Decreased response with age of the cardiac catecholamine sensitive adenylate cyclase system

The cardiac beta-adrenergic coupled adenylate cyclase system was examined in young and old male Wistar rats. The concentration of binding sites for (-)3H-DHA in membranes prepared from cardiac ventricles was 21.1 +/- 2.78 (SD) fmoles/mg protein in 3-4 month old rats (young rats) and 31.2 +/- 2.20 fmoles/mg protein in 24 month old rats (old rats). The dissociation constant, KD was 4.3 +/- 1.8 nM and 6.7 +/- 1.7 nM for young and old rats, respectively. Various compounds were used to study the characteristics of activation of adenylate cyclase in homogenates from cardiac ventricles. Basal adenylate cyclase was reduced 30% in old animals compared to young (6.1 pmoles/min/mg protein in 24 month vs. 8.6 pmoles/min/mg protein in 3-4 month). (-)Isoproterenol (10(-5) M) alone stimulated adenylate cyclase greater than two-fold in young rats (10.6 pmoles/min/mg protein above basal) and this stimulation was 34% lower in old animals. GppNHp (100 microM), fluoride (10 mM), and forskolin (100 microM) activation of adenylate cyclase above basal was reduced 38, 37, and 34%, respectively, in the old animals. No significant changes between the two groups were noted in the apparent affinity of GppNHp either alone or in the presence of (-)isoproterenol nor in the affinities of catecholamine agonists for activation of cyclase. These results suggest a reduction in the amount of functional regulatory protein or possibly cyclase in 24 month old rat ventricular tissue compared to 3-4 month old tissue. However, this data does not rule out the possibility of altered molecular interactions of a full complement of regulatory protein(s) with beta-adrenergic receptor and/or catalytic adenylate cyclase.