CA2-DEPENDENT AND CA2+-INDEPENDENT VASORELAXATION INDUCED BY CARDIOTONIC PHOSPHODIESTERASE INHIBITORS()

Cardiotonic agents that belong to a group of phosphodiesterase inhibit ors - vesnarinone, amrinone, enoximone, pimobendan, MS-857 and E-1020 - inhibited the 35 mM KCl- and 10(-7) M norepinephrine-induced contrac tions of helical strips from rat thoracic aorta in a concentration-dep endent manner. In the absence of extracellular Ca2+, 10(-7) M phorbol 12,13-dibutyrate caused a sustained contraction of the muscle strip wi thout an increase in intracellular Ca2+ level ([Ca2+]i). The phorbol 1 2,13-dibutyrate-induced contractions in Ca2+-free buffer were also inh ibited by the cardiotonic phosphodiesterase inhibitors. A cyclic GMP-i nhibited cyclic nucleotide phosphodiesterase was partially purified fr om rat aorta and the activity of the phosphodiesterase was inhibited b y the cardiotonic agents. The inhibitory effect of these agents on the KCl-, norepinephrine-and phorbol 12,13-dibutyrate-induced contraction s showed good correlations to the concentrations of the agents produci ng 50% inhibition (IC50) Of cyclic GMP-inhibited cyclic nucleotide pho sphodiesterase. Vesnarinone inhibited the norepinephrine-induced contr action with a decrease in [Ca2+]i, but inhibited the phorbol 12,13-dib utyrate-induced contraction in Ca2+-free buffer without significant ch anges in [Ca2+]i. Dibutyryl cyclic AMP and NKH477 also inhibited the p horbol 12,13-dibutyrate-induced contraction in Ca2+-free buffer withou t significant changes in [Ca2+]i. The six cardiotonic phosphodiesteras e inhibitors increased the cyclic AMP contents of the muscle strips. T hese 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 Ca2+-independent contractile process (or a decrease in Ca2+-sensitivity of contractile elements).