Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

The cardiostimulant effects of CGP12177, mediated through a β 1 ‐adrenoceptor site with low affinity for (−)‐propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3‐selective inhibitor cilostamide (300 n M ) and PDE4‐selective inhibitor rolipram (1  μ M ) on the positive inotropic and cyclic AMP‐enhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat. CGP12177 (under (−)‐propranolol 200 n M ) only increased contractile force in the presence of either cilostamide or rolipram with −logEC 50 M 6.7 ( E max =23% over basal) and 7.1 ( E max =50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with −logEC 50 M=7.7 and E max =178%. The positive inotropic effects of noradrenaline (−logEC 50 M=6.9) were potentiated by rolipram (−logEC 50 M=7.4) but not by cilostamide (−logEC 50 M=7.0). In the presence of rolipram and (−)‐propranolol, noradrenaline (2  μ M ) and CGP12177 (10  μ M ) produced matching inotropic effects but failed to increase cyclic AMP levels. 20  μ M (−)‐noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram. Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low‐affinity β 1 ‐adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (−)‐noradrenaline interacts with the β 1 ‐adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.British Journal of Pharmacology (2006) 147 , 158–163. doi: 10.1038/sj.bjp.0706498