Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal K_ATP channel blockade in the rat heart

Abstract

Chicco AJ, Johnson MS, Armstrong CJ, Lynch JM, Gardner RT, Fasen GS, Gillenwater CP, Moore RL. Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal KATP channel blockade in the rat heart. Am J Physiol Heart Circ Physiol 292: H2432-H2437, 2007. First published January 19, 2007; doi:10.1152/ajpheart.01301.2006.-The present study was conducted to determine whether the infarct sparing effect of shortterm exercise is dependent on the operation of the myocardial sarcolemmal ATP-sensitive K ϩ (KATP) channel. Adult male and female Sprague-Dawley rats were exercised on a motorized treadmill for 5 days. Twenty-four hours following the training or sedentary period, hearts were isolated and exposed to 1 h of regional ischemia followed by 2 h of reperfusion on a modified Langendorf apparatus in the presence or absence of the sarcolemmal KATP channel antagonist HMR-1098 (30 M). Following the ischemia-reperfusion protocol, infarct size was determined as a percentage of the total ischemic zone at risk (ZAR). Short-term exercise reduced infarct size by 24% in males (32 Ϯ 2% of ZAR; P Ͻ 0.01) and by 18% in females (26 Ϯ 2% of ZAR; P Ͻ 0.05). Sarcolemmal KATP channel blockade abolished the training-induced cardioprotection in both males and females, increasing infarct size to 43 Ϯ 3% and 52 Ϯ 4% of ZAR, respectively. In the absence of HMR-1098, infarct size was significantly lower in sedentary females than in males (33 Ϯ 4% vs. 42 Ϯ 2% of ZAR, respectively; P Ͻ 0.01). However, the presence of HMR-1098 abolished this sex difference, increasing infarct size by 58% in the sedentary females (P Ͻ 0.01) but having no effect on infarct size in sedentary males. This study demonstrates that the sex-specific and exercise-acquired resistance to myocardial ischemia-reperfusion injury is dependent on sarcolemmal KATP activity during ischemia. ischemia; infarction; sex differences; gender ISCHEMIC HEART DISEASE is a leading cause of mortality in industrialized countries throughout the world. Myocardial infarction is often the initial manifestation of ischemic heart disease, and survival is inversely proportional to the size of the myocardial infarction sustained (13). A variety of preconditioning stimuli has proven to be effective at reducing myocardial infarct size when administered immediately before ischemia (e.g, ischemic preconditioning and adenosine receptor agonists), but the protective effect of these treatments is lost after repetitive administration (38, 53). Exercise training, however, has been consistently shown to confer sustainable protection against myocardial infarction in animal models (10,26,40,56,57) and has been associated with improved survival following an ischemic event in humans (27,43). Despite substantial efforts to characterize the cardioprotective phenotype evoked by exercise training over the past decade, the precise mechanisms by which exercise reduces infarct size have not been fully elucidated.The infarct-sparing effect of exercise has been reported following both long-term (Ͼ10 wk) (9...

Mitochondrial KATPchannel inhibition blunts arrhythmia protection in ischemic exercised hearts

“…Collectively, previous and present findings may indicate the sarc K ATP channel mediates tissue preservation during IR, while the mito K ATP channel protects against arrhythmias (20). The protective contribution of the mito and sarc K ATP channels does not, however, appear to be consistent across all experimental paradigms and requires further investigation (12)(13)17). Accordingly, we employed a relatively short-duration ischemia (20 min) and proportionate reperfusion period (30 min) to evaluate the impact of these ion channels as potential mechanisms of anti-arrhythmic protection in the exercised heart and investigated biochemical outcomes in perfused and ischemic myocardium before the overt onset of tissue death occurred.…”

“…37). Characteristic of experimentation with pharmacological inhibitors, however, we cannot rule out the possibility of unknown pharmacological effects in the present study, including 5HD-specific effects on substrate availability (5,26) and sex specific effects (17). Despite the potential role of 5HD metabolism within the heart, the resulting implications for outcomes related to preconditioning remain unknown.…”

“…In accordance, we undertook the present investigation to test the hypothesis that the mito K ATP channel is essential for exercisemediated protection against IR-generated arrhythmias. Results from previous investigations of exercised hearts indicate the sarc K ATP channel is essential for myocardial infarct sparing effects of exercise (12,15,17). Thus we also tested the rival hypothesis that the sarc K ATP channel was responsible for the anti-arrhythmic protection provided by exercise.…”

The Effect of Erythropoietin on Potassium Levels During Ischemia Reperfusion Injury in Rats

“…Pollesellop et al [10] have shown that levosimendan has [10] vasodilatory and anti ischemic effects mediated via the opening of ATP-sensitive K channels in vascular smooth-muscle cells and also acts on mitochondrial ATPsensitive K (mito KATP) channels, an action thought to protect the heart against IR damage. Chicco et al abolished [11] the sarcolemmal K (ATP) channel blockade training-induced cardio protection increasing infarct size to 47.5±3.5% of zone at risk (ZAR) in rats. This study demonstrates that resistance to myocardial IR injury is dependent on sarcolemmal K (ATP) activity during ischemia.…”

“Roid-Rage” at the Cellular Level: Abolition of Endogenous Cardioprotection by Anabolic Steroids Reveals New Links Between the RAAS and Cardiac KATP Channels

“…While women are known to exhibit reduced risk of cardiovascular events and associated mortality compared to males, the molecular mechanisms of this sex-dimorphism remains incompletely understood [9][10][11]. Animal studies have demonstrated an intrinsic resistance of the female heart to ischemia/ reperfusion injury, which has been linked to a higher expression of sarcK ATP channel subunits in the female versus male heart [6,[12][13][14]. Estrogen upregulates sarcK ATP channel subunit expression in cardiomyocytes [15], suggesting a potential mechanism for its protective effects in the heart.…”