title: Enhanced vasoconstriction to endothelin-1, angiotensin II and noradrenaline in carriers of the GNB3 825T allele in the skin microcirculation.
abstract: Hypertension is associated with enhanced peripheral vascular resistance, which may be mediated by enhanced vasoconstriction. The impact of the recently detected G-protein beta3-subunit gene C825T polymorphism on the response to the major pressor mediators has been studied in vivo in the human microcirculation. We assessed the effects of endothelin-1 (ET-1), angiotensin II (AT), endothelin-antagonists (BQ-123 and BQ-788) and noradrenaline (NA, each 10-16-10-8 mol) on vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers (13 with CC genotype, 12 TC/TT genotype) using laser Doppler flowmetry. The effects of endothelium-derived vasodilation on NA-induced effects were studied using the NO-synthase inhibitor l-nitro-monomethyl-arginine (L-NMMA) and the alpha2-adrenoceptor-antagonist yohimbine (YO). ET-1, AT and NA caused a dose-dependent vasoconstriction (P < 0.001). In carriers of the 825T allele the response to ET-1, AT and NA was significantly enhanced leading to a shift to the left of the dose-response curve of up to two log units (ET-1: P < 0.001 vs. CC; AT: P < 0.01 vs. CC; NA: P < 0.05 vs. CC). After pretreatment with L-NMMA or YO, NA induced vasoconstriction was no longer different between subjects with the CC- and CT/TT genotypes. However, following combined pretreatment with both L-NMMA and YO, vasoconstriction to NA was significantly potentiated in carriers of the T-allele. Vasodilatation to an ETA-antagonist (BQ-123) was more pronounced in the CT/TT genotype, while ETB-antagonism (BQ-788) led to a more pronounced vasoconstriction in the CT/TT genotype (not significant vs. CC). Healthy, normotensive carriers of the 825T-allele have enhanced vasoconstriction to ET-1, AT and NA in the skin microcirculation. This enhanced vasoconstriction appears to be partially antagonized by an enhanced release of endothelium derived vasodilators mediated by the stimulation of endothelial alpha2-adrenoceptors. The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans.
authors.affiliation: Division of Nephrology & Hypertension, University Hospital, Essen, Germany. rene@rrwenzel.de
authors.forename: René R
authors.initials: RR
authors.lastname: Wenzel
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.forename: H
authors.initials: H
authors.lastname: Bruck
authors.forename: Thomas
authors.initials: T
authors.lastname: Philipp
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Schäfers
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000483:Alleles; D000804:Angiotensin II / Q000494:pharmacology*; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D021122:Protein Subunits; D012867:Skin / Q000098:blood supply*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; C454420:G-protein beta3 subunit; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D021122:Protein Subunits; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019323:omega-N-Methylarginine; D015016:Yohimbine; C086539:BQ 788; D019001:Nitric Oxide Synthase; D020962:Heterotrimeric GTP-Binding Proteins; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D009638:Norepinephrine