MCI-154-INDUCED RELAXATION IN VASCULAR SMOOTH MUSCLES OF GUINEA-PIG

We investigated the vasorelaxant effects of MCI-154, a cardiotonic age nt designed to target thin filaments in cardiac muscles in intact and skinned vessels from guinea pigs. In normal Krebs-Henseleit solution, MCI-154 (10(-7)-10(-4) M) inhibited the contractions induced by angiot ensin II, (Ang II), endothelin-1 (ET-1), phenylephrine, and phorbol 12 -myristate 13-acetate (PMA) in a concentration-dependent manner in gui nea pig aorta. In Ca2+-free solutions, ET-1 and PMA caused slowly deve loping and sustained contractions in guinea pig aorta, whereas phenyle phrine and caffeine induced transient contractions due to Ca2+ release from the sarcoplasmic reticulum (SR). MCI-154 (10(-7)-10(-4) M) inhib ited the contractile responses to ET-1 and PMA. MCI-154 also reduced t he contraction induced by Ca2+ release from phenylehrine- and caffeine -sensitive Ca2+ store sites. On the other hand, the relaxation respons e to MCI-154 was not affected by the presence of methylene blue, a gua nylate cyclase inhibitor or by the removal of endothelial cells. MCI-1 54 decreased the Ca2+-activated tension development in saponin-treated skinned fibers from guinea pig femoral arteries. The effects of MCI-1 54 were not potentiated in the presence of protein kinase A (PKA), whe reas those of cyclic AMP were potentiated, possibly because of lack of protein kinase A. The present experiments demonstrate that MCI-154 in hibits vascular contraction when the contractions are produced by any of three mechanisms: protein kinase C (PKC) activation, Ca2+ mobilizat ion from store sites, or sensitization of contractile elements by Ca2.