Susceptibility of the heart to ischaemia–reperfusion injury and exercise‐induced cardioprotection are sex‐dependent in the rat

Abstract

The cardioprotective effects of short-term exercise against myocardial ischaemia-reperfusion injury in male and female rats were examined. We subjected male and female rats to 0 (Sed; n = 8 males and 8 females), 1 (1 day; n = 10 males and 8 females), or 5 (5 day; n = 6 males and 6 females) days of treadmill running. Langendorff-perfused hearts underwent 1 h of regional ischaemia and 2 h of reperfusion, and infarct size (expressed as a percentage of the zone at risk; ZAR), left ventricular pressure development, and coronary flow were measured for each heart. Preischaemic pressure development and coronary flow did not differ between the sexes nor were they influenced by exercise. Sed females had significantly smaller infarct sizes (25 ± 3%) than Sed male hearts (37 ± 3%; P < 0.001). Short-term running significantly reduced infarct size following 1 day (27 ± 3%; P < 0.05) and 5 days (30 ± 4%; P < 0.10) of exercise in males. One day of running did not reduce infarct size in females (19 ± 3%; P = NS), but 5 day females did show a significant reduction in infarct size (13 ± 2%; P < 0.05). There was no relationship between postischaemic coronary vascular hyperaemia and infarct size across sexes or exercise training groups. Hearts from Sed females exhibited significantly higher manganese superoxide dismutase (MnSOD) protein expression than hearts from Sed males, but short-term exercise (neither 1 nor 5 days) did not alter MnSOD protein in either sex. Increased sarcolemmal ATP-sensitive K + (K ATP ) channel subunit protein expression (SUR2A and/or K ir 6.2) correlated closely with sex-dependent and exercise-acquired protection against myocardial infarction. These data indicate that: (1) sex-dependent and exercise-induced differences in the susceptibility of the heart to ischaemia-reperfusion injury are not associated with improved coronary flow or postischaemic hyperaemia; (2) increased MnSOD protein expression is not necessary for exercise-induced protection from infarction; and (3) one possible mechanism for sex-dependent and exercise-mediated reductions in infarct size involves an increased protein expression of cardiac sarcolemmal K ATP channels.

Mitochondrial KATPchannel inhibition blunts arrhythmia protection in ischemic exercised hearts

“…Early studies in myocytes from exercised hearts revealed that cardiac K ATP channel opening elicited resistance to anoxic stress, while the nonselective K ATP channel inhibitor, glibenclamide, abolished this protection (28). Follow-up study indicated that exercise stimulated overexpression of the sulfonylurea receptor portion of the sarc K ATP channel promoted protection against IR injury (15). Selective pharmacological blockade of the sarc K ATP channel demonstrated an essential role for this channel against long-duration ischemic insults, although protection against IR-generated arrhythmias was not evaluated (12).…”

“…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.…”

Models of gender differences in cardiovascular disease

“…[22] Pharmacologic inhibitor experiments further showed that reduced myocardial injury in females was dependent on the phosphatidylinositol-3 kinase and protein kinase C epsilon (PKCε) signaling pathways. Brown et al [23] demonstrated in a similar model that protection from injury in females was dependent on functional sarcolemmal K ATP channels. Wang et al performed in vitro, global ischemia experiments in Langendorff-perfused mouse hearts subjected to 20 minutes of ischemia followed by 60 minutes of reperfusion and observed reduced myocardial injury in female compared to male hearts, an effect that was lost in estrogen receptor α knockout mice supporting a role for this estrogen receptor isoform.…”

Cardioprotective Effects Induced by Preconditioning with Halogenated Anesthetics

“…28,29 At the end of the two hours of reperfusion, a colloidal pigment -Blue Evans (Evans blue, Sigma E2129) was administered in bolus through the femoral vein, in the amount of 4-5 ml for the delimitation of the infarct risk area. The heart is quickly dissected, the right ventricle is removed and the mentioned areas are excised.…”