Habitual Exercise and ETB Receptor Responses in Postmenopausal Women

Abstract

Age‐related declines in endothelial function can be reversed with habitual exercise (HEx) in older men by attenuating the vasoconstricting effects of endothelin‐1 (ET‐1), attributable in part by enhanced ETA receptor activity. Our laboratory has recently demonstrated that ET‐1 contributes to age‐related endothelial dysfunction in postmenopausal women (PMW) via the ETB receptor (ETBR). Although there is evidence for sex‐specific differences in ET‐1 receptor activity with aging, the impact of habitual exercise (HEx) on ET‐1 receptor responses in PMW has yet to be established.PURPOSETo test the hypothesis that ETBR responses would be attenuated in HEx PMW.METHODSIn a retrospective analysis, 30 PMW were grouped by self‐reported weekly exercise. We measured vasodilatory responses to local heating of the skin (laser Doppler flowmetry) during microdialysis perfusions of lactated Ringer’s (Control) and ETBR blockade (BQ‐788, 300nM) in 15 low (LEx: 2±2 d/wk, 57±4 yrs) and 15 high (HEx: 6±1 d/wk, 60±5 yrs) frequency exercisers. Cutaneous vascular conductance (CVC) was calculated during the plateau phase of local heating (42°C), and normalized to maximal vasodilation achieved by perfusion of sodium nitroprusside (28mM) and heating to 43°C. We analyzed the impact of weekly exercise frequency on vasodilatory responses to ETBR blockade using a two‐way ANOVA. Data presented are mean ± standard deviation.RESULTSGroups were well‐matched for body mass index (BMI) (LEx: 25±4 vs HEx: 24±2 kg/m2, P=0.31), resting heart rate (LEx: 60±8 vs HEx: 54±9 bpm, P=0.14), and resting mean arterial pressure (LEx: 90±10 vs HEx: 90±8 mmHg, P=0.96). Microvascular endothelial function was similar between LEx (control: 87±9 %CVCmax) and HEx (control: 88±6 %CVCmax, P=0.86). ETBR blockade improved vasodilation in LEx (BQ‐788: 93±7 %CVCmax, P=0.01 vs. control) but not in HEx (BQ‐788: 91±7 %CVCmax, P=0.11). To account for differences in age and time since menopause, we performed a sub‐analysis of age and BMI‐matched early PMW (<5 years since menopause) PMW (LEx, n=4: 53±2 yrs, 24±4 kg/m2; HEx, n=5: 53±3 yrs, 23±2 kg/m2). This sub‐analysis revealed a similar trend of enhanced vasodilation during ETBR blockade in LEx (control: 88±3 vs BQ‐788: 96±4 %CVCmax) but not HEx PMW (control: 87±6 vs BQ‐788: 85±13 %CVCmax; drug*exercise, P=0.07).CONCLUSIONBlocking ETBR improved microvascular endothelial function in LEx, indicating a removal of the vasoconstricting effects of ETBR in LEx but not HEx PMW. Therefore, these data suggest that exercise may attenuate ETBR‐mediated vasoconstriction in PMW. Additional data are needed to determine the impact of exercise on ETA receptor responses in PMW.Support or Funding InformationSupported by NIH R01 HL 146558, P20 GM 113125, AHA 16SDG30700015, and University of Delaware Research Foundation