Inotropic responses of the frog ventricle to dibutyryl cyclic AMP and 8-bromo cyclic GMP and related changes in endogenous cyclic nucleotide levels

Isolated frog ventricles were superfused with solutions containing either N⁶, O²-dibutyryl adenosine 3',5'-cyclic monophosphate (dibutyryl 3',5'-cyclic AMP) or 8-bromo guanosine 3',5'-cyclic monophosphate (8-br 3',5'-cyclic GMP) and changes in isometric twitch tension and in the levels of endogenous 3',5'-cyclic nucleotides were measured. The results show that dibutyryl 3',5'-cyclic AMP potentiates the twitch, whereas 8-br 3',5'-cyclic GMP depresses it. Both effects are dose-related. The magnitude of the decrease in contractile force produced by 8-br 3',5'-cyclic GMP, and of the increase caused by dibutyryl 3',5'-cyclic AMP, are each paralleled by quantitatively-equivalent changes in the ratio 3',5'-cyclic AMP: 3',5'-cyclic GMP. The effect of 8-br 3',5'-cyclic GMP on the twitch is associated with a marked reduction in endogenous 3',5'-cyclic AMP levels, which is linearly related to the increment in intracellular 3',5'-cyclic GMP (slope of regression line ± S.E.: ?10.4 ± 0.6 pmoles 3',5'-cyclic AMP·pmole^?1 increase in 3',5'-cyclic GMP). The entry of dibutyryl 3',5'-cyclic AMP into the fibres is accompanied by a relatively small change in intracellular 3',5'-cyclic GMP, in this case, an increase (slope of regression line ± S.E.: +0.018 ± 0.002 pmoles 3',5'-cyclic GMP·pmole^?1 increase in 3',5'-cyclic AMP). These results suggest that both 3',5'-cyclic nucleotides are normally involved in regulating contractility, 3',5'-cyclic AMP potentiating the twitch and 3',5'-cyclic GMP exerting a counter-action; and that 3',5'-cyclic GMP may constitute part of a feedback mechanism which serves to regulate 3',5'-cyclic AMP levels.