Vascular β -Adrenergic Receptor Adenylyl Cyclase System in Maturation and Aging

Abstract

M. A. Gaballa, A. D. Eckhart, W. J. Koch and S. Goldman. Vascular β -Adrenergic Receptor Adenylyl Cyclase System in Maturation and Aging. Journal of Molecular and Cellular Cardiology (2000) 32, 1745–1755. The objective of this study was to determine how maturation and aging affects beta (β)-adrenergic receptor (AR) control of arterial vasorelaxation. Left ventricular (LV) hemodynamics and arterial vasorelaxation in thoracic artery segments were studied in Brown Norway, Fisher 344 cross rats at 6 weeks, 6 months, and 23 months of age. We defined changes in maturation as occurring between 6 weeks and 6 months of age and changes in aging as occurring between 6 months and 23 months of age. With maturation, isoproterenol resulted in a downward shift in heart rate and an upward shift in both LV dP/dt and peripheral vascular resistance responses. Similar changes were noted with aging except for the downward shift in LV dP/dt isoproterenol response. There was a dose-dependent increase in arterial vasorelaxation in response to isoproterenol in all age groups, but the 6-week-old animals had a 5-fold (P<0.01) increase in vasorelaxation compared to other age groups. The isoproterenol-induced arterial vasorelaxation response was not altered by removal of the endothelium. The vasodilatory responses to nitroglycerin, acetylcholine, and adenosine were diminished (P<0.05) with aging. The vasorelaxation responses to forskolin and IBMX were unchanged with maturation and diminished with aging. Incubation of arterial rings in cholera toxin resulted in a reduction in relaxation only in arteries from 6-week-old rats. Maturation resulted in no change in β -AR density [20.2±0.7 v 18.5±0.5 fmol/mg protein, P=n.s., 6 weeks (n=2, 18 aortas were combined v 6-month-old rats)]. With maturation, there was no change in Gαi level. However, β ARK1 levels were increased (55.4±2.1 v 40.8±0.4, arbitrary densitometry units) and G αslevels were decreased (29.5±0.8 v 49.9±1.9, arbitrary densitometry units). Aging resulted in no change in β -AR density (15.3±1.7 v 18.5±0.5 fmol/mg membrane protein), but decreases in basal, isoproterenol-, naF-, and forskolin-stimulated AC activities. Compared to 6 week data, 23-month-old rats exhibited no change in either G αior β ARK1, however, G αswas decreased. In summary, β -AR-stimulated arterial vasorelaxation is depressed during maturation and aging. Since there is no change in β -AR density but a decrease in Gαs and in basal/stimulated AC activities, the defect in β -AR signaling during maturation and aging is probably a post receptor defect, i.e. possibly in the receptor-G protein coupling.