title: The cardioprotective and electrophysiological effects of cromakalim are attenuated by meclofenamate through a cyclooxygenase-independent mechanism.
abstract: Recent published studies indicate that the cyclooxygenase inhibitor meclofenamate can abolish preconditioning. Unpublished preliminary data from this laboratory suggest that meclofenamate may be blocking cardiac ATP-sensitive potassium channels (KATP channels), which may also mediate preconditioning. The purpose of the present study was to determine whether meclofenamate is a cardiac KATP channel blocker and it can abolish the anti-ischemic activity of the KATP channel opener cromakalim. This concept was tested initially in an isolated rat heart model of 25 min of ischemia and 30 min of reperfusion. Meclofenamate, in a concentration (5 microM) that did not cause proischemic effects alone, abolished the protective effect of cromakalim, as measured by recovery of contractile function, lactate dehydrogenase release and contracture formation. The preischemic coronary dilating activity of cromakalim was not attenuated by meclofenamate. The cyclooxygenase inhibitors indomethacin and SQ 29,109 had no effect on the cardioprotection afforded by cromakalim. Concentration-response curves for the ability of cromakalim to increase time to contracture during ischemia in rat hearts were generated alone or in the presence of 5 or 10 microM meclofenamate. Cromakalim increased the time to contracture with an EC25 of approximately 3 microM. Meclofenamate appeared to block this effect in a manner that was not surmountable by 100 microM cromakalim. Studies in guinea pig hearts showed that meclofenamate had no effect on action potential duration or effective refractory period when given alone. Meclofenamate attenuated the action potential duration shortening effects of cromakalim in this model. Thus, meclofenamate blocked the cardioprotective effects of cromakalim and this effect was not related to cyclooxygenase inhibition. Meclofenamate appears to be a cardiac KATP channel blocker.
authors.affiliation: Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
authors.forename: G J
authors.initials: GJ
authors.lastname: Grover
authors.forename: A J
authors.initials: AJ
authors.lastname: D'Alonzo
authors.forename: P G
authors.initials: PG
authors.lastname: Sleph
authors.forename: S
authors.initials: S
authors.lastname: Dzwonczyk
authors.forename: T A
authors.initials: TA
authors.lastname: Hess
authors.forename: R B
authors.initials: RB
authors.lastname: Darbenzio
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019806:Cromakalim; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology; D015221:Potassium Channels / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D016861:Cyclooxygenase Inhibitors; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D008469:Meclofenamic Acid; D011451:Prostaglandin-Endoperoxide Synthases