G Protein Alterations in Hypertension and Aging

Abstract

Abstract Defective vasodilator function could be important in the pathogenesis and/or maintenance of the hypertensive state and the predisposition of the elderly to hypertension. Impaired β-adrenergic–mediated vasodilation and reduced lymphocyte β-adrenergic activation of adenyl cyclase have been demonstrated both in aging and with hypertension. The cellular mechanisms responsible for these alterations remain unclear. To determine if these defects may be due to alterations in guanine nucleotide regulatory proteins (G proteins) that link receptor activation with effector function, we assessed (1) human lymphocyte adenyl cyclase activity, (2) stimulatory G proteins by cholera toxin–mediated [ 32 P]ADP ribosylation and, in hypertensive subjects, with α s -specific and β-subunit antisera, and (3) inhibitory G proteins by pertussis toxin–mediated [ 32 P]ADP ribosylation and, in older subjects, with α i1,2 - and β-subunit–specific antisera. Lymphocytes from older subjects and from hypertensive subjects demonstrated a comparable reduction in isoproterenol-stimulated adenyl cyclase. However, aluminum fluoride–stimulated activity was reduced only in lymphocytes from hypertensive subjects. Furthermore, aluminum fluoride–stimulated activity was inversely correlated with mean arterial pressure. In lymphocytes from younger hypertensive subjects, cholera toxin–mediated labeling was significantly reduced; however, stimulatory G protein labeling by immunodetection was unaltered. In lymphocytes from older subjects, cholera toxin–mediated labeling was not altered; however, pertussis toxin–mediated labeling was significantly increased. In contrast, inhibitory G protein labeling by immunodetection was unaltered. Overall, the study suggests alterations of G protein function in hypertension and aging. In both conditions, stimulation of adenyl cyclase is impaired. However, these defects are associated with divergent alterations in stimulatory and inhibitory G proteins.