Effects of systemic endothelin A receptor antagonism in various vascular beds in men: In vivo interactions of the major blood pressure–regulating systems and associations with the GNB3 C825T polymorphism

Objective We used the orally available endothelin A (ET A ) receptor antagonist darusentan to characterize interactions between the major blood pressure‐regulating systems in healthy men. Mediators of the endothelin system, the sympathetic nervous system, and the renin‐angiotensin system act via G protein‐coupled receptors with a possible involvement of the G‐protein β3 subunit ( GNB3 ) C825T polymorphism. We studied the influence of this polymorphism on the responses to ET A antagonism in the presence of endothelin 1 (ET‐1), norepinephrine (NA), and angiotensin II (ANGII). Methods Thirty‐seven individuals were included in a randomized, double‐blind, placebo‐controlled, crossover trial with 100 mg darusentan. Systemic hemodynamics and plasma ET‐1, NA, and ANGII concentrations were assessed. Local studies were performed in the dorsal hand veins (n = 18) and skin microcirculation (n = 12), respectively. Results Darusentan lowered systolic and diastolic blood pressure ( P < .001 versus placebo) without any differences according to genotype (mean maximum Δ systolic blood pressure, −7 ± 2 mm Hg for CT/TT versus −5 ± 3 mm Hg for CC, P = .37; mean maximum Δ diastolic blood pressure, −3 ± 2 mm Hg for CT/TT versus −4 ± 2 mm Hg for CC, P = .96). Venoconstriction to ET‐1 and NA was not affected by ET A blockade in either group; however, carriers of the 825T allele demonstrated a markedly enhanced venoconstriction to ET‐1 and NA (median effective concentration [ED 50 ] for ET‐1 after darusentan [placebo]: 2.5 ± 0.2 pmol/min for CT/TT [2.7 ± 0.3 pmol/min], P = .42; 3.9 ± 0.6 pmol/min for CC [4.6 ± 0.3 pmol/min], P = .42; P = .046 [ P = .0005] for CT/TT versus CC) (ED 50 for NA after darusentan [placebo]: 5.2 ± 1.2 ng/min for CT/TT [7.3 ± 1.2 ng/min], P = .20; 32.9 ± 7.1 ng/min for CC [19.7 ± 5.5 ng/min], P = .75; P = .0008 [ P = .026] for CT/TT versus CC). Darusentan dilated veins at baseline in CC homozygous subjects (+0.21 ± 0.05 mm, P = .004 versus placebo). Systemic ET A antagonism inhibited constriction to ET‐1 and also to NA and ANGII in the skin microcirculation without differences according to genotype (ET‐1, P = .017 for all individuals versus placebo; NA, P = .0005; and ANGII, P = .002). Conclusion GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men. However, it determined venoconstriction to exogenous ET‐1 and NA. Darusentan markedly inhibited not only ET‐1–induced but also NA‐induced and ANGII‐induced vasoconstriction in the skin microcirculation. In contrast, it had no effects on either ET‐1–mediated or NA‐mediated venoconstriction, indicating that, in the presence of high local ET‐1 concentrations, constrictive endothelin B receptors may be of greater importance in the venous vasculature than has been recognized so far. Clinical Pharmacology & Therapeutics (2004) 76 , 396–408; doi: 10.1016/j.clpt.2004.07.011