Ca2+(-)dependent and Ca2+(-)independent vasorelaxation induced by cardiotonic phosphodiesterase inhibitors

Cardiotonic agents that belong to a group of phosphodiesterase inhibitors--vesnarinone, amrinone, enoximone, pimobendan, MS-857 and E-1020--inhibited the 35 mM KCl- and 10(-7) M norepinephrine-induced contractions of helical strips from rat thoracic aorta in a concentration-dependent manner. In the absence of extracellular Ca2+, 10(-7) M phorbol 12,13-dibutyrate caused a sustained contraction of the muscle strip without an increase in intracellular Ca2+ level ([Ca2+]i). The phorbol 12,13-dibutyrate-induced contractions in Ca2+(-)free buffer were also inhibited by the cardiotonic phosphodiesterase inhibitors. A cyclic GMP-inhibited cyclic nucleotide phosphodiesterase was partially purified from rat aorta and the activity of the phosphodiesterase was inhibited by the cardiotonic agents. The inhibitory effect of these agents on the KCl-, norepinephrine-and phorbol 12,13-dibutyrate-induced contractions showed good correlations to the concentrations of the agents producing 50% inhibition (IC50) of cyclic GMP-inhibited cyclic nucleotide phosphodiesterase. Vesnarinone inhibited the norepinephrine-induced contraction with a decrease in [Ca2+]i, but inhibited the phorbol 12,13-dibutyrate-induced contraction in Ca(2+)-free buffer without significant changes in [Ca2+]i. Dibutyryl cyclic AMP and NKH477 also inhibited the phorbol 12,13-dibutyrate-induced contraction in Ca(2+)-free buffer without significant changes in [Ca2+]i. The six cardiotonic phosphodiesterase inhibitors increased the cyclic AMP contents of the muscle strips. These results suggest that the inhibitory actions of these cardiotonic phosphodiesterase inhibitors on cyclic GMP-inhibited cyclic nucleotide phosphodiesterase may cause vasorelaxation through a decrease in [Ca2+]i and an inhibitory effect on a Ca(2+)-independent contractile process (or a decrease in Ca(2+)-sensitivity of contractile elements).