Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 287, Issue 5, Pages H2070-H2077Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00431.2004
Keywords
ischemia-reperfusion; nitric oxide synthase; pharmacological preconditioning; signaling; NS-1619
Funding
- NHLBI NIH HHS [HL-51045, HL-49469, HL-07537] Funding Source: Medline
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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 muM) 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 mu M). 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-omega-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 alpha- and beta-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.
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