MCI-154-induced relaxation in vascular smooth muscles of guinea pig.
We investigated the vasorelaxant effects of MCI-154, a cardiotonic agent 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 angiotensin II, (Ang II), endothelin-1 (ET-1), phenylephrine, and phorbol 12-myristate 13-acetate (PMA) in a concentration-dependent manner in guinea pig aorta. In Ca(2+)-free solutions, ET-1 and PMA caused slowly developing and sustained contractions in guinea pig aorta, whereas phenylephrine and caffeine induced transient contractions due to Ca2+ release from the sarcoplasmic reticulum (SR). MCI-154 (10(-7)-10(-4) M) inhibited the contractile responses to ET-1 and PMA. MCI-154 also reduced the contraction induced by Ca2+ release from phenylehrine- and caffeine-sensitive Ca2+ store sites. On the other hand, the relaxation response to MCI-154 was not affected by the presence of methylene blue, a guanylate cyclase inhibitor or by the removal of endothelial cells. MCI-154 decreased the Ca(2+)-activated tension development in saponin-treated skinned fibers from guinea pig femoral arteries. The effects of MCI-154 were not potentiated in the presence of protein kinase A (PKA), whereas those of cyclic AMP were potentiated, possibly because of lack of protein kinase A. The present experiments demonstrate that MCI-154 inhibits vascular contraction when the contractions are produced by any of three mechanisms: protein kinase C (PKC) activation, Ca2+ mobilization from store sites, or sensitization of contractile elements by Ca2+.
Kitada
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Y
Pharmaceutical Laboratory I, Yokohama Research Center, Mitsubishi Chemical Corporation, Japan.
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D005263:Femoral Artery / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D011724:Pyridazines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D002110:Caffeine; C052228:MCI 154; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D008751:Methylene Blue