Mechanisms underlying the inhibitory effect of dibutyryl cyclic AMP in vascular smooth muscle

Abstract

The mechanism by which dibutyryl cyclic AMP (db-cAMP) induces vasodilatation was examined in isolated rat aorta. The contraction induced by norepinephrine (NE) was more sensitive to the inhibitory effect of db-cAMP than that induced by high K +, and the contraction induced by lower concentrations of each stimulant was more sensitive to db-cAMP than that induced by higher concentrations. Db-cAMP at 10 μM inhibited the increases in muscle tension and cytosolic Ca 2+ level ([Ca 2+] i) without changing the [Ca 2+] i-tension relationship, suggesting that the inhibitory effect is mainly due to a decrease in [Ca 2+] i. A higher concentration (300 μM) of db-cAMP inhibited muscle tension more strongly than [Ca 2+] i suggesting that db-cAMP decreases Ca 2+ sensitivity of contractile elements. In contrast, 10 μM verapamil inhibited the NE-stimulated [Ca 2+] i more strongly than the NE-induced contraction. The verapamil-insensitive portion of the NE-stimulated [Ca 2+] i and contraction was inhibited by db-cAMP, suggesting that db-cAMP and verapamil act by different mechanisms. In Ca 2+-free solution, 1 μM NE induced transient increases in muscle tension and [Ca 2+] i. The transient contraction was inhibited by 1 mM db-cAMP more strongly than [Ca 2+] i. An activator of adenylate cyclase, forskolin, showed inhibitory effects similar to those of db-cAMP. The inhibitory effects of db-cAMP and forskolin were inversely proportional to [Ca 2+] i before the addition of these inhibitors. These results suggest that db-cAMP inhibits smooth muscle contraction by decreasing [Ca 2+] i and the Ca 2+ sensitivity of contractile elements, and that both of these effects are stronger when [Ca 2+] i is lower.