Muscarinic antagonism of the effects of phosphodiesterase inhibitor (methylisobutylxanthine) in embryonic chick ventricle.

Methylisobutylxanthine (MIX) augmented contractions and Ca++-dependent action potentials in ventricles isolated from embryonic and hatched chicks. Acetylcholine (ACh) inhibited these effects of MIX. In ventricles from chicks on the 18th incubation day, cyclic AMP content was increased to about 150% of basal after 3 min in 3 X 10(-4) M MIX. ACh (10(-6) M) did not reduce the cyclic AMP accumulation caused by MIX, although the increase in twitch tension was abolished. However, 10(-4) M ACh blocked the MIX-induced increases in both twitch tension and cyclic AMP. We conclude, therefore, that ACh antagonizes the effects of MIX both by blocking the action of elevated cyclic AMP and in higher concentrations, also by inhibiting the accumulation of cyclic AMP. In homogenates of chick ventricles. ACh neither stimulated phosphodiesterase activity nor blocked the inhibition of phosphodiesterase by MIX. Therefore, inhibition of cyclic AMP accumulation by higher concentrations of ACh may result from an inhibition of adenylate cyclase activity. Since neither 10(-6) nor 10(-4) M ACh reduced basal cyclic AMP content, basal adenylate cyclase is presumably not affected by ACh. We speculate that MIX may indirectly increase adenylate cyclase activity by antagonizing an inhibitory effect of endogenous adenosine. Furthermore, ACh may interfere with this effect of MIX, thereby facilitating the inhibition of adenylate cyclase by adenosine.