Methoxamine-induced inhibition of the positive inotropic effect of endothelin via alpha1-adrenoceptors in the rabbit heart.

The influence of methoxamine on the positive inotropic effect of endothelin was assessed in the isolated rabbit ventricular myocardium. Methoxamine by itself elicited a positive inotropic effect and it simultaneously inhibited the positive inotropic effects of endothelin-1 and endothelin-3 without affecting the acceleration of the hydrolysis of phosphoinositide that was induced by the endothelin isopeptides. By contrast, the positive inotropic effects induced by elevation of concentration of external Ca2+ ions, by Bay k 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate), by dihydroouabain and by forskolin were unaffected by methoxamine. The inhibitory action of methoxamine was abolished by alpha1-adrenoceptor antagonists, such as prazosin, WB 4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) and (+/-)-tamsulosin; and it was inhibited to a lesser extent by chlorethylclonidine. In addition, methoxamine did not modify the specific binding of [125I]endothelin-3 to ventricular membrane fraction. These results indicate that methoxamine antagonizes the positive inotropic effect of endothelin isopeptides at the level of the signal-transduction process, subsequent to acceleration of the hydrolysis of phosphoinositide, via activation of alpha1-adrenoceptors in the rabbit ventricular myocardium.