Role of Endothelin-A Receptors in Ischemic Contracture and Reperfusion Injury

Brünner, Friedrich; Opie, Lionel H.

doi:10.1161/01.cir.97.4.391

Cited by 48 publications

(26 citation statements)

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“…[12][13][14][37][38][39] In the present study, we also observed that ABT-627 alone and the combination of ABT-627/A-192621 had similar protective effects against postischemic cardiac dysfunction in rat hearts. Previous studies have demonstrated that ET-1 mRNA expression and its peptide production are increased in cardiomyocytes subjected to ischemia 40 and that plasma ET-1 levels are elevated in both humans 5 and experimental animals 11,41 with myocardial infarction.…”

Section: Discussionsupporting

confidence: 82%

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

et al. 2005

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Background-Endothelin (ET)-1 and norepinephrine (NE) are involved in myocardial ischemia/reperfusion injury. We investigated the role of ET-1 in ischemia/reperfusion-induced NE overflow and cardiac dysfunction using a selective ET A receptor antagonist (ABT-627), a selective ET B receptor antagonist (A-192621), and the spotting lethal (sl) rat, which carries a naturally occurring deletion in the ET B receptor gene. Methods and Results-According to the Langendorff technique, isolated hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. In Sprague-Dawley rat hearts, ischemia/reperfusion-induced cardiac dysfunctions such as decreased left ventricular developed pressure and coronary flow and increased left ventricular end-diastolic pressure were worsened by treatment with A-192621. This agent enhanced excessive NE overflow in the coronary effluent from the postischemic heart. In contrast, treatment with ABT-627, in the absence or presence of A-192621, significantly improved postischemic cardiac dysfunction and markedly suppressed NE overflow to the same extent. Postischemic cardiac dysfunction and NE overflow in the heart of ET B receptor-deficient homozygous (sl/sl) rats were highly observed compared with cases in wild-type rats, and exaggerated responses to ischemia/reperfusion in sl/sl rats were abolished by ABT-627 treatment. Exogenously applied ET-1 produced severe cardiac dysfunction and a significant increase in NE overflow in a dose-dependent manner, but these responses were markedly suppressed in the presence of 5-N-ethyl-N-isopropyl-amiloride, an inhibitor of the Na ϩ /H ϩ exchanger (NHE). Conclusions-Pharmacological blockade or genetic deficiency of ET B receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET A receptor activation. ET A /NHEmediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

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Section: Discussionsupporting

confidence: 82%

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

et al. 2005

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“…Endogenous ET is also released into the coronary perfusate of The protocol was approved by the institutional Animal isolated perfused rat hearts during ischaemia / reperfusion Ethics Committee. Male Porton rats weighing 40669 g [7]. In cultured human endothelium, hypoxia induces ET (n570) were anaesthetised with an intraperitoneal injecgene expression and secretion [8].…”

Section: Introductionmentioning

confidence: 99%

Endothelin B receptor-mediated vasoconstriction induced by endothelin A receptor antagonist

Zhang

Oliver

Horowitz

1998

Cardiovascular Research

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presence or absence of myocardial ischaemia / reperfusion. Methods: Isolated rat hearts were perfused using a Langendorff preparation. Global ischaemia was induced on average by 6862% (6standard error of the mean) reduction of a baseline perfusion flow-rate 10 min after introduction of ET antagonists. Thirty minutes of ischaemia was followed by 30 min reperfusion. ET-1 efflux in coronary perfusate 26 was measured by radioimmunoassay. Results: In non-ischaemic hearts (n57), BQ-123 (10 M) perfusion induced a progressive decrease in coronary flow-rate compared with control group. This flow reduction persisted after wash-out of BQ-123. In contrast, bosentan 25(10 M, n57) induced no change in perfusion rate. In the absence of ET antagonists (n516), there was a 2266% post-ischaemic increase in perfusion flow-rate. BQ-123 (n55) but not bosentan (n512) abolished this post-ischaemic increase in flow-rate. Neither BQ-123 nor bosentan induced significant variation in force of contraction. In ischaemic hearts, ischaemia per se induced a transient decrease in force of contraction. Bosentan significantly (P,0.05) accentuated and BQ-123 tended to accentuate (P50.06) this decrease in force of contraction during ischaemia. Bosentan but not BQ-123 significantly impaired the recovery of systolic function during reperfusion (P,0.05). Both BQ-123 and bosentan perfusion increased ET-1 efflux rate to 7306188% and 315681% respectively. This effect was abolished during ischaemia for BQ-123, but not for bosentan. Conclusions: In isolated perfused rat hearts, both BQ-123 and bosentan increased ET-1 efflux, but only BQ-123 exerted vasoconstrictor effects. These results thus generated the hypothesis that: (1) ET-1 release within the coronary vascular bed may be physiologically subject to negative feedback regulation mediated via ET receptors; A (2) ET receptor antagonists increase ET-1 efflux, which may lead to net vasoconstriction via unopposed ET stimulation. Furthermore, A B the negative inotropic effects observed during ischaemia suggest that ET is critical to the maintenance of systolic function during ischaemia.

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“…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).…”

mentioning

confidence: 99%

“…No attempt is made to investigate the mechanism underlying ET-1 recognition by cardiac myocytes, because it is known to involve ET type A receptors (9,10,19,43). However, by testing the effect of TMZ, a recognized anti-anginal and anti-ischemic agent (13), one may understand the site of action of TG.…”

mentioning

confidence: 99%

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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Role of Endothelin-A Receptors in Ischemic Contracture and Reperfusion Injury

Abstract: The data indicate that ET-1 exacerbates ischemic contracture and worsens ventricular and coronary reperfusion dysfunction by activating ET(A) receptors via a mechanism likely involving activation of Na+/H- exchange in this model.

Cited by 48 publications

References 48 publications

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

Endothelin B receptor-mediated vasoconstriction induced by endothelin A receptor antagonist

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

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