The angiotensin II receptor antagonist valsartan inhibits endothelin 1-induced vasoconstriction in the skin microcirculation in humans in vivo: influence of the G-protein beta3 subunit (GNB3) C825T polymorphism.

OBJECTIVE: We investigated the influence of angiotensin II receptor blockade on angiotensin II-induced, endothelin 1 (ET-1)-induced, and norepinephrine-induced vasoconstriction to further characterize interactions of the 3 major pressor systems. ET-1, angiotensin II, and norepinephrine act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to angiotensin II antagonism in the presence of ET-1, norepinephrine, and angiotensin II. METHODS: Twenty-five healthy men (mean age, 28.6 +/- 4 years; n = 14 CC, n = 9 CT, and n = 2 TT) were included in a double-blind, randomized, placebo-controlled crossover study. We used a laser Doppler imager to evaluate skin perfusion changes after injection of ET-1, angiotensin II, and norepinephrine (10(-18), 10(-16), and 10(-14) mol) after oral intake of the angiotensin II receptor antagonist valsartan (80 mg) or placebo. Data were analyzed with ANOVA or t test and are expressed as arbitrary perfusion units (PU) (mean +/- SEM). RESULTS: Valsartan abolished angiotensin II-induced vasoconstriction and, more importantly, also ET-1-induced vasoconstriction in the skin microcirculation (ET-1 placebo versus valsartan, - 33 +/- 10 PU versus +33 +/- 21 PU for CC [P = .02] and -71 +/- 25 PU versus +108 +/- 21 PU for CT/TT [P < .001]). For both ET-1 and angiotensin II, valsartan effects were greater in GNB3 835T-allele carriers (P = .007 and P = .03 for ET-1 and angiotensin II, respectively, for CC versus CT/TT). Norepinephrine-mediated constriction was not influenced by valsartan. These effects were independent of blood pressure. CONCLUSION: Our results indicate that the renin-angiotensin system may significantly contribute to ET-1-mediated microvascular responses. Valsartan inhibited local vasoconstriction to angiotensin II and ET-1 to a greater degree in carriers of the GNB3 825T allele, which adds to data from earlier studies implicating the C825T polymorphism as a pharmacogenetic marker for drug effects.

Clonidine lowers blood pressure by reducing vascular resistance and cardiac output in young, healthy males.

PURPOSE: Clonidine is a classical sympatholytic drug that is widely used for the treatment of hypertension. Experimental and clinical studies suggest that Clonidine may activate baroreflex. The aim of this study was to determine the hemodynamic response to Clonidine under physiological conditions and to test the hypothesis that Clonidine would reduce cardiac output and blood pressure resulting in an increase in total peripheral resistance. METHODS: Clonidine's hemodynamic effect was evaluated in 28 young, healthy subjects after a single i.v. dose of 1 microg x kg(- 1). Impedance cardiography, systolic time intervals and pulse wave analysis were used to characterize myocardial and vascular function. RESULTS: Clonidine lowered blood pressure, heart rate, left ventricular ejection time, and pulse wave velocity and increased pre-ejection period. Stroke volume and cardiac output decreased gradually over the investigation time of 240 min. Central systolic blood pressure (SBP) was lowered to a larger extent than peripheral SBP. Total peripheral resistance was characterized by an immediate fall of short duration followed by a continuous rise above baseline after 120 min. Placebo did not have any significant effect on hemodynamic parameters. CONCLUSIONS: Clonidine's blood pressure lowering effect is mediated by both an immediate decrease in vascular resistance and a prolonged decrease in cardiac output, and Clonidine lowers central SBP more than peripheral SBP.

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 (ETA) 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 beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to ETA 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 Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg 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 [ED50] 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) (ED50 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.