Endothelin release during ischaemia and reperfusion of isolated perfused rat hearts

Brünner, Friedrich; Ef, Du Toit; Lh, Opie

doi:10.1016/0022-2828(92)93095-2

Cited by 100 publications

(42 citation statements)

References 31 publications

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“…Studies in isolated hearts showed that ET-1 release increases on early reperfusion after ischemia, thereby contributing to injury (7), and that ET-1 is a major factor that depresses cardiac function (6) and causes cell necrosis (8). These findings are consistent with other studies (21,23,30) demonstrating a relationship between ET-1 and the pathogenesis of myocardial ischemia.…”

supporting

confidence: 85%

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

Monti

Allibardi

Piatti³

et al. 2001

American Journal of Physiology-Heart and Circulatory Physiology

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. Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine. Am J Physiol Heart Circ Physiol 281: H1122-H1130, 2001.-There is growing evidence that hypertriglyceridemia exacerbates ischemic injury. We tested the hypothesis that triglycerides impair myocardial recovery from low-flow ischemia in an ex vivo model and that such an effect is related to endothelin-1. Hyperglycemic (glucose concentration ϭ 12 mmol/l) and hyperinsulinemic (insulin concentration ϭ 1.2 mol/l) isolated rat hearts were perfused with Krebs-Henseleit buffer (PO 2 ϭ 670 mmHg, pH 7.4, 37°C) added with increasing triglycerides (0, 1,000, 2,000, and 4,000 mg/dl, n ϭ 6-9 rats/group). Hearts were exposed to 60 min of low-flow ischemia (10% of basal coronary flow), followed by 30 min of reperfusion. We found that increasing triglycerides impaired both the diastolic (P Ͻ 0.005) and systolic (P Ͻ 0.02) recovery. The release of endothelin-1 during reperfusion increased linearly with triglyceride concentration (P ϭ 0.0009). Elevated triglycerides also increased the release of nitrite and nitrate (NO x), the end products of nitric oxide, up to 6 mol/min. Trimetazidine (1 mol) further increased NO x release, blunted endothelin-1 release, and protected myocardial function during recovery. We conclude that high triglyceride levels impair myocardial recovery after low-flow ischemia in association with endothelin-1 release. The endothelium-mediated effect of triglycerides on both contractile recovery and endothelin-1 release is prevented by 1 M trimetazidine. nitric oxide ACCUMULATING EPIDEMIOLOGICAL EVIDENCE suggests that the situation characterized by elevated plasma triglycerides (TG) is associated with increased cardiovascular risk independent of factors such as hyperglycemia and elevated plasma cholesterol (3). Hypertriglyceridemia is also a critical risk factor for coronary heart disease (CHD) mortality in subjects with impaired glucose tolerance or diabetes (18). Furthermore, hypertriglyceridemia is a common finding in survivors of acute myocardial infarction (27). This epidemiological evidence suggests that TG influence myocardial performance after ischemia-reperfusion independently of atherosclerosis progression.Although its role in acute ischemia-reperfusion is controversial, endothelin-1 (ET-1) is known to exacerbate injury, likely via activation of ET type A receptors (9). Studies in isolated hearts showed that ET-1 release increases on early reperfusion after ischemia, thereby contributing to injury (7), and that ET-1 is a major factor that depresses cardiac function (6) and causes cell necrosis (8). These findings are consistent with other studies (21, 23, 30) demonstrating a relationship between ET-1 and the pathogenesis of myocardial ischemia. In humans, acute hypertriglyceridemia stimulates ET-1 release in normal subjects (36). In addition, hypertriglyceridemia is related with elevated plasma levels of ET-1 in glucose-intolerant and type II diabetic patients with insulin resistance syndrome (37). H...

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supporting

confidence: 85%

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

Monti

Allibardi

Piatti³

et al. 2001

American Journal of Physiology-Heart and Circulatory Physiology

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“…Moreover, ischaemia/reperfusion of the isolated perfused heart of the rat enhances the coronary vasoconstriction elicited by ET-1 (Neubauer et al, 1990b;1991;Stewart & Baffour, 1990;Brunner et al, 1992;Grover et al, 1992;Watts et al, 1992;McMurdo et al, 1993b). Enhanced plasma levels of ET-1 in man are associated with a variety of cardiovascular disorders including acute myocardial infarction (Miyauchi et al, 1989;Salminen et al, 1989), angina pectoris (Nakao et al, 1989), coronary artery vasospasm (Matsuyama et al, 1990) and congestive heart failure (Grenier et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

The effects of the endothelin ET_A receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion

McMurdo

Thiemermann

Vane

1994

British J Pharmacology

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1 The effects were investigated of the ETA receptor antagonist, FR 139317, on endothelin-1 (ET-1)-induced coronary vasoconstriction in the isolated perfused heart of the rabbit. In addition, this study examined whether FR 139317 reduced infarct size in a rabbit model of coronary artery occlusion and reperfusion.2 In the rabbit isolated perfused heart, ET-1 (1-100pmol) elicited a dose-dependent increase in coronary perfusion pressure (CPP). For example, 30 pmol ET-1 caused CPP to rise by 22 ± 8 mmHg and 100 pmol ET-1 by 47 ± 10 mmHg (n = 8). Infusion of FR 139317 (1 f.M) significantly attenuated the increase in CPP caused by ET-1 (30 pmol: 3 ± 1 mmHg, 100 pmol: 8 ± 2 mmHg; n = 8). 3 In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 45 or 60 min of coronary artery occlusion followed by 2 h of reperfusion was 47 ± 6% (n = 6) and 55 ± 7%(n = 5), respectively. A continuous infusion of FR 139317 (0.2 mg kg-Imin-preceded by a loading dose of 1.0 mg kg-', i.v.; n = 5-6) had no effect on the extent of the myocardial infarct size (45 min: 47 ± 6%; 60 min: 49 ± 7%). Even a three-times higher dose (0.6 mg kg-min-' preceded by a loading dose of 3 mg kg-', i.v.; n = 4) of FR 139317 had no effect on myocardial infarct size (48 ± 5%) after 45 min occlusion of the antero-lateral branch of the left coronary artery (LAL) and 2 h reperfusion. 4 In a separate group of experiments, the LAL was occluded for 60 min and subsequently reperfused for 6 h. FR 139317 (0.6mg kg-Imin' preceded by a loading dose of 3 mg kg', i.v.; n =4) had no significant effect on infarct size even in this long reperfusion model (control: 48 ± 3%, FR 139317: 61 ± 6%). Thus, the vasoconstrictor effects elicited by ET-1 in the coronary vasculature of the rabbit are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, FR 139317. However, an enhanced formation of endogenous ET-1 does not play a major role in ischaemia/ reperfusion injury of the rabbit heart, for FR 139317 had no effect on infarct size.

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“…We and others have demonstrated that cardiac ET-1 production is increased by ischemia, followed by reperfusion 6,23 and that increased ET-1 is involved in the postischemic cardiac dysfunction by enhancing NE overflow via the stimulation of ET A receptor existing in the sympathetic nerve endings. [7][8][9][10]14 In addition, we obtained evidence that exogenously applied ET-1 to the ischemic heart further enhanced the NE overflow and exacerbates the postischemic cardiac dusfunction.…”

Section: Discussionmentioning

confidence: 88%

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

et al. 2010

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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

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Endothelin release during ischaemia and reperfusion of isolated perfused rat hearts

Cited by 100 publications

References 31 publications

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

The effects of the endothelin ET_A receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion

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

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Endothelin release during ischaemia and reperfusion of isolated perfused rat hearts

Cited by 100 publications

References 31 publications

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

Triglycerides impair postischemic recovery in isolated hearts: roles of endothelin-1 and trimetazidine

The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion

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

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The effects of the endothelin ET_A receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion