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 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 KCa-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 Nω-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 α- and β-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.

Cardiac protection by mitoKATP channels is dependent on Akt translocation from cytosol to mitochondria during late preconditioning

“…We have previously demonstrated that activation of mitoK ATP channels elicits strong protection against Ca 2ϩ overload and ischemic injury (23,25,26). These conclusions are well supported by several recent studies (9 -11, 26) that document mitoK ATP channel as the end effector in cardioprotection against ischemia during late preconditioning.…”

Hydrogen sulfide preconditioning or neutrophil depletion attenuates ischemia-reperfusion-induced mitochondrial dysfunction in rat small intestine

“…However, it is known that these agents produce other effects. For example, paxilline has been shown to inhibit sarco/endoplasmic reticulum Ca 2ϩ -ATPase both in vitro and in vivo, albeit at concentrations higher than were achieved in our experiments (47,52). NS-1619 has also been reported to inhibit complex I of the mitochondrial respiratory chain in tumor cells (30), but again, inhibitor concentrations required to achieve this effect were Fig.…”

“…However, the results of several recent studies point to the importance of another set of potassium channels, the BK Ca channels, as critical triggers for the development of a protected phenotype in response to preconditioning stimuli (40,47,56). BK Ca channels are expressed on the plasmalemma of cells in a variety of tissues, including endothelial and vascular smooth muscle cells, and are comprised of a poreforming ␣-subunit and an auxiliary ␤-subunit that modulates channel activity and sensitivity to specific agonists (12,44,48,55,64,66,67).…”

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

“…Mitochondria are one of these important convergence points, due to their critical function in cell survival and death; notably, ATP production and apoptosis [10,12,48]. Key mitochondrial proteins, such as several potassium (K + ) channels [49][50][51][52][53] and the mitochondrial permeability transition pore (mPTP) [48,[54][55][56], act as effectors integrating these upstream signals into cardioprotective responses. The mechanisms by which CYP metabolites alter these important effectors are not well defined and require further experimentation.…”