Vascular beta-adrenergic receptor adenylyl cyclase system in maturation and aging

The objective of this study was to determine how maturation and aging affects beta (beta)-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 beta -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 G alpha(i)level. However, beta ARK1 levels were increased (55. 4+/-2.1 v. 40.8+/-0.4, arbitrary densitometry units) and G alpha(s)levels were decreased (29.5+/-0.8 v. 49.9+/-1.9, arbitrary densitometry units). Aging resulted in no change in beta -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 alpha(i)or beta ARK1, however, G alpha(s) was decreased. In summary, beta -AR-stimulated arterial vasorelaxation is depressed during maturation and aging. Since there is no change in beta -AR density but a decrease in G alpha(s)and in basal/stimulated AC activities, the defect in beta -AR signaling during maturation and aging is probably a post receptor defect, i.e. possibly in the receptor-G protein coupling.