Dissociation of the positive inotropic effect of methoxamine from the hydrolysis of phosphoinositide in rabbit ventricular myocardium: a comparison with the effects of phenylephrine and the subtype of the alpha-1 adrenoceptor involved.
The effects of methoxamine on the contractile force and the hydrolysis of phosphoinositide (PI) were examined and compared with those of phenylephrine in the rabbit ventricular myocardium. Methoxamine, as well as phenylephrine, caused the concentration-dependent accumulation of [3H]inositol monophosphate in rabbit ventricular slices. The maximal responses of the two drugs were equivalent, but methoxamine was approximately 10 times less potent than phenylephrine. The extents and time courses of accumulation of [3H]inositol phosphates induced by 10(-4) M methoxamine and 10(-5) M phenylephrine were very similar, whereas the positive inotropic effect (PIE) of methoxamine developed much more slowly and its extent was much smaller than that of phenylephrine. The maximal inotropic response achieved with 10(-4) M methoxamine was one third of that achieved with phenylephrine. The PIE of methoxamine induced by a single administration was markedly attenuated when the same dose was given by cumulative administration. The concentration-response curve for the PIE of phenylephrine was shifted to the right and downward in the presence of methoxamine in a concentration-dependent manner. These results indicate that methoxamine accelerates the hydrolysis of PI as effectively as does phenylephrine, but it has a smaller PIE because of its depressant effect on the process subsequent to acceleration of the hydrolysis of PI induced by alpha-1 adrenoceptors. The accumulation of [3H]inositol 1,4,5-trisphosphate induced either by methoxamine or by phenylephrine was abolished by 10(-5) M chlorethylclonidine, whereas the maximal inhibition induced by WB 4101 was 60%.(ABSTRACT TRUNCATED AT 250 WORDS)
Yang
H T
HT
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Endoh
M
M
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*
D010716:Phosphatidylinositols; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D008729:Methoxamine; D011224:Prazosin