Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151814 (coronary occlusion)
 3,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The aims of the present study were to characterize the pharmacological profile of a new endothelin (ET) receptor antagonist, TAK-044 and to consider whether it limits the extension of myocardial infarct size in rats. 2. Binding of [125I]-ET-1 to ET receptors on rabbit ventricular and cerebellar membrane fractions was inhibited by TAK-044 with IC50 values of 3.8 nM and 130 nM, respectively. 3. It inhibited ET-1, ET-2 and ET-3-induced vasoconstriction of porcine isolated coronary arteries in a competitive (ET-1, ET-2) and a non-competitive (ET-3) manner. 4. In the rat in vivo, the ET-1-induced blood pressure changes including transient hypotension followed by sustained hypertension, were inhibited by TAK-044 (0.1-10 mg kg-1, i.v.) in a dose-dependent manner. 5. Acute myocardial infarction induced by 1 h coronary occlusion followed by 24 h reperfusion in rats caused an infarct size of 60 +/- 2% (n = 12) of the area-at-risk by weight. 6. Intravenous injection of TAK-044 10 min before coronary occlusion reduced the infarct size in a dose-dependent manner: 32% and 54% reductions at 1 and 3 mg kg-1, respectively. 7. TAK-044 administered 10 min before or 1 h after reperfusion (1 mg kg-1, i.v.) showed similar inhibitory effects: 34% and 23% reductions, respectively. 8. We conclude that TAK-044 is an ETA/ETB receptor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion-reperfusion in rats.
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PMID:Pharmacology of a non-selective ETA and ETB receptor antagonist, TAK-044 and the inhibition of myocardial infarct size in rats. 778 Jun 49

The aims of this study were to determine if the ETB receptor agonist, sarafotoxin 6c (S6c) reduces myocardial infarct size following myocardial ischemia and reperfusion and to investigate whether any changes in mRNA for endothelin receptors in the injured myocardium were modified by S6c pretreatment. Hypnorm/Hypnovel anesthetized rats were subjected to occlusion of the left main coronary artery for 30 minutes, followed by 120 minutes reperfusion. Animals were administered a bolus dose of S6c (0.24 nmol kg-1 i.v., n = 10) or saline (n = 15) 5 minutes prior to occlusion. At the end of reperfusion, hearts were stained with Evan's Blue dye to delineate area at risk. A 1.5- to 2.0-mm thick slice was cut transmurally 1 mm below the site of ligation for assessment of infarct size by triphenyltetrazolium chloride. A further transmural slice (2.5-3-mm thick) was cut for assessment of receptor mRNA levels by RTPCR. Administration of S6c caused a transient fall in mean arterial blood pressure (MABP) prior to occlusion and attenuated the fall in MABP induced by coronary occlusion. S6c significantly reduced infarct size (13 +/- 4% of area of slice at risk) compared with control hearts (35 +/- 5%; P < 0.05). In control hearts, there was a marked reduction in mRNA content for both ETA (50% reduction) and ETB (70% reduction) receptors in the ischemic zone, compared with non-ischemic tissue. In hearts pre-treated with S6c there was a reduction in ETA, but not ETB receptor mRNA in the ischemic zone. This study has shown that S6c reduces myocardial infarct size and results in preservation of ETB receptor mRNA in ischemic/reperfused tissue.
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PMID:Sarafotoxin 6c (S6c) reduces infarct size and preserves mRNA for the ETB receptor in the ischemic/reperfused myocardium of anesthetized rats. 1524 94

Sudden cardiac death constitutes a major health-related problem. In the majority of cases, sudden cardiac death is due to ventricular tachyarrhythmias secondary to acute myocardial infarction. The pathophysiologic chain of events leading to ventricular tachyarrhythmias after acute coronary occlusion is complex and incompletely understood. Experimental and clinical studies have indicated that endothelin-1 production rises markedly very early in the course of myocardial infarction. Endothelin-1 exerts significant electrophysiologic actions on ventricular cardiomyocytes and participates in the genesis of ischemic ventricular tachyarrhythmias. Endothelin-1, acting via two G-protein-coupled receptors (ETA and ETB), prolongs the action potential duration and increases the occurrence of spontaneous calcium transients, resulting in early afterdepolarizations and ventricular tachyarrhythmias via triggered activity. Moreover, endothelin-1 enhances sympathetic stimulation, a well established contributor to ventricular arrhythmogenesis during acute myocardial infarction. Despite these considerations, the therapeutic potential of endothelin receptor antagonists as antiarrhythmic drugs during myocardial ischemia/infarction is still under investigation. To date, a number of endothelin-1 receptor antagonists are available, presenting different degrees of selectivity for ETA and ETB receptors. The arrhythmogenic effects of endothelin-1 are exerted mainly via stimulation of the ETA receptors, but the role of ETB receptors remains controversial, as previous studies have produced conflicting results. This review summarizes the current state-of-the-art on the role of endothelin-1 in the genesis of ventricular arrhythmias during acute myocardial infarction and raises some hypotheses that could be explored in future studies.
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PMID:Do endothelin receptor antagonists have an antiarrhythmic potential during acute myocardial infarction? Evidence from experimental studies. 2053 2

Ventricular arrhythmogenesis during acute coronary syndromes is a common cause of sudden cardiac death, but the underlying mechanisms remain incompletely understood. Recent evidence indicates an emerging pathophysiologic role of endothelin-1 during myocardial ischaemia and evolving infarction. At the early stages post-coronary occlusion, endothelin-1 enhances sympathetic activation, an effect mediated via the ETA receptor, whereas the ETB receptor exerts protective actions. The importance of this interaction is clearly decreased during subsequent stages, during which endothelin-1 may participate in the genesis of ventricular tachycardia or fibrillation via other mechanisms; of these, the effects of endothelin-1 on repolarizing potassium currents and electrical conduction via gap junctions merit further research. The relative roles of ETA and ETB receptors during this phase are unclear. Evaluation of the arrhythmogenic effects of endothelin-1 during acute coronary syndromes may provide the tools towards lowering sudden cardiac death rates.
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PMID:Ventricular tachyarrhythmias during acute myocardial infarction: the role of endothelin-1. 2448 3