Amir Snapir

Background: Dexmedetomidine, a selective alpha2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating alpha2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic alpha2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. Methods: The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. Results: The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. Conclusions: In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.

Common naturally occurring polymorphisms have been identified in the coding regions of the α1A-, α2B-, β1- and β2-adrenoceptor (AR) genes [α1A-AR R492C, α2B-AR insertion/deletion (I/D), β1-AR R389G, β2-AR G16R and β2-AR Q27E] and are associated with modified in vivo and in vitro functionality. We tested their possible effects on the haemodynamic responses to intravenous adrenaline (20, 40, 80 and 160ng/kg of body weight per min; 5min for each infusion rate) before and after β-blockade (propranolol) in 16 young healthy men. We monitored changes in heart rate, blood pressure (BP), ECG, coronary flow velocity and plasma adrenaline and noradrenaline. The Cys/Cys (CC) genotype of the α1A-AR R492C polymorphism was associated with a longer ECG PR interval before and during the adrenaline infusions. The deletion/deletion (D/D) genotype of the α2B-AR I/D polymorphism was associated with blunted coronary blood flow increases during the adrenaline infusion before β-blockade. The β1-AR R389G polymorphism was not associated with modified responses to infused adrenaline. Subjects carrying the Gly/Gly (GG) genotype of the β2-AR G16R polymorphism demonstrated increases in diastolic BP upon adrenaline infusion, whereas diastolic BP was decreased in the other genotype groups. These results suggest that, upon acute adrenaline infusion, the α2B-AR D/D genotype confers increased vasoconstriction and that the β2-AR GG genotype confers reduced vasodilatation.

Several recent studies have indicated that a C825T polymorphism in the gene encoding the G-protein β3 subunit is a significant risk factor for hypertension and obesity. In this study, we tested whether this polymorphism is associated with hypertension and obesity in white men. Population-based prospective cohort study. We followed a cohort of 903 men, aged 42–61 years at baseline, for an average time of 4.2 years. Genotyping was performed by polymerase chain reaction. The genotype distribution was in Hardy–Weinberg equilibrium: 514 (57%) had the CC genotype, 49 (5%) had the TT genotype and 340 (38%) were heterozygous (T:C = 0.24:0.76). There was no statistically significant difference between the genotype groups in respect to baseline and end of follow-up risk for hypertension or obesity, systolic or diastolic blood pressure, or body mass index. We conclude that the C825T polymorphism of the G-protein β3 subunit gene does not notably contribute to the development of hypertension or obesity, and is not a significant determinant for blood pressure and body mass index in white men.