential approach for managing excessive sympathetic activity. An increase in nitric oxide (NO) bioavailability via dietary supplementation alters efferent sympathetic outflow. For example, a previous study demonstrated that acute dietary supplementation with beetroot juice reduced muscle sympathetic outflow at rest and during exercise in normotensive individuals (Notay et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Findings suggest that dietary therapy may represent a target to reduce central sympathetic overactivation induced by the MMR during exercise.\u003c/p\u003e \u003cp\u003eAn extract of grape seed has been manufactured via hydrolysis of specific enzymes, and the manufacturing process results in a grape seed extract (GSE) highly purified and rich in polyphenolic compounds (Meganatural BP; Polyphenolics, Madera, CA) (Shrikhande et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Studies has demonstrated that the extract lowers BP via an increase in peripheral vasodilation and this health effect is related to the activation of endothelial nitric oxide synthase (eNOS) and, in turn, production of nitric oxide (NO) (Qui\u0026ntilde;ones et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). This GSE consists of total phenolics (90\u0026ndash;93%), gallic acid (\u0026ge;\u0026thinsp;2%), and catechins and epicatechins (\u0026ge;\u0026thinsp;5%). The ingredients of phenolic compounds are 9% monomers, 69% oligomers, and 22% polymers as measured by high-performance liquid chromatography (HPL-C). However, even though the NO is known to reduce central sympathetic output and peripheral vasoconstriction, potential beneficial effects of this extract on exercising BP response evoked by the MMR in human subjects have not been revealed. Thus, this study was hypothesized that dietary supplementation with GSE reduces the BP response to the MMR in healthy young individuals.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e12 healthy, recreationally active participants (7 males, 5 females) aged between 18 and 30 years volunteered to participate in the study. All participants were informed of any potential risks that may or may not occur during their participation, along with being provided a written consent for them to read and sign. A health history was provided using the Physical Activity Readiness Questionnaire (PAR-Q) survey to determine the eligibility for this study. Prior to any study procedures, the participants completed the PAR-Q survey and signed an informed consent form. Exclusion criteria was as followed: taking medications that affected cardiovascular responses to exercise, musculoskeletal diseases, and cardiovascular diseases. All participants were asked to refrain from smoking, exercising, and ingesting caffeine and/or alcohol 24 hours prior to their lab visit. The current study was approved by the California Baptist University Institutional Review Board (107-2122-EXP). This study was registered in Clinicaltrials.gov (NCT05945771).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eExperimental Procedures\u003c/h2\u003e \u003cp\u003eAt first visit, the baseline data such as height (m) and weight (kg) were measured. Both measurements were used to calculate the body mass index (BMI) of the participant by using the following equation: kg/m\u003csup\u003e2\u003c/sup\u003e. The participants sat on a chair and quietly rested for at least 5 minutes with their back supported on a chair and both feet on the floor. After 5 minutes, resting BP was measured by a sphygmomanometer and BP cuff placed on the participant\u0026rsquo;s dominant arm. Next, to determine the relative exercise intensity of static handgrip exercise (SHE), maximal voluntary contraction (MVC) of the dominant forearm was performed via the handgrip dynamometer test twice at maximal effort for \u0026lt;\u0026thinsp;1s; the peak value was used as their MVC. The static exercise was performed at 30% of MVC (Kim et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUpon the start of the second and third visit, the participant quietly rested for 20 minutes before undergoing the SHE. The participant used their dominant hand to exert the amount of force that was to be determined based on their first visit\u0026rsquo;s relative exercise intensity while seated for 3\u0026ndash;5 minutes. They performed SHE by using the dominant hand at 30% MVC with visual feedback of the force via a mark on the display. Participants completed 3 min of static exercise followed by 2 min of post exercise muscular ischemia (PEMI). To isolate only the effect of the MMR, the dominant arm was occluded at 200 mmHg via an inflatable occlusion cuff for 2 min.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMeasurement of Hemodynamic Responses\u003c/h2\u003e \u003cp\u003eA noninvasive device was continuously used to measure HR, stroke volume (SV) and cardiac output (CO) via impedance cardiography at rest, and during static exercise and PEMI (Physio Flow, Manatec Biomedical, France)(Naylor et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Shariffi et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). To measure both HR and SV, two electrodes were placed on the left side of the neck, two electrodes were placed on the chest to measure the electrocardiography (ECG), and two electrodes were placed on the xiphoid process. This device was known to have good reliability and validity at rest and during submaximal steady-state exercise in individuals (Charloux et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Gordon et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). SBP and DBP were measured from the participant\u0026rsquo;s non-dominant arm at the last 30 seconds of each stage. Mean arterial BP (MAP) was calculated using the following formula: MAP = [(SBP \u0026ndash; DBP) x 1/3]\u0026thinsp;+\u0026thinsp;DBP. CO was measured using the following equation: CO\u0026thinsp;=\u0026thinsp;SV x HR. Total peripheral resistance (TPR) was measured using the following equation: TPR\u0026thinsp;=\u0026thinsp;MAP/CO.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSupplementations\u003c/h2\u003e \u003cp\u003eAll participants were randomly assigned via a double-blind, cross-over design to evaluate the effects of acute GSE supplementation on the MMR. All participants were randomly assigned and instructed to take GSE (300 mg, 2 capsules) or placebo (PL) (300 mg, 2 capsules containing starch) 2 hours before their laboratory visit. Both treatments looked identical to uphold the blinded aspect of the study between the participant and instructor. Each trial was separated by a 72-hour washout period, but no longer than 7 days.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SE. During SHE and the MMR, the peak 20-s average response for each variable were assessed just prior to the end of both contraction and PEMI. A two-way repeated measures ANOVA and Tukey\u0026rsquo;s post hoc test was used to compare the effects of GSE supplementation on hemodynamic responses (supplementations x conditions). Significant level was set at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. To calculate the sample size, a power test was used to assess the appropriate sample size of any statistically significant change in BP before and after supplementations (power\u0026thinsp;=\u0026thinsp;0.80) and it revealed the necessity for 10 participants. Effect size (ES) was calculated by Cohen\u0026rsquo;s D formula as the mean difference (between GSE and PL) divided by the pooled standard deviation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe characteristics of the participants were presented in Table\u0026nbsp;1. By study design, all participants had normal blood pressure and body mass index (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e indicates the absolute peak 20-s average changes from rest in SBP, DBP, and MAP in response to 3 min of SHE and 2 min of MMR activation after supplementation with GSE and PL. A repeated-measures two-way analysis of variance indicated a significant interactive effect (condition x supplement) in both SBP and DBP. The MMR and SHE substantially increased SBP after either GSE or PL supplement (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but the increase in SBP was significantly attenuated after GSE supplementation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.050, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011, respectively). The rise in DBP were significantly increased following PL treatment during only SHE compared to GSE treatment (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). A condition effect and a supplementation effect were observed for the changes in MAP (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, respectively). The MAP was significantly increased after PL supplementation during SHE and MMR activation compared to the GSE supplementation.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e indicates the absolute peak 20-s average changes from rest in HR, SV, CO and TPR in response to 3 min of SHE and 2 min of MMR activation after supplementation with GSE and PL. A condition effect and a supplementation effect were observed for the changes in HR and CO (HR: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030, respectively; CO: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021, respectively). The HR and CO were significantly increased after GSE supplementation during static exercise and MMR activation compared to the PL supplementation. A condition effect was observed for the changes in SV (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). SV was significantly decreased during static exercise in both conditions compared to the MMR activation. A repeated-measures two-way analysis of variance indicated a significant interactive effect (condition x supplement) in TPR. The static exercise and MMR substantially increased TPR after either GSE or PL supplement, but the increase in TPR was significantly attenuated after GSE supplementation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008, respectively).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main finding from this study was that acute GSE supplementation substantially affected BP in response to SHE and MMR activation. SHE and MMR activation increased MAP in both GSE and PL conditions, but the increase was attenuated following the GSE supplementation. CO was significantly increased during static exercise and MMR activation with significant differences between two conditions. SHE had an increase in TPR in both conditions, but GSE supplementation had a lower increase compared to PL. Thus, the reduced MAP response occurred in concert with significant decreases in peripheral vascular constriction. Based on observations from the study, dietary supplementation with GSE decreased MAP to SHE and this reduction may be due to attenuated strength of the MMR.\u003c/p\u003e\n\u003ch3\u003eGSE Supplementation During Static Exercise\u003c/h3\u003e\n\u003cp\u003eThis current study found that supplementation with GSE attenuated MAP responses to static exercise in the healthy young participants due to reduction in TPR (ES\u0026thinsp;=\u0026thinsp;1.1) despite a larger increase in CO (ES\u0026thinsp;=\u0026thinsp;0.98) compared to PL condition. The contribution of peripheral vasoconstriction plays a key role in regulating BP response to exercise. One potential explanation contributing to the depressed pressor response to SHE may be due to an improvement in endothelial function via increased production of NO (Kim et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). This phenomenon has been observed in in human normotensive and prehypertensives during dynamic exercise (Dillon et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Shariffi et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Collectively, findings indicate that GSE supplementation can attenuate BP response to exercise via an increase in vascular conductance. However, what is not clear, was whether this depressed reflex was due to changes in MMR or muscle mechanoreflex (components of EPR), or some combination of the two.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eGSE Supplementation During Muscle Metaboreflex\u003c/h2\u003e \u003cp\u003ePEMI has been used previously in humans to stimulate thin-fiber metaboreceptors in skeletal muscle (Kim et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Michikami et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Nishiyasu et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e1998\u003c/span\u003e). The assumption underlying the use of muscular ischemia induced immediately following exercise was that this maneuver stimulates muscle afferents that contribute to the EPR. PEMI was an excellent non-invasive technique resulting in reflex-induced elevations in BP that were independent of concurrent effects of mechanoreceptor stimulation and central command that occur during exercise in humnas (Eldridge et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e1981\u003c/span\u003e; Waldrop et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1996\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAccordingly, this present study performed PEMI to only isolate the role of muscle metaboreceptors on exercise-induced BP response and then assessed whether GSE supplementation attenuated an increase in BP mediated by the MMR. The study demonstrated that MMR substantially increased MAP in both conditions, but the increase was much lower in GSE condition compared to PL. The reflex also increased TPR in both conditions with less increase in GSE condition. After GSE supplementation, a larger increase in CO occurred with MMR activation yet the pressor response was significantly lower. The lower pressor response may occur because with less contribution of an increase in CO (ES\u0026thinsp;=\u0026thinsp;0.81), increase in peripheral vascular constriction was depressed (ES\u0026thinsp;=\u0026thinsp;0.92) compared to PL. The MMR increases the pressor response via an increase in CO with little change in peripheral vascular conductance (Kim et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). However, GSE supplementation attenuates the reflex-induced pressor response through reduction in TPR despite an increase in CO.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEffects of GSE Supplementation on Peripheral Vasoconstriction\u003c/h2\u003e \u003cp\u003ePrevious studies reported that static exercise-induced MMR activation increased muscle sympathetic nerve activity (MSNA) in human subjects (Hansen et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1994\u003c/span\u003e; Jellema et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). It would be assumed that GSE supplementation can contribute to a reduction in MSNA to contracting skeletal muscles and in turn decrease peripheral vasoconstriction, since an increase in NO production via dietary supplementation has been known to decrease MSNA (Notay et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). However, the findings of the present study need to be viewed within the context of limitations because the MSNA in response to MMR activation was not recorded. Another study assessed the effects of GSE supplementation on exercising BP and peripheral vasoconstriction in prehypertensive individuals and reported that the supplement decreased exercise-induced BP response via reduction in peripheral vasoconstriction due, partially, to endothelium-dependent vasodilation. These findings indicate that GSE supplementation plays an important role in decreasing BP to MMR activation via increased peripheral vascular conductance mediated by possibly improved endothelial function (Kim et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eLimitations of the Study\u003c/h2\u003e \u003cp\u003eThe current study was limited by the fact that MSNA was not measured to determine the effects of GSE on peripheral vasoconstriction during static exercise and PEMI. It has been reported that an increase in NO production induced by dietary supplementation decreased MSNA during exercise in normotensive individuals (Notay et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) and NO plays an important role in altering sympathetic vasoconstriction in the exercising skeletal muscle (Chavoshan et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). Furthermore, evidence indicated that endothelium-dependent flow-mediated vasodilation makes a small contribution to peripheral vascular conductance during MMR activation (Senador et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Thus, increased NO bioavailability may play a key role in modulating sympathoexcitation observed during MMR activation. However, the inability to measure MSNA in response to MMR activation in the current study limits to conclude whether GSE supplementation decreases peripheral vasoconstriction via reduction in sympathetic output or an increase in the production of NO. It has established that blood pressure fluctuates during the phases of the menstrual cycle (Choi et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Accordingly, this study was conducted during late follicular menstrual phases with 3-day washout periods to minimize effects of the menstrual cycle on resting BP. We found that there were no differences in resting BP between two conditions.\u003c/p\u003e \u003cp\u003eIn conclusion, the current study demonstrated that acute GSE supplementation reduced the increases in MAP in normotensive young adults during SHE and PEMI. Depressed MAP responses occurred by decreased peripheral vasoconstriction despite an increase in CO. Thus, attenuated BP responses to SHE can likely derive from altered strength of MMR. Consequently, this study suggested that dietary supplementation with GSE decreased the MMR-induced pressor response via a decrease in peripheral vasoconstriction.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eEach author has declared that they do not have a conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.A ., J.K.K: Conception and design of research and data analysis; A.A., L.A: performed experiments; B.W., T.G., S.S., A.H; interpreted results of experiments and edited and revised manuscript; A.A., J.K.K: drafted manuscript; A.A., B.W., T.G., S.S., A.H., A.L., J.K.K: approved final version of manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the volunteers for their earnest participation in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCharloux, A., Lonsdorfer-Wolf, E., Richard, R., Lampert, E., Oswald-Mammosser, M., Mettauer, B.,.. . 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Scandinavian journal of work, environment \u0026amp; health, 10(6 Spec No), 397\u0026ndash;402.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHureau, T. J., Weavil, J. C., Thurston, T. S., Wan, H. Y., Gifford, J. R., Jessop, J. E., Buys, M. J., Richardson, R. S., \u0026amp; Amann, M. (2019). Pharmacological attenuation of group III/IV muscle afferents improves endurance performance when oxygen delivery to locomotor muscles is preserved. Journal of applied physiology (Bethesda, Md.: 1985), 127(5), 1257\u0026ndash;1266.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaeda S., Iemitsu M., Miyauchi T., Kuno S., Matsuda M., Tanaka H. 2005. Aortic stiffness and aerobic exercise: mechanistic insight from microarray analyses. Med Sci Sports Exerc 37: 1710\u0026ndash;1716.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurohara T., Asahara T. 2002. Nitric oxide and angiogenesis in cardiovascular disease. Antioxid Redox Signal 4: 825\u0026ndash;831.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurphy, R. M., Watt, M. J., \u0026amp; Febbraio, M. A. (2020). Metabolic communication during exercise. Nature metabolism, 2(9), 805\u0026ndash;816.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRomero, S. A., Minson, C. T., \u0026amp; Halliwill, J. R. 2017. The cardiovascular system after exercise. Journal of applied physiology (Bethesda, Md.: 1985), 122(4), 925\u0026ndash;932.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"622\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"64.14790996784566%\" colspan=\"5\" valign=\"bottom\"\u003e\n \u003cp\u003eTable 1. Physical characteristics of the subjects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.897106109324758%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.897106109324758%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.057877813504824%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"46.69887278582931%\" valign=\"bottom\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eSubjects (n=12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.04669887278583%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e169.6 \u0026plusmn; 11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.04669887278583%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e70.3 \u0026plusmn; 13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.04669887278583%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eAge (yrs)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e24.6 \u0026plusmn; 3.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.04669887278583%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e24.3 \u0026plusmn; 3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.04669887278583%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eResting SBP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e112.9 \u0026plusmn; 3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.04669887278583%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eResting DBP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e72.1 \u0026plusmn; 5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"51.04669887278583%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eResting HR (bpm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.916264090177133%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.993558776167472%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e68.7 \u0026plusmn; 8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are expressed as means \u0026plusmn; standard error. BMI: body mass index; SBP: systolic blood\u003c/p\u003e\n\u003cp\u003ePressure; DBP: diastolic blood pressure, HR: heart rate.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"sport-sciences-for-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ssfh","sideBox":"Learn more about [Sport Sciences for Health](http://link.springer.com/journal/11332)","snPcode":"11332","submissionUrl":"https://submission.nature.com/new-submission/11332/3","title":"Sport Sciences for Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"grape seed extract, cardiac output, static exercise, muscle metaboreflex","lastPublishedDoi":"10.21203/rs.3.rs-4349992/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4349992/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eStudies demonstrated that grape seed extract (GSE) increases the production of nitric oxide (NO) and reduces central sympathetic output. However, limited data have reported regarding the potential beneficial effects of this extract on blood pressure (BP) to increased sympathetic activity induced by the muscle metaboreflex (MMR) activation. Accordingly, the aim of this study was to determine whether GSE supplementation could reduce the BP in response to static exercise and post exercise muscular ischemia (PEMI) in normotensive young adults. In 12 healthy subjects (7 male and 5 female, 24.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u0026nbsp;year), we compared acute effect of both GSE (600 mg) and placebo (PL: 600 mg) on changes from rest in systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) during static exercise (SE) and PEMI. Subjects completed 2 min of SE at 30% of maximal voluntary contraction (MVC) followed by 2 min of PEMI. MAP was significantly increased during SE and MMR in both conditions, but the rise was significantly attenuated following GSE supplementation compared to PL supplementation (20\u0026thinsp;\u0026plusmn;\u0026thinsp;2 mmHg vs. 25\u0026thinsp;\u0026plusmn;\u0026thinsp;2 mmHg). CO was significantly increased during SE and MMR in both conditions, but the rise was significantly higher in GSE treatment than PL treatment. TPR was significantly increased in both conditions, but the rise was significantly higher following PL treatment compared to GSE treatment (SE: 3.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 mmHg/L/min vs. 0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6 mmHg/L/min; MMR: 2.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 mmHg/L/min vs. 1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 mmHg/L/min). Our findings suggest that GSE is effective in reducing BP response mediated by the MMR activation. The current study may have potential clinical significance that this extract at least partially buffers an exaggerated BP response evoked during exercise in hypertensive individuals.\u003c/p\u003e","manuscriptTitle":"Effects of Acute Grape Seed Extract Supplementation on Muscle Metaboreflex in Healthy Young Individuals","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-10 21:19:25","doi":"10.21203/rs.3.rs-4349992/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-31T18:55:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-02T19:22:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-30T13:49:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286765531115810388345749088910575622659","date":"2024-09-09T10:58:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134108057506403983370797430151942018513","date":"2024-09-08T02:42:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-06T21:05:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-02T09:13:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-02T09:13:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Sport Sciences for Health","date":"2024-04-30T15:06:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sport-sciences-for-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ssfh","sideBox":"Learn more about [Sport Sciences for Health](http://link.springer.com/journal/11332)","snPcode":"11332","submissionUrl":"https://submission.nature.com/new-submission/11332/3","title":"Sport Sciences for Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5a3fd893-acce-4854-9d6e-2af5364009e5","owner":[],"postedDate":"May 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-11T16:00:52+00:00","versionOfRecord":{"articleIdentity":"rs-4349992","link":"https://doi.org/10.1007/s11332-025-01499-3","journal":{"identity":"sport-sciences-for-health","isVorOnly":false,"title":"Sport Sciences for Health"},"publishedOn":"2025-08-04 15:57:25","publishedOnDateReadable":"August 4th, 2025"},"versionCreatedAt":"2024-05-10 21:19:25","video":"","vorDoi":"10.1007/s11332-025-01499-3","vorDoiUrl":"https://doi.org/10.1007/s11332-025-01499-3","workflowStages":[]},"version":"v1","identity":"rs-4349992","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4349992","identity":"rs-4349992","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}