Positive inotropic effect of the thromboxane analog U-46619 on guinea pig left atrium: mediation by specific receptors and association with increased phosphoinositide turnover.
U-46619, a stable epoxymethano analog of thromboxane A2 elicited a direct positive inotropic effect on guinea pig left atrium paced at a constant rate (EC50 = 2.5 nM). This novel observation contrasts with previous reports of a decrease in myocardial contractility by thromboxane mimetic compounds in coronary-perfused preparations, an action recognized as secondary to vasoconstriction. The positive inotropic effect of U-46619 was competitively antagonized by the specific thromboxane receptor blocker L-655,240 (pA2 = 8.02; identical to that reported in smooth muscle), but was unaffected by blockers of alpha 1-, beta 1-, and H1-receptors and by cyclooxygenase and lipoxygenase inhibitors. Increased tissue levels of inositol phosphates, but not cAMP, were associated with the positive inotropic action of U-46619, in analogy to the actions of alpha 1- and H1-receptor agonists. However, the inotropic effect of U-46619 and the concomitant increase in phosphoinositide breakdown were both selectively antagonized by L-655,240. Thus, U-46619 acts on specific thromboxane receptors in guinea pig left atrium and elicits a positive inotropic effect that probably results from an increase in phosphoinositide metabolism.
Sakuma
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Department of Pharmacology, Cornell University Medical College, New York, NY 10021.
Gross
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Levi
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D016275:Atrial Function; D002316:Cardiotonic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010716:Phosphatidylinositols / Q000378:metabolism; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000378:metabolism; D017482:Receptors, Thromboxane; D013268:Stimulation, Chemical; D014316:Tritium
D002316:Cardiotonic Agents; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014316:Tritium; D007294:Inositol; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000242:Cyclic AMP