Effects of an endothelin receptor antagonist TAK-044 on myocardial energy metabolism in ischemia/reperfused rat hearts.
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 microM, 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.
Iimuro
M
M
Third Department of Internal Medicine, Hamamatsu University School of Medicine, Japan.
Kaneko
M
M
Matsumoto
Y
Y
Fujise
Y
Y
Watanabe
T
T
Hayashi
H
H
D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D004734:Energy Metabolism / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065128:Endothelin Receptor Antagonists; D016877:Oxidants; D010456:Peptides, Cyclic; C088196:TAK 044; D006861:Hydrogen Peroxide; D003402:Creatine Kinase