Suppression of cAMP by phosphoinositol/Ca2+ pathway in the cardiac kappa-opioid receptor

To determine whether the phosphoinositol/Ca2+ pathway interacts with the adenylate cyclase/adenosine 3',5'-cyclic monophosphate (cAMP) pathway in the cardiac kappa-receptor, the effects of U-50488, a specific kappa-receptor agonist, on the intracellular Ca2+ concentration ([Ca2+]i) and forskolin-induced accumulation of cAMP in rat ventricular myocytes were determined after interference of the phosphoinositol/Ca2+ pathway. U-50488 suppressed the forskolin-induced accumulation of cAMP and elevated [Ca2+]i, which were blocked by norbinaltorphimine, a specific kappa-receptor antagonist, and pertussis toxin. The effects of U-50488 were qualitatively similar to those of A-23187, a Ca2+ ionophore, but opposite to those of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic 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-73122 and neomycin, abolished the effects of U-50488 on both [Ca2+]i and forskolin-induced accumulation of cAMP. The results showed for the first time that kappa-receptor stimulation may suppress cAMP accumulation via activation of the phosphoinositol/Ca2+ pathway in the rat heart.