SUPPRESSION OF CAMP BY PHOSPHOINOSITOL CA2+ PATHWAY IN THE CARDIAC KAPPA-OPIOID RECEPTOR/

To determine whether the phosphoinositol/Ca2+ pathway interacts with t he adenylate cyclase/adenosine 3',5'-cyclic monophosphate (cAMP) pathw ay in the cardiac kappa-receptor, the effects of U-50488, a specific k appa-receptor agonist, on the intracellular Ca2+ concentration ([Ca2+] (i)) and forskolin-induced accumulation of cAMP in rat ventricular myo cytes were determined after interference of the phosphoinositol/ Ca2pathway. U-50488 suppressed the forskolin-induced accumulation of cAMP and elevated [Ca2+](i), which were blocked by norbinaltorphimine, a s pecific kappa-receptor antagonist, and pertussis toxin. The effects of U-50488 were qualitatively similar to those of A-23187, a Ca2+ ionoph ore, but opposite to those of ,2-bis(2-aminophenoxy)ethane-N,N,N',N'-t etraacetic acid (BAPTA)-acetoxymethyl ester (AM), a [Ca2+](i) chelator . Abolition of U-50488-induced elevation of [Ca2+](i) by BAPTA-AM also abolished the effect of U-50488 on forskolin-induced accumulation of cAMP. Inhibition of the phospholipase C by specific inhibitors, U-7312 2 and neomycin, abolished the effects of U-50488 on both [Ca2+](i) and forskolin-induced accumulation of cAMP. The results showed for the fi rst time that kappa-receptor stimulation may suppress cAMP accumulatio n via activation of the phosphoinositol/Ca2+ pathway in the rat heart.