Both metabolic inhibition and mitochondrial KATP channel opening are myoprotective and initiate a compensatory sarcolemmal outward membrane current

Abstract

Background - Blockade of oxidative phosphorylation may activate ATP sensitive mitochondrial potassium (mitoKATP) channels. We examined whether both metabolic inhibition and mitoKATP channel openers protect both the whole organ and isolated cells from ischemia. Methods and Results - Using a Langendorff preparation, one group of isolated rabbit hearts were exposed to ischemic preconditioning (IPC) via 2 episodes of flow interruption. The second group of hearts was preconditioned with 2 episodes of either the metabolic inhibitor, sodium cyanide (NaCN), or the mitoK ATP channel opener, diazoxide. The third group of hearts was exposed to the mitoKATP channel inhibitor, 5-hydroxydecanoic acid (5-HD) prior to preconditioning with NaCN, diazoxide or IPC. Controls had no drug infused. Then, ischemia was induced in all hearts by left anterior descending coronary artery occlusion and infarct size was determined, Compared with controls (40±3%), infarct size was significantly reduced in hearts preconditioned with NaCN, diazoxide or IPC (18±3%, 26±3%, 21±2%, respectively; P<0.05 versus control). These reductions were reversed by 5-HD (36±3%, 33±2%, 37±2%; NaCN, diazoxide, IPC, respectively). Secondly, whole cell patch clamped isolated guinea pig ventricular myocytes were preconditioned with 2 episodes of either NaCN or diazoxide followed by Tyrodes perfusion with membrane potential set to -70 mV. Control cells were exposed to Tyrodes solution. All cells were then clamped to -20 mV and exposed to NaCN, which caused induction of an outward potassium current. Compared with controls, the average time to induction of the outward current was significantly reduced in cells preconditioned with either brief application of NaCN (11.6±1.8 versus 5.1±1.0 minutes, control versus NaCN, P<0.05) or diazoxide (5.5±1.4 versus 2.0±0.8 minutes, control versus diazoxide, P<0.05). Conclusion - Preconditioning protects the heart through mitoKATP. This protection also alters a surface membrane current, which may be important in myocardial protection.