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

Ischaemic heart disease claimed more lives worldwide in 2002 than any other single disease (World Health Organization, 2003). Myocardial infarction is commonly the initial manifestation of ischaemic heart disease (Manfroi et al. 2002), and exercise training has been shown to decrease a number of the risk factors for myocardial infarction including hypertension, hyperlipidaemia, obesity, and insulin resistance, and has also been reported to improve chance of survival in humans after an ischaemic event (Morris et al. 1980). Sex (gender) also appears to have an influence on the occurrence of myocardial infarction, with the incidence of ischaemic heart disease being much lower in premenopausal women than age-matched men. Previous investigations using animal models in rat (Li & Kloner, 1995) and dog (Przyklenk et al. 1995; Lee et al. 2000) have examined the effect of sex on myocardial infarct size using in situ preparations, but the results have been equivocal, with males having either larger infarct sizes than females (Lee et al. 2000) or no difference (Li & Kloner, 1995; Przyklenk et al. 1995). While exercise-induced enhancement of postischaemic myocardial function has been shown to differ between rat sexes (Paroo et al. 2002), no study to date has examined the effect of exercise training on infarct size between males and females. Evidence from the literature demonstrating exercise-mediated infarct-sparing has either been performed in male (Yamashita et al. 1999; Yamashita et al. 2001) or female (Brown et al. 2003; Hamilton et al. 2003) rats, and the duration of the exercise regimen has varied among these studies. Since a discrepancy appears to exist regarding the protective effects of exercise between the sexes, a primary objective of the present study was to test the hypothesis that short-term exercise alters the susceptibility of rat heart to ischaemia–reperfusion tissue injury in a sex-dependent manner. Our previous work (Brown et al. 2003) showed that chronic exercise training reduced infarct size in female rats. We attributed the exercise-induced cardioprotection to increases in manganese superoxide dismutase (MnSOD) protein expression and better preservation of coronary flow in the trained animals (Brown et al. 2003). While exercise-induced cardioprotection in rat heart has commonly been associated with increases in MnSOD (Yamashita et al. 1999; Brown et al. 2003; Hamilton et al. 2003), few studies have examined infarct size in an experimental setting where coronary flow can be measured. Since both sex and short-term exercise have been shown to influence porcine vascular reactivity (Laughlin et al. 2003a, b), we assessed coronary flow in a setting of myocardial infarction to determine if sex- and exercise-dependent differences in infarct size could be ascribed to differences in coronary flow in the rat. Finally, we examined the myocardial protein content of the sarcolemmal ATP-sensitive potassium (KATP) channel. The opening of these channels with pharmacological agents has been shown to reduce infarct size in dogs (Gross & Auchampach, 1992)and channel blockade can ameliorate the beneficial effects of ischaemic preconditioning (Gross & Auchampach, 1992). While the role of these channels has received much attention in the context of ischaemic preconditioning across mammalian species (O'Rourke, 2000; Gross & Peart, 2003), whether or not these channels play a role in exercise-induced protection from infarction is unknown. Therefore, a final objective of this study was to examine the effects of exercise and sex on myocardial protein content of both the inwardly rectifying pore-forming subunit of the channel, Kir6.2, and the sulphonylurea receptor (SUR), the regulatory subunit of the sarcolemmal KATP channel (Inagaki et al. 1995).