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.

The use of short-term (1-5 days) treadmill running is becoming increasingly common as a model to study physiological adaptations following the exercise. Although the beneficial effects of acute exercise seem clear, a paucity of data exist describing potential markers of stress in response to forced running. We subjected male and female Sprague-Dawley rats to 0, 1, 2, 5, or 10 days of treadmill running. Twenty-four to 32 h after the last bout of exercise animals were killed and examined for training-induced changes in several physiological variables. No effect of skeletal citrate synthase activity was observed in the male animals after any duration, and only at 10 days of running did females show a significant increase in citrate synthase. Myocardial heat shock protein 72 (HSP72) content was higher in male rats than female rats, and exercise led to increased HSP72 in both sexes, although the time course was different between males and females. Animals displayed several markers of systemic stress in response to the treadmill running, and this was done in a sex-dependent manner. Serum corticosterone was significantly elevated in both sexes 24 h after exercise in three of four exercise groups. Corticosterone-binding globulin was higher in females, and decreased after running in female rats. Body and spleen weights decreased in males (but not females) in response to the exercise training, and running did not alter adrenal gland weights in either sex. These data indicate that in response to short-term treadmill running both male and female rats show signs of systemic stress, but that the pattern of changes occurs in a sex-specific manner.

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...

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The PARAGON Investigators* Background-Unstable angina and non-Q-wave myocardial infarction involve coronary arterial plaque rupture, platelet activation, and thrombus formation. This study tested the benefit of different doses of lamifiban (a platelet IIb/IIIa antagonist) alone and in combination with heparin in patients with these conditions to select the most promising lamifiban regimen for subsequent evaluation. Methods and Results-At 273 hospitals in 20 countries, 2282 patients were randomly assigned to lamifiban (2ϫ2 factorial design: low-dose [1 g/min] with and without heparin versus high-dose [5 g/min] with and without heparin) or to standard therapy (placebo and heparin). All patients received aspirin. The composite primary end point of death or nonfatal myocardial infarction at 30 days occurred in 11.7% of those receiving standard therapy, 10.6% receiving low-dose lamifiban, and 12.0% receiving high-dose lamifiban (Pϭ0.668). By 6 months, this composite was lowest for those assigned to low-dose lamifiban (Pϭ0.027) and intermediate for those assigned to high-dose lamifiban (Pϭ0.450) compared with control (13.7%, 16.4%, and 17.9%, respectively). Compared with control, the combination of high-dose lamifiban and heparin resulted in more intermediate or major bleeding (12.1% versus 5.5%; Pϭ0.002) and a similar rate of ischemic events. Conversely, low-dose lamifiban and heparin yielded similar bleeding rates as in the control group but fewer ischemic events at 6 months (12.6% versus 17.9%; Pϭ0.025). Conclusions-In unstable angina and non-Q-wave infarction, platelet IIb/IIIa antagonism with lamifiban reduces adverse ischemic events at 6 months beyond that of aspirin and heparin therapy. The role of conjunctive heparin remains uncertain but appears more favorable with low-dose IIb/IIIa antagonism. Larger-scale study is needed to more reliably estimate these effects. (Circulation. 1998;97:2386-2395.)