Sympathetic potentiation of cyclic ADP-ribose formation in rat cardiac myocytes

We examined the role of cyclic ADP-ribose (cADP-ribose) as a second messeng er downstream of adrenergic receptors in the heart after excitation of symp athetic neurons. To address this question, ADP-ribosyl cyclase activity was measured as the rate of [H-3]cADP-ribose formation from [H-3]NAD(+) in a c rude membrane fraction of rat ventricular myocytes. Isoproterenol at 1 mu M increased ADP-ribosyl cyclase activity by 1.7-fold in ventricular muscle; this increase was inhibited by propranolol, The stimulatory effect on the c yclase was mimicked by 10 nM GTP and 10 mu M guanosine 5'-3-0(thio)triphosp hate, whereas 10 mu M GTP inhibited the cyclase, Cholera toxin blocked the activation of the cyclase by isoproterenol and GTP. The above effects of is oproterenol and GTP in ventricular membranes were confirmed by cyclic GDP-r ibose formation fluorometrically, These results demonstrate the existence o f a signal pathway from beta-adrenergic receptors to membrane-bound ADP-rib osyl cyclase via G protein in the ventricular muscle cells and suggest that increased cADP-ribose synthesis is involved in up-regulation of cardiac fu nction by sympathetic stimulation.