Single inhibition of either PDE3 or PDE4 unmasks beta(2)-adrenoceptor-mediated inotropic and lusitropic effects in the left but not right ventricular myocardium of rat

摘要

Cyclic nucleotide phosphodiesterase (PDE)3 and PDE4 provide the major PDE activity in cardiac myocytes and shape beta(1)-adrenoceptor-dependent cardiac CAMP signaling but their role in regulating beta(2)-adrenoceptor-mediated responses is less well known. We investigated potential differences in PDE3 and PDE4 activities between right (RV) and left (LV) ventricular myocardium, and their role in regulating beta(2)-adrenoceptor effects. PDE3 activity in the microsomal fraction was lower in RV than in LV but was the same in the cytosolic fraction. However, no significant difference between RV and LV was found when the PDE4 activity was studied. beta(2)-adrenoceptor activation increased inotropism and lusitropism in LV when measured in the presence of either the PDE3 inhibitor cilostamide, the PDE4 inhibitor rolipram or a nonselective PDE inhibitor IBMX. However, the joint inhibition of both PDE3 and PDE4 was necessary in RV to uncover beta(2)-adrenoceptor-induced inotropic and lusitropic effects. Our results indicate different regulation of beta(2)-adrenoceptor-mediated contractility by PDE3 and PDE4 in RV and LV of the rat heart. In the case of PDE3 due to a different contribution of the enzyme in the microsomal fraction whereas in the case of PDE4 it can be attributed to differences in the intracellular distribution and coupling to beta(2)-adrenoceptors. (C) 2015 Elsevier B.V. All rights reserved.