Abstract |
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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Authors | T Watanabe, Y Awane, S Ikeda, S Fujiwara, K Kubo, T Kikuchi, K Kusumoto, M Wakimasu, M Fujino |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 114
Issue 5
Pg. 949-54
(Mar 1995)
ISSN: 0007-1188 [Print] England |
PMID | 7780649
(Publication Type: Journal Article)
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Chemical References |
- Endothelin Receptor Antagonists
- Iodine Radioisotopes
- Peptides, Cyclic
- TAK 044
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Topics |
- Animals
- Blood Pressure
(drug effects)
- Brain
(metabolism)
- Coronary Vessels
(drug effects)
- Endothelin Receptor Antagonists
- Endothelium, Vascular
(physiology)
- In Vitro Techniques
- Iodine Radioisotopes
- Male
- Membranes
(metabolism)
- Muscle, Smooth, Vascular
(drug effects)
- Myocardial Infarction
(drug therapy, pathology)
- Myocardial Reperfusion Injury
(drug therapy)
- Myocardium
(metabolism, pathology)
- Peptides, Cyclic
(pharmacology, therapeutic use)
- Rabbits
- Rats
- Rats, Wistar
- Swine
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