Cardioprotective Effects of Sarcolemmal and Mitochondrial K-ATP Channel Openers in an Experimental Model of Autoimmune Myocarditis

Abstract

SummaryIt has been reported that K-ATP channel openers have a cardioprotective effect in acute ischemia as a pharmacological preconditioning effect. In the present study, the chronic effects of clinical K-ATP channel openers, ie, nicorandil (Nic) and mexiletine (Mex), on cardiac function were evaluated in a rat model of experimental autoimmune myocarditis (EAM). Nicorandil (3 or 10 mg/kg/day) or Mex (10 or 25 mg/kg/day) was administered to the EAM rats, and the effects were compared with those in untreated EAM rats (control EAM) and sham rats without EAM on day 21 (acute phase) or day 60 (chronic phase). In the acute phase, the control EAM rats exhibited a reduced left ventricular ejection fraction (LVEF) and prolonged monophasic action potential duration (MAPD). Neither drug had an affect on the LVEF or degree of myocarditis, but Mex 25 mg suppressed the MAPD prolongation. In the chronic phase, EAM+Nic and EAM+Mex 25 mg exhibited a higher LVEF than the control EAM. Although the control EAM exhibited sustained MAPD prolongation, the other groups showed recovery of the MAPD in the chronic phase. The mitochondorial redox state was lower in the control EAM than in the sham, and EAM+Nic exhibited a similar level of the redox state as the sham in the chronic phase. Nicorandil exhibited a cardioprotective effect through the protection of mitochondrial function. Mexiletine exhibited a cardioprotective effect possibly through a reduction in the calcium overload by shortening the MAPD in the acute phase. (Int Heart J 2012; 53: 139-145)

What Is the Arrhythmic Substrate in Viral Myocarditis? Insights from Clinical and Animal Studies

“…Thus, EADs can be inhibited the late I Na (Belardinelli et al, 2013 ), whereas DADs could be abolished by blocking RyR2 (Savio-Galimberti and Knollmann, 2015 ) or NCX (Sipido et al, 2006 ). K ATP channel openers such as mexiletine, with previously demonstrated cardioprotective effects during ischaemia, could suppress APD prolongation during acute myocarditis and may therefor protect against Ca 2+ overload, DADs and spatial heterogeneities in APDs (Niwano et al, 2012 ).…”

Alterations of Cardiac K_ATP Channels and Autophagy Contribute in the Late Cardioprotective Phase of Exercise Preconditioning

“…29,30) Our study suggests that exhaustive exercise can cause acute myocardial injury, ischemia/hypoxia of myocardial cells, cardiac stress or dysfunction, and so increase Kir6.2 and SUR2A protein levels and regulate the number of KATP channels. Opening of cardiac KATP channels exerts cardioprotective phenotype; 31) however, over-expression of KATP channels subunits might increase the risk of ventricular arrhythmias. Interestingly, implementation of EP before exhaustive exercise significantly decreased Kir6.2 and SUR2A protein expression, suggesting that EP-induced late cardioprotection against exhaustive exercise in rats through decreased levels of KATP channel subunit Kir6.2 and SUR2A protein.…”

A Lipophilic Nitric Oxide Donor and a Lipophilic Antioxidant Compound Protect Rat Heart Against Ischemia–Reperfusion Injury if Given as Hybrid Molecule but Not as a Mixture

“…Adenosine and bradykinin can activate eNOS not only in the endothelial cells but also in cardiomyocytes via sarcolemmal G-protein coupled receptors (GPCR) (61). Independently of its origin, NO leads to the opening of both sarcolemmal and mito K ATP channels in cardiomyocytes via GS-cGMP-PKG pathway (62). While the opening of the former limits Ca 2+ flux into the cell, the activation of the latter prevents the opening of mPTP.…”

“…While the opening of the former limits Ca 2+ flux into the cell, the activation of the latter prevents the opening of mPTP. Both these effects result in the limitation of infarct size (62,63).…”

“…In fact, in response to nitrosylation, L-type Ca 2+ channels and mitochondrial F1-ATPase are inactivated, while sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA2) increases its own activity (65,66). Moreover, also the NO-induced phosphorylation of sarcolemmal K ATP channels limits Ca 2+ entrance by shortening action potential (62).…”