title: Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice.
abstract: Opening of Ca2+-activated K+ (KCa) 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+ (KATP) channels. Adult male ICR mice were pretreated with the KCa-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 microM) 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 KCa-channel blocker paxilline (1 microM). 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 Nomega-nitro-L-arginine methyl ester (15 mg/kg ip). Unlike diazoxide (the opener of mitochondrial KATP 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 KCa channels in mouse heart tissue. We conclude that opening of KCa channels leads to both early and delayed preconditioning effects through a mechanism that is independent of nitric oxide.
authors.affiliation: Division of Cardiology, Box 980281, Virginia Commonwealth Univ., Richmond, VA 23298-0281, USA.
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Wang
authors.forename: Chang
authors.initials: C
authors.lastname: Yin
authors.forename: Lei
authors.initials: L
authors.lastname: Xi
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D001562:Benzimidazoles / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology* / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D002316:Cardiotonic Agents; D024681:Potassium Channels, Calcium-Activated; D020033:Protein Isoforms; C086491:NS 1619; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse