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Effects of an Endothelin Receptor Antagonist TAK-044 on Myocardial Energy Metabolism in Ischemia/Reperfused Rat Hearts

2000; Lippincott Williams & Wilkins; Volume: 35; Issue: 3 Linguagem: Inglês

10.1097/00005344-200003000-00009

1533-4023

Masaru Iimuro, Masanori Kaneko, Yuji Matsumoto, Yutaka Fujise, Toshifumi Watanabe, Hideharu Hayashi,

Electron Spin Resonance Studies

The purpose of this study was to investigate the effects of an endothelin-receptor antagonist TAK-044 on functional defects and metabolic derangement in myocardial ischemia/reperfusion injury. We sequentially measured high-energy phosphate metabolites and intracellular pH by phosphorus magnetic resonance spectroscopy during 35-min global ischemia followed by 60-min reperfusion in Langendorff-perfused rat hearts. TAK-044 (initial loading by 3 mg/kg followed by perfusion with 100 nM solution) was administered in two different ways: before ischemia or immediately after reperfusion. In addition, we investigated the effects of TAK-044 on functional defects and metabolic alterations induced by hydrogen peroxide (200 μM, 30 min). The recoveries of left ventricular developed pressure after reperfusion in TAK-044 groups (51 ± 12% in TAK-I, 61 ± 12% in TAK-R) were better than in control (10 ± 5% in control; p < 0.01). Increases in left ventricular end-diastolic pressure (LVEDP) in TAK-044 groups (22 ± 5 mm Hg in TAK-I, 24 ± 5 mm Hg in TAK-R) were less than in control (38 ± 3 mm Hg; p < 0.01). Adenosine triphosphate (ATP) (33 ± 5% in TAK-I, 28 ± 4% in TAK-R) in TAK-044 groups were higher than in control (13 ± 3%; p < 0.01). The creatine phosphokinase (CPK) release during reperfusion in TAK-044 groups (3.3 ± 1.5 IU/g wet wt/60 min in TAK-I, 3.5 ± 2.5 IU/g wet wt/60 min in TAK-R) were lower than in control (13.8 ± 3.9 IU/g wet wt/60 min; p < 0.05). In contrast, TAK-044 did not attenuate the myocardial injury induced by hydrogen peroxide. TAK-044, even if administered simultaneous with coronary reperfusion, attenuated myocardial ischemia/reperfusion injury. The energy-preservative effect of TAK-044 could be associated with the good functional recovery in ischemia/reperfused rat hearts.