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Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET A receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/ reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt max ) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET B receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET A receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET B receptors to exert its related beneficial actions. Keywords: big endothelin-1; endothelin-1; ischemia/reperfusion; norepinephrine INTRODUCTION Endothelin-1 (ET-1) was originally found as a 21-amino-acid vasoconstrictor peptide produced by vascular endothelial cells. 1 This peptide is most abundant in the cardiovascular system, and at least two distinct ET receptors, ET A and ET B , have been identified. ET A receptors mediate vasoconstriction and cell proliferation, whereas ET B receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin. 2 There is accumulating evidence that ET-1 is closely related to the pathogenesis and development of several cardiovascular diseases. 3,4 It has been demonstrated that ischemia increases ET-1-binding sites in cardiac membranes. 5 In addition, we have recently noted that left ventricular ET-1 content is increased by ischemia/reperfusion in isolated rat hearts, and postischemic cardiac dysfunction is improved by suppressing the ET-1 biosynthesis. 6 These findings imply that endogenously generated ET-1 plays an important role in the pathophysiology of myocardial ischemia/reperfusion. Indeed, both selective

We investigated whether the cardioprotective effect of ischemic postconditioning (postC) against ischemia/reperfusion (I/R)-induced cardiac dysfunction is associated with the negative control of I/R-enhanced norepinephrine (NE) overflow, an aggravating factor of I/R injury, in comparison with the effects induced by ischemic preconditioning (preC). According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. PostC, consisting of three cycles of 30-second reperfusion followed by 30-second ischemia at the end of the 40-minute ischemia, improved I/R-induced cardiac dysfunction. However, the potency of this postC-induced improvement was somewhat weaker than that produced by preC, consisting of three cycles of 5-minute ischemia followed by 5-minute reperfusion before 40-minute ischemia. The preC treatment markedly suppressed I/R-enhanced NE overflow, whereas postC had no apparent effect. A nonselective nitric oxide synthase inhibitor, N-nitro-L-arginine, almost completely abolished postC-induced cardiac protection without affecting NE overflow, whereas the effect of preC on I/R-induced cardiac dysfunction and NE overflow was only partially inhibited by N-nitro-L-arginine. These findings indicate that the beneficial effect of postC on I/R-induced cardiac dysfunction depends on nitric oxide and is irrelevant to NE overflow after reperfusion in contrast to the preC effect.

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We have recently shown that an appropriate amount of exogenous big endothelin-1 (ET-1) has beneficial effects on ischemia-/reperfusion-induced norepinephrine overflow and cardiac dysfunction in rat hearts and that these effects occur through a conversion to ET-1 by endothelin-converting enzyme and following stimulation of ETB receptor. In this study, we examined the possible involvement of nitric oxide (NO) in the big ET-1-induced cardioprotective effects. According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Exogenous big ET-1 (0.3 nM) significantly increased NOx (NO2/NO3) level in the coronary effluent after onset of reperfusion. This effect was markedly attenuated by treatment with SM-19712 (selective endothelin-converting enzyme inhibitor), A-192621 (selective ETB receptor antagonist), or NG-nitro-l-arginine (nonselective NO synthase inhibitor), respectively. In addition, N-nitro-l-arginine blunted big ET-1-induced suppression of norepinephrine overflow and improvement of cardiac dysfunction after ischemia/reperfusion. These findings suggest that NO produced by ETB receptor activation plays an important role in exogenous big ET-1-induced actions.