The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion

Grover, Gary J.; Dzwonczyk, Steven; Parham, Charles S.

doi:10.1093/cvr/27.9.1613

Cited by 146 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. In humans, acute hypertriglyceridemia stimulates ET-1 release in normal subjects (36).…”

supporting

confidence: 86%

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: 86%

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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“…Endothelin levels are elevated in patients with congestive heart failure, hypertension, and postmyocardial infarction and contribute to myocardial ischemic-reperfusion injury (12,32,38). Understanding the mechanism by which vasodilators counter endothelin-induced vasoconstriction may aid in developing pharmacological tools to counter the pathophysiological effects of endothelin.…”

Section: Discussionmentioning

confidence: 99%

Gender-specific K⁺-channel contribution to adenosine-induced relaxation in coronary arterioles

Heaps

Bowles

2002

Journal of Applied Physiology

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Heaps, Cristine L., and Douglas K. Bowles. Gender-specific K ϩ -channel contribution to adenosine-induced relaxation in coronary arterioles. J Appl Physiol 92: 550-558, 2002. First published October 5, 2001 10.1152/ japplphysiol.00566.2001.-We examined the contribution of K ϩ -channel activity on basal tone and adenosine-mediated relaxation of coronary arterioles isolated from sexually mature male and female miniature swine. Arterioles (ϳ100-200 m ID) isolated from the apical region of the heart were cannulated and studied using videodimensional analysis under constant intraluminal pressure. Coronary arterioles from male and female pigs demonstrated similar levels of basal tone and reductions in basal diameter in response to the K ϩ -channel blockers 4-aminopyridine (4-AP; 1 mM), tetraethylammonium (1 mM), and glibenclamide (Glib; 10 M), with 4-AP producing significantly greater constriction than tetraethylammonium or Glib. After endothelin-induced preconstriction, relaxation responses to adenosine were not significantly different between coronary arterioles of male and female pigs. Inhibition of 4-AP-sensitive channels significantly impaired adenosine-mediated relaxation in arterioles from male but not female pigs. However, inhibition of K ϩ channels with iberiotoxin (100 nM) or Glib had no effect on adenosine-induced relaxation in either sex. Results obtained in the presence of nitric oxide synthase inhibition suggest a potential interaction of 4-AP-sensitive channels and nitric oxide at low adenosine concentrations. In conclusion, our data indicate that 4-AP-sensitive channels 1) contribute significantly to basal tone in coronary arterioles of both male and female pigs, 2) contribute to adenosine-mediated relaxation in male but not female pigs, and 3) can contribute to adenosine-induced relaxation independent of nitric oxide production in male pigs. These data are consistent with a significant role for voltage-dependent K ϩ channels in adenosine-mediated relaxation of coronary arterioles from males. potassium channel; smooth muscle; endothelium; nitric oxide synthase; endothelin ADENOSINE IS AN ENDOGENOUS vasodilator that produces vascular smooth muscle relaxation through a variety of mechanisms that act to reduce intracellular Ca 2ϩ levels and decrease Ca 2ϩ sensitivity of the contractile apparatus. K ϩ -channel activation has been identified as an important component of adenosine-mediated relaxation (7,13,19,31). Increased K ϩ -channel activity hyperpolarizes smooth muscle and thereby reduces smooth muscle contraction via reduced Ca 2ϩ entry through voltage-dependent Ca 2ϩ channels.Both Ca 2ϩ -activated K ϩ (K Ca ) channels and ATPsensitive K ϩ (K ATP ) channels have been reported to contribute to adenosine-mediated relaxation in vascular smooth muscle. Price and colleagues (7, 31) have demonstrated significant roles for K Ca channels in both basal tone and adenosine-mediated relaxation in pressurized canine coronary arterioles. In contrast, Kuo and colleagues (13,19) reported that inhibition of K ATP chan...

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“…Likewise, Grover et al reported that BQ-123 had no effect on regional myocardial blood flow in ischemic and non-ischemic tissue [34].…”

Section: Discussionmentioning

confidence: 98%

The Effect of Selective Endothelin Receptor a Antagonism by Bq-123 on Myocardial Ischemia-Reperfusion Induced Apoptotic Cell Death

Çolak¹,

Parlakpınar²,

Ermiş³

et al. 2012

Med-Science

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The objective of the present study was to investigate the possible impact of specific endothelin-A (ET A ) receptor blockage by BQ-123 on myocardial ischemia-reperfusion (MI/R) induced apoptosis in rats. To produce MI/R, a branch of the descending left coronary artery was occluded for 30 min followed by 2 h reperfusion. Thirty-two rats were randomly assigned to four groups equally: (1) sham-operated group, (2) MI/R group, (3) MI/R+BQ-123-treated group, and (4) MI/R+ET-1+BQ

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The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion

Abstract: These data indicate that endothelin-1 release during ischaemia may be involved in the pathogenesis of myocardial ischaemia and infarction.

Cited by 146 publications

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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

Gender-specific K⁺-channel contribution to adenosine-induced relaxation in coronary arterioles

The Effect of Selective Endothelin Receptor a Antagonism by Bq-123 on Myocardial Ischemia-Reperfusion Induced Apoptotic Cell Death

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The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion

Abstract: These data indicate that endothelin-1 release during ischaemia may be involved in the pathogenesis of myocardial ischaemia and infarction.

Cited by 146 publications

References 0 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

Gender-specific K+-channel contribution to adenosine-induced relaxation in coronary arterioles

The Effect of Selective Endothelin Receptor a Antagonism by Bq-123 on Myocardial Ischemia-Reperfusion Induced Apoptotic Cell Death

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Gender-specific K⁺-channel contribution to adenosine-induced relaxation in coronary arterioles