Preconditioning and limitation of stunning: one step closer to the protected protein(s)?

21 21 Brief periods of ischaemia, are known to induce a shifts of the p[Ca ] /Mg -ATPase curves induced by 21 reversible deficit in myocardial function despite the Ca sensitizer as observed with isolated myofibrils from maintenance of histological and metabolic integrity, a stunned pig myocardium [6]. Moreover, another group 21 phenomenon initially described by Heyndrickx et al. in found a decrease in the Ca sensitivity of isometric 1975, and called stunning several years after [1]. In that tension and the rate of cross-bridge cycling in skinned first study it was reported that several hours were required myocytes isolated from stunned pig myocardium [7]. for complete recovery of regional contractility following a Regarding the mechanism(s) upstream of the contractile 5 min occlusion of the left anterior descending coronary apparatus, it has become clear that oxidant stress and 21 artery in conscious dogs and up to 24 h were needed for Ca -overload are the two initial triggers that induce complete recovery following a 15 min occlusion [1]. myocardial stunning [8]. However, the chain of events 21 Therefore, myocardial stunning is considered to represent between free radical burst, increased [Ca ] and developi reversible injury contrasting the irreversible injury of ment of the abnormalities in the myofilaments remains to myocardial infarction. The phenomenon has been debe established. scribed in every species studied so far, does occur in One or several brief episode(s) of ischaemia, of inseveral clinical settings and likely plays an important role sufficient duration to cause myocyte necrosis, do(es) not in the morbidity of patients with coronary artery disease only induce myocardial stunning but is (are) also known to [2]. Although the principal cause of the reversible contracincrease the heart’s tolerance to a subsequent sustained tile dysfunction is not fully understood, there is now period of ischaemia, such that there is a delay of myocar21 consensus that loss of Ca responsiveness of the myofiladial necrosis. This beneficial effect on the heart, first ments represents a major underlying mechanism as first described by Murry et al. in 1986, is termed ischaemic proposed by Kusuoka et al. in 1987 on basis of experipreconditioning and has also been demonstrated in a wide ments with isolated perfused ferret hearts [3]. Initially variety of species including man [9]. The protective state some studies suggested an additional role of failing afforded by the preconditioning stimulus lasts 1–2 h 21 sarcoplasmic reticulum Ca pump, but this could not be depending on the species and model. This is called the first substantiated [4]. There is evidence that abnormalities in window of protection in contrast to the second window of myofilaments also underly stunning induced in clinically protection present after 24 h. At first, a cause and effect relevant large animal models. For instance, it was shown in relationship between stunning and preconditioning was 21 the in situ porcine model that the potent Ca sensitizer suggested because both phenomena are observed in re(EMD 60263), without phosphodiesterase inhibitory propversibly injured myocardium. However, results described erties, increased segment length shortening to a greater in a second report by Murry et al. [10] proved that extent in stunned than in non-stunned myocardium [5]. stunning is not involved in preconditioning which was These findings were consistent with the left-and upward confirmed by others (see e.g. ref. [12]). For instance, whereas a 15 min coronary occlusion followed by a 5 min