We evaluated the effect of glucagon on cardiac automaticity as well as the possible role of cyclic nucleotide phosphodiesterases (PDE) in regulating this effect. Concentration response curves for glucagon in the absence and in the presence of the non-selective PDE inhibitor IBMX were performed in the isolated right ventricle of the rat. We found that glucagon produces only a minor increase of ventricular automaticity (11.0+/-4.1, n=5) when compared to the full agonist of beta-adrenoceptor isoproterenol (182.2+/-25.3, n=7). However, IBMX enhances the maximal efficacy of glucagon on cardiac automaticity (11.0+/-4.1, in the absence and 45.3+/-3.2 in the presence of IBMX, n=5, P<0.05). These results indicate that PDE blunts proarrhythmic effects of glucagon in rat myocardium.