ADENOSINE ATTENUATION OF ISOPROTERENOL-STIMULATED ADENYLYL-CYCLASE ACTIVITY IS ENHANCED WITH AGING IN THE ADULT HEART

Interstitial levels and release of adenosine have been shown to be gre ater for aged adult hearts compared to young adult hearts. Furthermore , blockade of A(1) adenosine receptors in the aged adult heart prevent s the reduced contractile and metabolic response to isoproterenol. The aim of this study was to determine whether there is an enhanced antia drenergic effect of adenosine in the aged adult heart. Ventricular mem branes from young and aged adult hearts were incubated in the presence of isoproterenol (ISO) and phenylisopropyladenosine (PIA) either alon e or in combination. Basal and ISO-enhanced adenylyl cyclase activity were significantly reduced in the membranes from aged rats. PIA alone, at 0.1 nM to 100 mu M, had no direct effect on basal adenylyl cyclase activity in membranes from either group. In the presence of either 10 0 nM or 1 mu M ISO, 100 mu M PIA significantly attenuated ISO-enhanced adenylyl cyclase activity to a greater extent in the aged adult heart membranes (78 or 48% for the aged vs. 37 or 25% for the young). Moreo ver, in the presence of 100 nM ISO the IC50 for the PIA concentration response curve was shifted to the left for the aged ventricular membra nes as compared to the membranes from young adults (1.62x10(-7)M vs 1. 5x10(-6)M, aged vs young, respectively). The enhanced inhibition of ad enylyl cyclase is associated with an increase in adenosine A(1) recept or density (23.7+/-3.5 vs 14.7+/-1.7 fmol/mg, aged vs young) and K-d ( 6.1+/-1.7 vs 2.2+/-0.5 nM, aged vs young) in the aged adult heart memb ranes as determined by [H-3]DPCPX binding. These results suggest that the reduced response to catecholamines in the aged adult heart may be due, at least in part, to an enhanced expression of the antiadrenergic effect of adenosine on beta-adrenergic receptor mediated activation o f adenylyl cyclase.