Haemodynamic characterization of young normotensive men carrying the 825T-allele of the G-protein ß3 subunit

Abstract

A C825T polymorphism was recently identified in the gene for the G-protein beta3 subunit, the T-allele being associated with hypertension. To better understand the underlying pathophysiological mechanisms, we compared the haemodynamics of young healthy males with and without the T-allele. In three studies, subjects were investigated with regard to cardiac and vascular function at rest and following intravenous administration of the beta-adrenoceptor antagonist, propranolol, and the alpha2-adrenoceptor agonist, alpha-methylnoradrenaline, and with regard to local venous vasoconstriction in the dorsal hand vein in situ following infusion of the alpha2-adrenoceptor agonist, azepexol. alpha2-Adrenoceptor agonists were chosen as vasoconstrictor drugs since alpha2-adrenoceptors couple to pertussis toxin (PTX)-sensitive G-proteins and since in-vitro studies have demonstrated enhanced signal transduction of PTX-dependent pathways in the presence of the T-allele. Total peripheral resistance was determined as a parameter of vasoconstrictor tone and heart rate, stroke volume and systolic time intervals for cardiac function. T-allele carriers had a significantly elevated stroke volume and lower total peripheral resistance at baseline. After propranolol, their fall in stroke volume was significantly greater. During alpha-methylnoradrenaline infusion, elevation of total peripheral resistance was not increased relative to controls. Similarly, the constriction response of the dorsal hand vein to azepexol was not different. Our study does not support the idea of increased vasoconstrictor tone in T-allele carriers either at rest or during stimulation of alpha2-adrenoceptors. However, this allele may be associated with elevated cardiac stroke volume.

Ethnic and Genetic Determinants of Cardiovascular Response to the Selective α 2 -Adrenoceptor Agonist Dexmedetomidine

“…26 In population studies, the C825T variant has been variably associated with increased risk of hypertension, atherosclerosis, myocardial infarction, and stroke. 15 Although GNB3 genotype did not affect the vasoconstricting effect of peripherally acting ␣ 2 -agonists, mediated by vascular ␣ 2 -receptors, 27 the sympathoinhibitory response to the centrally acting ␣ 2 -agonist clonidine differed by GNB3 genotype: In keeping with the in vitro findings, a study in 30 White Europeans found that clonidine reduced blood pressure, total peripheral resistance, and plasma norepinephrine concentrations significantly more in carriers of the T825 allele than in noncarriers. 4 Our study included a similar number of C allele homozygotes and 4 times as many carriers of the T allele, and found no genotype effect on the centrally mediated dexmedetomidine responses.…”

G protein β3 polymorphism and hemodynamic and body composition phenotypes in the HERITAGE Family Study

“…There are no previous studies on the associations between the GNB3 C825T genotype and submaximal exercise hemodynamic phenotypes. However, Schafers et al (30) reported an elevated resting stroke volume and a greater fall in resting stroke volume in response to acute administration of propranolol, a ␤-adrenoceptor antagonist, in healthy young men carrying the GNB3 825T allele compared with the CC homozygotes.…”

Alpha 2 -Adrenergic Receptor–Induced Vascular Constriction in Blacks and Whites

“…We found that dexmedetomidine resulted in dose-dependent venoconstriction in the hand vein model, with a maximum of approximately 75%, which is greater than the maximum responses reported with clonidine (27% to 54%) 15,16,21 and the more specific ␣ 2 -AR agonist, azepexol (52% to 68%). 16,22 The sensitivity to dexmedetomidine among individuals varied considerably, resulting in a Ͼ1000-fold range in ED 50 . However, venous sensitivity in blacks and whites did not differ, indicating that increased ␣ 2 -AR sensitivity in blacks is unlikely to explain our previous observation that the reduction in blood pressure after clonidine was attenuated in blacks.…”