Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Abstract

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

Contribution of Nitric Oxide in Big Endothelin-1–induced Cardioprotective Effects on Ischemia/Reperfusion Injury in Rat Hearts

“…4,13 In fact, we have recently shown that exogenous big ET-1 inhibits NE overflow after ischemia/reperfusion and that this contributes to suppression of deterioration of cardiac function. 8 In this study, the treatment with big ET-1 in the presence of NOARG failed to exert beneficial effects against ischemia/ reperfusion-induced NE overflow and subsequent cardiac dysfunction, as in the case of SM-19712 or A-192621 observed in our previous work. 8 It is widely recognized that NO has protective effects against several cardiovascular diseases.…”

“…8 Although several signaling pathways are activated in response to ET B receptor stimulation, NO is one of the most prominent mediator, because NOS inhibition can attenuate ET B receptor-mediated responses. 9,10 In this study, there was a marked increase in NO x levels in the coronary effluent in the case of exogenous big ET-1 application, which was abolished by the combination with NOARG, a nonselective NOS inhibitor.…”

“…As recently reported, A-192621 and SM-19712 significantly attenuated the big ET-1-induced decreasing effect on the NE overflow. 8 …”

“…[5][6][7] Recently, however, we have shown that the suppression of NE overflow and improvement of cardiac dysfunction after ischemia/reperfusion are observed by appropriate amount of exogenous big ET-1 application. 8 In addition, the above big ET-1-induced actions were mediated by a conversion to ET-1 by ECE and following stimulation of ET B receptor.…”

Endothelin-1 during myocardial ischaemia: a double-edged sword?

“…7 In Langendorff-perfused rat hearts, subjected to global ischaemia (40-min) followed by (30-min) reperfusion, big-ET-1 was administered in the perfusate, beginning 15 min before ischaemia until 5 min after the onset of reperfusion. Three concentrations (0.1, 0.3 and 1 nM) were tested, and indices of left ventricular function after ischemia/reperfusion were measured.…”