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 μM 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 M3 receptor antagonist, 4-diphenyl-acetoxy-N-methlpiperidine, inhibited the late positive inotropic action. Blockade of prostaglandin (PG) E2 or F2α receptor by 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) or 9α, 15R-dihydroxy-11β-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 PGE2 and PGF2α, 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 M3 receptor stimulation.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.156992
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ABBREVIATIONS:
- ACh
- acetylcholine
- PTX
- pertussis toxin
- PG
- prostaglandin
- CCh
- carbachol
- COX
- cyclooxygenase
- DAPI
- 4′,6-diamidino-2-phenylindole
- NS-398
- N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide
- AH6809
- 6-isopropoxy-9-oxoxanthene-2-carboxylic acid
- AL8810
- 9α, 15R-dihydroxy-11β-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta 5Z, 13E-dien-1-oic acid
- SQ29,548
- [1S-[1α,2α(Z), 3α, 4α]]-7-[3-[[2-[(phenyl-amino]carbonyl]hydrazine)methyl)-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid
- EP
- prostaglandin E2
- FP
- prostaglandin F2α
- TP
- thromboxane A2
- 4-DAMP
- 4-diphenyl-acetoxy-N-methylpiperidine.
- Received June 1, 2009.
- Accepted September 10, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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