Endothelium-dependent rhythmic contractions induced by cyclopiazonic acid in rat mesenteric artery

The action of cyclopiazonic acid, the putative inhibitor of the Ca(2+)-ATPase of endoplasmic reticulum, on phenylephrine-evoked-isometric contractions in rat isolated mesenteric arteries were investigated. Cyclopiazonic acid (3 microM) induced an initial relaxation followed by rhythmic contractions of the phenylephrine-precontracted arteries with intact endothelium. Removal of endothelium abolished the effect of cyclopiazonic acid. Pretreatment of tissues with NG-nitro-L-arginine (100 microM) abolished the initial relaxation but not the rhythmic contractions. Indomethacin and glibenclamide did not affect the cyclopiazonic acid-induced response. Charybdotoxin (100 nM) converted the cyclopiazonic acid-induced rhythmic contractions to the sustained tension in the absence or presence of NG-nitro-L-arginine (100 microM). Pretreatment of charybdotoxin (100 nM) abolished cyclopiazonic acid-induced rhythmic activity but not the initial relaxation. Nifedipine (10 nM) abolished the effect of cyclopiazonic acid. Moderate increase of extracellular K+ (20 mM) reduced the initial relaxation but completely abolished rhythmic contractions induced by cyclopiazonic acid. The remaining relaxation was reversed or prevented by NG-nitro-L-arginine (100 microM). The results of the present investigation indicate that cyclopiazonic acid caused endothelium-dependent response in rat isolated mesenteric arteries probably by releasing nitric oxide responsible for the initial relaxation, and probably by releasing endothelium-derived hyperpolarizing factors primarily responsible for activation of charybdotoxin-sensitive K+ channels and induction of rhythmic contractile activity.