Rolipram reduces the inotropic tachyphylaxis of glucagon in rat ventricular myocardium.

Glucagon increases cardiac contractility through G(s) protein-coupled glucagon receptors, but the inotropic responses fade. The fade could be due to receptor desensitisation or to the action of phosphodiesterases (PDE), or to both mechanisms. We investigated the effects of the PDE4 inhibitor rolipram (1 microM) on the inotropic and cAMP-responses to glucagon in paced right ventricular strips of the rat heart. Responses to the partial agonist dobutamine, mediated through beta(1)-adrenoceptors, were studied for comparison. Glucagon increased contractility (-logEC(50)M=7.3 for maximum responses with E(max)=32% of the response to 9 mM Ca(2+)), but the responses tended to fade (-logEC(50)M=7.1 for faded responses with E(max)=11.5%). Dobutamine (-logEC(50)M=5.8, E(max)=56%) produced positive inotropic effects that did not fade. Rolipram did not affect basal contractility and cAMP levels. Rolipram enhanced the contractile responses to glucagon and reduced fade (-logEC(50)M=7.5 and 7.3 with E(max)=74% and 45% for maximum and faded responses respectively). The response to glucagon (0.1 microM) completely faded in the absence of rolipram, but only partially faded and then remained stable in the presence of rolipram (1 microM). Rolipram enhanced contractile responses to dobutamine (-logEC(50)M=6.0, E(max)=75%). Dobutamine (3 microM), but not glucagon (0.1 microM), increased tissue levels of cAMP. Consistent with the inotropic data, rolipram caused glucagon to augment cAMP and enhanced the effects of dobutamine. Thus, PDE4 activity limits the responses mediated through both glucagon receptors and beta(1)-adrenoceptors. PDE4-catalysed hydrolysis of cAMP contributes to the inotropic tachyphylaxis of glucagon.