血管紧张素II受体拮抗剂缬沙坦可抑制人体内皮素-1诱导的皮肤微循环血管收缩：G蛋白β3亚基（GNB3）C825T基因多态性的影响

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.

作者信息

Mitchell Anna, Rushentsova Uljana, Siffert Winfried, Philipp Thomas, Wenzel Rene R

机构信息

Department of Nephrology and Hypertension and Institute of Pharmacology, University of Duisburg-Essen Medical School, Essen, Germany.

出版信息

Clin Pharmacol Ther. 2006 Mar;79(3):274-81. doi: 10.1016/j.clpt.2005.11.008. Epub 2006 Feb 3.

DOI:10.1016/j.clpt.2005.11.008

PMID:16513451

Abstract

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.

摘要

目的

我们研究了血管紧张素II受体阻断对血管紧张素II诱导、内皮素-1（ET-1）诱导和去甲肾上腺素诱导的血管收缩的影响，以进一步明确这3种主要升压系统之间的相互作用。ET-1、血管紧张素II和去甲肾上腺素通过G蛋白偶联受体发挥作用，G蛋白β3亚基（GNB3）C825T多态性可能参与其中。我们研究了这种多态性对在ET-1、去甲肾上腺素和血管紧张素II存在的情况下血管紧张素II拮抗反应的影响。

方法

25名健康男性（平均年龄28.6±4岁；n = 14为CC型，n = 9为CT型，n = 2为TT型）纳入一项双盲、随机、安慰剂对照的交叉研究。我们使用激光多普勒成像仪评估口服血管紧张素II受体拮抗剂缬沙坦（80 mg）或安慰剂后注射ET-1、血管紧张素II和去甲肾上腺素（10⁻¹⁸、10⁻¹⁶和10⁻¹⁴ mol）后皮肤灌注的变化。数据采用方差分析或t检验进行分析，并以任意灌注单位（PU）表示（平均值±标准误）。

结果

缬沙坦消除了血管紧张素II诱导的血管收缩，更重要的是，也消除了皮肤微循环中ET-1诱导的血管收缩（ET-1：安慰剂组与缬沙坦组相比，CC型为-33±10 PU对+33±21 PU [P = 0.02]，CT/TT型为-71±25 PU对+108±21 PU [P < 0.001]）。对于ET-1和血管紧张素II，缬沙坦对GNB3 835T等位基因携带者的作用更大（ET-1和血管紧张素II分别为CC型与CT/TT型相比，P = 0.007和P = 0.03）。去甲肾上腺素介导的血管收缩不受缬沙坦影响。这些作用与血压无关。