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This Article Full Text Full Text (PDF) All Versions of this Article: 287/5/H2070    most recent 00431.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (19) Citing Articles via Google Scholar Google Scholar Articles by Wang, X. Articles by Kukreja, R. C. Search for Related Content PubMed PubMed Citation Articles by Wang, X. Articles by Kukreja, R. C.

Opening of Ca²⁺-activated K⁺ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice

Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298-0281

Submitted 6 May 2004 ; accepted in final form 22 June 2004

Opening of Ca²⁺-activated K⁺ (K_Ca) channels has been shown to confer early cardioprotection. It is unknown whether the opening of these channels also induces delayed cardioprotection. In addition, we determined the involvement of nitric oxide synthases (NOSs), which have been implicated in cardioprotection induced by opening of mitochondrial ATP-sensitive K⁺ (K_ATP) channels. Adult male ICR mice were pretreated with the K_Ca-channel opener NS-1619 either 10 min or 24 h before 30 min of global ischemia and 60 min of reperfusion (I/R) in Langendorff mode. Infusion of NS-1619 (10 µM) for 10 min before I/R led to smaller infarct sizes as compared with the vehicle (DMSO)-treated group (P < 0.05). This infarct-limiting effect of NS-1619 was associated with improvement in ventricular functional recovery after I/R. The NS-1619-induced protection was abolished by coadministration with the K_Ca-channel blocker paxilline (1 µM). Similarly, pretreatment with NS-1619 (1 mg/kg ip) induced delayed protection 24 h later (P < 0.05). Interestingly, the NS-1619-induced late protection was not blocked by the NOS inhibitor N-nitro-L-arginine methyl ester (15 mg/kg ip). Unlike diazoxide (the opener of mitochondrial K_ATP channels), NS-1619 did not increase the expression of inducible or endothelial NOS. Western blot analysis demonstrated the existence of - and -subunits of K_Ca channels in mouse heart tissue. We conclude that opening of K_Ca channels leads to both early and delayed preconditioning effects through a mechanism that is independent of nitric oxide.

ischemia-reperfusion; nitric oxide synthase; pharmacological preconditioning; signaling; NS-1619

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