Relaxant mechanisms of cyclic AMP-increasing agents in porcine coronary artery.

We investigated the relaxant mechanisms of the cyclic AMP (cAMP)-increasing agents, isoproterenol, T-0509, forskolin and 3-isobutyl-1-methylxanthine (IBMX), on porcine coronary arteries contracted with U46619 (300 nM), a thromboxane A2 analogue, or 30 mM KCl, by measuring force simultaneously with intracellular Ca2+ concentration ([Ca2+]i) or cAMP and cyclic GMP (cGMP) levels. In U46619-contracted arteries, these agents decreased [Ca2+]i and force of contraction to almost the same extent in a concentration-dependent manner, whereas in KCl-contracted arteries these agents, except IBMX at higher concentrations, produced a relaxation with little change in [Ca2+]i. These agents all elevated tissue cAMP levels, and in addition, IBMX at higher concentrations increased cGMP levels. In Ca(2+)-free medium, these agents produced a concentration-dependent inhibition of Ca2+ release from intracellular Ca2+ stores induced by U46619 but not by 25 mM caffeine. Isoproterenol at a high concentration (3 microM) transiently decreased [Ca2+]i but steadily relaxed KCl-contracted arteries. This decrease in [Ca2+]i, but not the relaxation was inhibited by ryanodine and caffeine treatments. These results suggest that the relaxant mechanism of these agents on KCl-contracted arteries is mainly due to phosphorylation of myosin light chain kinase via cAMP-dependent protein kinase, resulting in a reduction of the Ca2+ sensitivity of contractile elements. Their relaxant mechanism in U46619-contracted arteries seems due to the inhibition of signal transduction of the agonist, resulting in a decrease in [Ca2+]i and inhibition of the Ca2+ sensitization.