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).


CONCLUSIONS
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.
Mitchell
Anna
A
Department of Nephrology and Hypertension, Essen University Hospital, Germany.
Lückebergfeld
Birte
B
Bührmann
Sandra
S
Rushentsova
Uljana
U
Nürnberger
Jens
J
Siffert
Winfried
W
Schäfers
Rafael F
RF
Philipp
Thomas
T
Wenzel
René R
RR
D000328:Adult; D000804:Angiotensin II / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins / Q000235:genetics / Q000502:physiology; D005260:Female; D005838:Genotype; D006225:Hand / Q000098:blood supply; D006439:Hemodynamics / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D010666:Phenylpropionates / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology; D012867:Skin / Q000098:blood supply
D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; C454420:G-protein beta3 subunit; D018377:Neurotransmitter Agents; D010666:Phenylpropionates; D011743:Pyrimidines; D000804:Angiotensin II; C107831:darusentan; D020962:Heterotrimeric GTP-Binding Proteins