ETB receptor contribution to vascular dysfunction in postmenopausal women

Abstract

Endothelin-1 (ET-1) contributes to age-related endothelial dysfunction in men via the ET_A receptor. However, there are sex differences in the ET-1 system, and ET_B receptors are modulated by sex hormones. The purpose of this study was to test the hypothesis that ET_B receptors contribute to impaired vasodilatory function in postmenopausal women (PMW). We measured flow-mediated dilation (FMD) using ultrasound, and cutaneous nitric oxide-mediated vasodilation during local heating (42°C) via laser Doppler flowmetry in 18 young women (YW; 22 ± 1 yr) and 16 PMW (56 ± 1 yr). Cutaneous microdialysis perfusions of lactated Ringer (control), an ET_B receptor antagonist (BQ-788, 300 nM), and an ET_A receptor antagonist (BQ-123, 500 nM), were done through separate fibers, followed by perfusions of sodium nitroprusside (28 mM) and local heating to 43°C (max). Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flow/mean arterial pressure and expressed as a percent of maximal dilation. FMD (YW: 7.5 ± 0.5 vs. PMW: 5.6 ± 0.6%) and cutaneous vasodilation (YW: 93 ± 2 vs. PMW: 83 ± 4%CVC_max) were lower in PMW (both P < 0.05). Blockade of ET_B receptors decreased cutaneous vasodilation in YW (87 ± 2%CVC_max; P < 0.05 vs. control) but increased vasodilation in PMW (93 ± 1%CVC_max; P < 0.05 vs. control). ET_A receptor blockade had minimal effect in YW (92 ± 1%CVC_max) but increased cutaneous vasodilation in PMW (91 ± 2%CVC_max; P < 0.05 vs. control). In conclusion, ET_B receptors mediate vasodilation in YW, but this effect is lost after menopause. Impaired vasodilatory function in PMW is due in part to a loss of ET_B-mediated dilation.

Keywords: aging; cutaneous circulation; endothelial function; endothelin-1.

Fig. 1.

Measures of vasodilatory function using flow-mediated dilation (FMD, A) and local heating-induced plateau (B) expressed as cutaneous vascular conductance (CVC) in young women (YW) and postmenopausal women (PMW). *P < 0.05 vs. YW.

Fig. 2.

Cutaneous vasodilatory responses to local heating during cutaneous microdialysis perfusions of ET_B (BQ-788) and ET_A (BQ-123) receptor antagonists in YW (A) and PMW (B). *P < 0.05 vs. control.