The Arg389Gly Beta1-Adrenoceptor Polymorphism and Catecholamine Effects on Plasma-Renin Activity

ObjectivesThe purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (β1AR) genotype-dependent.BackgroundIn vitro Arg389Gly-β1AR polymorphism exhibits decreased receptor signaling.MethodsWe studied 10 male homozygous Arg389-β1AR subjects and 8 male homozygous Gly389β1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-β1AR. Subjects were infused with dobutamine (1 to 6 μg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed.ResultsWith regard to PRA, dobutamine increased PRA more potently in Arg389-β1AR versus Gly389-β1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-β1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-β1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-β1AR subjects.ConclusionsCodon 389 β1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, β1AR polymorphisms may be useful for predicting therapeutic responses to βAR-blocker treatment

Age-Dependent Changes in Cardiac Muscarinic Receptor Function in Healthy Volunteers

AbstractObjectives. This study was conducted to determine possible age-dependent changes in the responsiveness of human cardiac muscarinic receptors.Background. It is well known that the baroreflex activity decreases with aging. However, the mechanisms underlying this phenomenon are not completely understood at present.Methods. In six healthy young (mean [±SEM] age 26 ± 2 years) and six healthy older volunteers (mean age 60 ± 2 years), we determined 1) the effects of graded doses of atropine (bolus application, six doses, each for 20 min, range 0.03 to 0.96 mg) and the M1-cholinoceptor selective antagonist pirenzepine (bolus application, eight doses, each for 20 min, range 0.04 to 10 mg) on heart rate, blood pressure and systolic time intervals (as measure of inotropism); and 2) the baroreflex activity by assessing the bradycardic response to phenylephrine.Results. Atropine and pirenzepine caused biphasic effects on heart rate: At lower doses (<0.12 mg for atropine, <5 mg for pirenzepine) they decreased heart rate, whereas at higher doses they increased heart rate. Heart rate decreases induced by both antimuscarinic drugs were significantly larger in the young volunteers than in the older volunteers, whereas heart rate increases were not significantly different for both drugs. Atropine and pirenzepine did not significantly affect blood pressure and systolic time intervals. Infusion of graded doses of phenylephrine (four doses ranging from 0.1 to 1.0 μg/kg body weight per min for 15 min each) caused a higher increase in systolic blood pressure and a smaller decrease in heart rate at each dose in the older volunteers than in the young volunteers. The slopes of the regression lines were 16 ± 2.3 ms/mm Hg for the young and 6 ± 0.5 ms/mm Hg for the older volunteers (p < 0.01).Conclusions. Human cardiac muscarinic receptor activity is diminished with increasing age; such decreased cardiac muscarinic receptor activity could contribute to the decrease in baroreflex activity with aging. In contrast, antimuscarinic drugs seem to have no effect on human cardiac contractility.(J Am Coll Cardiol 1997;29:187–93)