A DUAL-COMPONENT POSITIVE INOTROPIC EFFECT OF ENDOTHELIN-1 IN GUINEA-PIG LEFT ATRIA - A ROLE OF PROTEIN-KINASE-C

This study was designed to analyze the mechanism(s) underlying the pos itive inotropic effect (PIE) of endothelin-1 (ET-1) in the guinea pig left atrium. ET-1 exhibited a greater PIE at lower frequencies of paci ng and potentiated significantly the postrest contraction similar to i soproterenol. However, ET-1 prolonged the duration of a single contrac tion, whereas isoproterenol shortened it. ET-1 was similar to methyl 4 -(2-trifluoromethylphenyl)-pyridine-5-carboxylate in the prolonged dur ation of a single contraction but different from this drug in the forc e-frequency relationship. ET-1 at concentrations of 10 nM and higher c aused a dual-component PIE composed of an initial increasing phase (ea rly component) and a second greater positive inotropic phase (late com ponent). The early component was correlated to the ET-1 -induced prolo ngation of the duration of the action potential in the time course. Bo th nifedipine and ryanodine suppressed the late component much more th an the early component. ET-1 (greater-than-or-equal-to 3 nM) produced significant stimulation of phosphoinositide hydrolysis as measured by [H-3]inositol monophosphate accumulation. ET-1 was found to activate p rotein kinase C (PKC) instantaneously but transiently (evaluated by th e translocation of PKC activity to the particulate fraction). Pretreat ment with 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and staurospo rine, PKC inhibitors, markedly inhibited the late component of the PIE of ET-1 without affecting the early component. These data indicate th at the two components of the PIE induced by ET-1 in the guinea pig lef t atrium may be mediated by different mechanisms. The early component may be attributed to the increased Ca++ influx as a result of the prol ongation of the duration of the action potential, whereas the late com ponent may be linked to stimulation of phosphoinositide hydrolysis and subsequent PKC activation.