Interaction of phosphodiesterase inhibitor and isoproterenol in human and guinea-pig ventricular tissues and myocytes.

We studied the interaction of phosphodiesterase inhibitor and isoproterenol in human and guinea-pig ventricular muscle fibers and guinea-pig ventricular myocytes. In ventricular trabeculae obtained from the explanted hearts of 5 patients with dilated cardiomyopathy, isoproterenol (Iso, 10(-8)-10(-6)M) increased twitch force in a concentration-dependent manner. Isobutylmethyl-xanthine (IBMX, 3 x 10(-6)M) alone did not change significantly the twitch force but potentiated the effect of Iso and reduced the concentration for half maximal effect (EC50) of Iso from 140 to 18 x 10(-9)M. As compared to the diseased human heart tissues, papillary muscles obtained from 6 healthy guinea-pigs were much more sensitive to the positive inotropic action of Iso but less reactive to the potentiative effect of IBMX on Iso. The EC50 for the inotropic action of Iso (10(-9) approximately 10(-7)M) in the absence and presence of 3 x 10(-6)M IBMX were 28 and 15 x 10(-9)M, respectively. In 16 guinea-pig ventricular myocytes isolated enzymatically, L-type Ca currents (ICa,L) were recorded in K-free superfusate with whole-cell voltage-clamp technique. The increase in ICa,L induced by the lowest concentration (10(-9)M) of Iso was not significant. Those induced by 10(-8)M and 10(-7)M Iso were about the same (+108 +/- 29% and +75 +/- 20%, respectively). IBMX potentiated the effect of Iso. It is concluded that indeed the ventricular muscles obtained from the failing hearts are poorly responsive to the beta-adrenoceptor agonist. This defect could be corrected at least partially by the PDE inhibitor IBMX. However, the concentration-dependent inotropic and arrhythmogenic effects in guinea-pig ventricular muscle were not accompanied by a parallel increase in iCaL at high concentration of Iso(10(-7)M), suggesting involvement of other mechanisms such as actions on intracellular Ca2+ regulation induced by Iso.