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

Abstract

To determine whether the phosphoinositol/Ca2+ pathway interacts with the adenylate cyclase/adenosine 3′,5′-cyclic monophosphate (cAMP) pathway in the cardiac κ-receptor, the effects of U-50488, a specific κ-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 κ-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+]ichelator. Abolition of U-50488-induced elevation of [Ca2+]iby 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+]iand forskolin-induced accumulation of cAMP. The results showed for the first time that κ-receptor stimulation may suppress cAMP accumulation via activation of the phosphoinositol/Ca2+ pathway in the rat heart.