Cardiac mitochondrial Ca 2+ ‐dependent big K + channels are open during early reperfusion

Abstract

Ca2+ -dependent “Big” conductance K+ (mBKCa) channels exist in inner mitochondrial (m) membranes of guinea pig myocytes. Our aim was to explore if mBKCa channels are active during early reperfusion (RP) after global ischemia and act to mitigate ischemia reperfusion (IR) injury. Guinea pig isolated hearts (n= 12) were subjected to 30 min of global ischemia and 120 min of RP. Groups were: untreated (CON) and Paxilline treated (PAX). PAX hearts were perfused with 1 μM Paxilline, a putative blocker of mBKCa channels, during the first 10 min of RP. Developed left ventricular pressure (systolic–diastolic LVP, mmHg) was recorded along with spectrofluorometric measures of mitochondrial matrix calcium [mCa2+] by Indo 1 AM, and redox state (NADH and FAD) at the same wavelengths by autofluorescence. Infarct size was measured by the TTC method. ANOVA (mean±sem; ∗PAX vs. CON, p <0.05). At 60 min RP: LVP was higher in CON (36±1∗) than after PAX (28±3); [mCa2+] was lower in CON (259±31∗) than after PAX (326±26); NADH was higher in CON (0.48±0.04) than after PAX (0.40±0.03); FAD at 60 min RP was higher after PAX (0.65±0.02) than in CON (0.62±0.01) and infarct size at 120 min RP was higher after PAX (50±2) than in CON (43±1). Blocking mBKCa channels during early RP resulted in reduced myocardial contractility and NADH, increased [mCa2+] and infarct size. These results suggest that mBKCa channels are opened during early RP after ischemia and intrinsically contribute to reducing IR injury, and provide a better understanding of cardioprotection after ischemia and may lead to new therapeutic options to treat ischemic heart disease.