title: Involvement of cyclooxygenase-2 in carbachol-induced positive inotropic response in mouse isolated left atrium.
abstract: The mouse heart is expected to have characteristic contractile properties. However, basic information on the function of the mouse heart has not been accumulated sufficiently. In this study, the involvement of cyclooxygenase (COX)-2 in carbachol (CCh)-induced inotropic response was investigated in mouse isolated left atrium. Influences of CCh and their mechanisms of action on developed tension elicited by electrical stimulation were examined pharmacologically. The presence of COX-2 in atrium was examined by Western blotting and immunohistochemical analysis. CCh (3 microM for 15 min) produced a biphasic inotropic response: a transient decrease in contractile force followed by a late increase. Atropine suppressed the biphasic inotropic response to CCh. A muscarinic M(3) receptor antagonist, 4-diphenyl-acetoxy-N-methlpiperidine, inhibited the late positive inotropic action. Blockade of prostaglandin (PG) E(2) or F(2alpha) receptor by 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) or 9alpha, 15R-dihydroxy-11beta-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta 5Z, 13E-dien-1-oic acid (AL8810), respectively, significantly suppressed the positive inotropic response to CCh. A nonselective COX inhibitor, indomethacin, and a selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) inhibited the positive response. A COX-1 inhibitor, valeroyl salicylate, did not affect the positive response. The positive response was almost completely abolished in the endocardial endothelium-deprived atria. Existence of COX-2 in endocardial endothelium was confirmed by Western blotting and immunohistochemical analysis. The present study indicated that the CCh-induced positive inotropic response was mediated by PGs, possibly PGE(2) and PGF(2alpha), released in part from endocardial endothelium. Furthermore, for the first time, we demonstrated that the production of PGs depended in part on COX-2 in endocardial endothelium through the muscarinic M(3) receptor stimulation.
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada City, Aomori 034-8628, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hara
authors.forename: Asako
authors.initials: A
authors.lastname: Ike
authors.forename: Riyo
authors.initials: R
authors.lastname: Tanida
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002217:Carbachol / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D011453:Prostaglandins / Q000378:metabolism
chemical_list: D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011453:Prostaglandins; D002217:Carbachol; D051546:Cyclooxygenase 2