Positive inotropic effect of histamine on guinea pig left atrium: H1-receptor-induced stimulation of phosphoinositide turnover.
The purpose of this study was to investigate the mechanism of histamine's H1-receptor-mediated positive inotropic effect, a response which is not associated with an increase in cyclic AMP levels. We found that the concentration-response curve for the positive inotropic effect of histamine on cavian left atrium was similar to that of the alpha-1 agonist phenylephrine, in terms of slope and maximum response. Additionally, both agents slightly prolonged time-to-peak tension and relaxation times. In contrast, the concentration-response relationship for the beta-agonist isoproterenol, whose positive inotropic effect is mediated by an increase in cyclic AMP, had a steeper slope and a much greater maximum. Furthermore, isoproterenol abbreviated time-to-peak tension and relaxation times. As reported previously for alpha-1 agonists, the development of the contractile response to a submaximal histamine concentration (10 microM) coincided with a rapid increase in left atrial tissue levels of inositol triphosphate. The concentration-response curves for histamine effects on contractility and phosphoinositide (PI) turnover were both unaffected by the H2-antagonist tiotidine, but were shifted markedly to the right by the H1-antagonist pyrilamine. High-performance liquid chromatography techniques were applied to resolve the various inositol mono-, di- and tri-phosphate isomers and to assess the possible production of higher phosphates (IP4, IP5 and IP6) in control and histamine-treated (10 microM) atria. Under both conditions IP products were qualitatively similar, but quantitatively greater after treatment with histamine; these products included inositol(1)phosphate, inositol(4)phosphate,inositol(1,4)diphosphate and inositol(1,4,5)triphosphate. No evidence of higher phosphate production was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)
Sakuma
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I
Department of Pharmacology, Cornell University Medical College, New York, New York.
Gross
S S
SS
Levi
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D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D013268:Stimulation, Chemical
D010716:Phosphatidylinositols; D011969:Receptors, Histamine H1; D006632:Histamine; D000242:Cyclic AMP; D007545:Isoproterenol