Function of cyclic GMP in acetylcholine-induced contraction of coronary smooth muscle

Summary

Increasing evidence indicates that cyclic GMP is involved in smooth muscle relaxation by various nitrocompounds which stimulate guanylate cyclase. Since, however, rises in cGMP were also observed in association with contractile effects, the role of cGMP in acetylcholine-induced contraction was studied in isolated bovine coronary artery strips.

Concentration response experiments were performed with acetylcholine (ACh) in the absence and in the presence of a) the cGMP-phosphodiesterase inhibitor M & B 22,948, and of b) methylene blue which was found to inhibit NO-, and azide-induced stimulation of guanylate cyclase (Katsuki et al. 1977b), and changes in cGMP-levels (RIA) and in smooth muscle tone were monitored.

• 1. ACh (55 nM to 55 μM) concentration dependently raised cGMP up to the 4.4-fold control value concomitantly with, but slightly prior to its contractile effects.

• 2. In the presence of 370 μM M & B 22,948, cGMP-levels as well as their ACh-induced increases were 2–3 times higher than in its absence, whereas the contractile responses to ACh were diminished at normal (2.68 mM) K⁺ (DR=8.7) and —to a lesser extent — also at high (26.8 mM) K⁺-concentration (DR=2.2).

• 3. Methylene blue (50 μM) at normal K⁺ (2.68 mM) attenuated the ACh-induced rises in cGMP-levels (DR=4.4; lower maximum response) but potentiated the contractile effects (DR=4.0; higher maximum response). At high (26.8 mM) K⁺ the changes in dose ratios were less pronounced but the lower maximum rise in cGMP and the higher maximum contractile response were even more pronounced than at normal K⁺.

• 4. These results demonstrate that the rises in cyclic GMP-levels under the different conditions studied are inversely correlated with the magnitude of the contractile responses, suggesting that cGMP is likely to function as a physiologic negative feedback signal to limit and/or to reverse the contractile effects of ACh in smooth muscle.