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.


CONCLUSIONS
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.
Mitchell
Anna
A
Department of Nephrology and Hypertension and Institute of Pharmacology, University of Duisburg-Essen Medical School, Essen, Germany. anna.mitchell@uni-essen.de
Rushentsova
Uljana
U
Siffert
Winfried
W
Philipp
Thomas
T
Wenzel
Rene R
RR
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D005838:Genotype; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D019332:Endothelin-1; C454420:G-protein beta3 subunit; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000068756:Valsartan; D020962:Heterotrimeric GTP-Binding Proteins; D014633:Valine; D009638:Norepinephrine