New insights into adenosine-mediated myocardial protection.

The cardiovascular effects of the endogenous purine, adenosine, have been recognized since 1929 when Drury & Szent-Gyorgyi (1929) reported that an extract isolated from bullock heart muscle produced rapid, transient decreases in heart rate, atrioventricular conduction and arterial blood pressure in dogs and guinea pigs. Forty years later, the first pharmacological evidence of adenosine receptors in the brain was postulated based on the effects of the methylxanthine, theophylline (Sattin & Rall, 1970). Since that time there is substantial evidence that adenosine exerts its effects in numerous tissues via the activation of at least four adenosine receptor subtypes. The notion that adenosine can also protect the heart (as well as other organs) during ischemia–reperfusion has similarly evolved over the years. Initial studies, nearly two decades ago, were based on the hypotheses that adenosine exerted its cardioprotective effects by stimulating the purine salvage pathway for ATP synthesis and via increased coronary blood flow. Although these effects are clearly beneficial, the results of numerous studies with adenosine receptor agonists and antagonists support the hypothesis that adenosine's cardioprotective effects are mediated primarily via the activation of cardiac adenosine receptor subtypes, expressed on ventricular cardiomyocytes and endothelial cells. The study by Manintveld et al. (2005) entitled ‘Intravenous adenosine protects the myocardium primarily by activation of a neurogenic pathway' raises several interesting new insights into adenosine cardioprotection. These authors observed that the infarct reducing effect of intravenous adenosine in intact rats was blocked by both the ganglionic blocker hexamethonium and the nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine (LNNA). Surprisingly, despite the fact that rats were administered adenosine at a dose of ∼500 μg kg−1 min−1, the authors observed no increase in cardiac interstitial fluid (ISF) adenosine levels or its metabolites. Thus these observations support the authors' hypothesis that adenosine exerted its beneficial effect via vascular and/or extracardiac mechanisms. We (Lasley & Mentzer, 1998; Lasley et al., 1999) have previously observed in both in vitro and in vivo preparations that adenosine must be delivered at a concentration sufficient to reach the myocardial ISF to exert its protection against postischemic myocardial dysfunction. So it is possible that, as the authors discussed, their inability to detect an increase in adenosine or its metabolites in myocardial ISF may have been due to the low recovery rate of their dialysis fibers. Alternatively, the end point in the present study was myocardial infarction, and there may be differences in the mechanisms by which adenosine reduces reversible and irreversible myocardial ischemic injury. The conclusions of Manintveld et al. (2005) do support an increasing body of evidence that adenosine may exert its cardioprotective effects via multiple mechanisms. It has previously been reported that polyadenylic acid, which is confined to the vascular space due to its large size, protected in vivo rabbit myocardium when administered during reperfusion presumably by an adenosine A2a receptor mechanism (Todd et al., 1996). An intravascular-confined adenosine A1 receptor agonist has been reported to induce a negative dromotropic effect in isolated guinea pig hearts (Rubio et al., 1999). Interestingly, this effect was blocked by an NOS inhibitor, consistent with the current results of Manintveld et al. (2005). Additional support for intravascular and extracardiac mechanisms of adenosine cardioprotection are the results of an increasing number of remote preconditioning studies, in which arterial occlusions at various sites (infrarenal aorta, mesenteric, skeletal muscle, cerebral) induce myocardial protection (for a review, see Przyklenk et al., 2003). Several studies have implicated a role for adenosine receptors in this phenomenon (Liem et al., 2002; 2005). Given the rapid metabolism of adenosine by erythrocytes and endothelial cells, it is unlikely (although not yet reported) that these remote interventions induce an increase in cardiac ISF adenosine levels. It is also possible that there may be tissue-specific mechanisms of remote preconditioning. The present authors have reported that in intact rats, mesenteric artery occlusion remote preconditioning is blocked by hexamethonium (Liem et al., 2002), whereas Weinbrenner et al. (2002) reported that infrarenal aortic occlusion remote preconditioning in rats was not blocked by ganglionic blockade. Several additional questions arise from this study that are pertinent to both experimental and clinical myocardial ischemia. Myocardial preconditioning protocols with adenosine receptor agonists are typically associated with both decreases in heart rate and blood pressure, which raises the possibility that reflex mechanisms associated with these responses may contribute to their protection. In addition to adenosine, opioids and bradykinin have been implicated as mediators of remote preconditioning (Schoemaker & Van Heijningen, 2000; Patel et al., 2002; Przyklenk et al., 2003). Thus although the heart appears to possess numerous preconditioning mechanisms, it still remains unknown why one receptor antagonist can essentially block this protection. A more complete understanding of the heart's intrinsic and extrinsic defense mechanisms may ultimately lead to the design of new therapies for the treatment of ischemic heart disease.