Protective effect of the specific endothelin-1 antagonist BQ610 on mechanical function and energy metabolism during ischemia/reperfusion injury in isolated perfused rat hearts.
Endothelin-1 (ET-1) has been suggested to be involved in the pathophysiology of ischemia/reperfusion injury, but direct proof for this is still sparse. We tested whether protection of high-energy phosphate metabolism contributes to the beneficial effects of ETA receptor antagonists during ischemia/reperfusion. In isolated, buffer-perfused rat hearts, isovolumic function was measured by a left ventricular (LV) balloon, and 31P nuclear magnetic resonance spectra were continuously recorded. Two protocols were performed: (a) 15-min control, 30-min total, global ischemia, and 15-min reperfusion; and (b) 15-min control, 15-min total, global ischemia, and 30-min reperfusion. Treatment with BQ610 (1.75 micrograms/min) or saline was started during control and continued throughout the protocol. BQ610 did not affect function or energy metabolism under control conditions. In BQ610-treated hearts subjected to 30-min ischemia, time to ischemic contracture was significantly delayed (treated 10.6 +/- 0.4 min; untreated 8.1 +/- 0.7 min), and end-diastolic pressure (EDP) remained lower (after 30-min ischemia 26 +/- 2 vs. 35 +/- 2 mm Hg). In addition, recovery of mechanical function in BQ610-treated hearts was accelerated during reperfusion. BQ610 did not affect ATP but significantly accelerated and increased creatine phosphate (51 +/- 7 vs. 37 +/- 3%) recovery on reperfusion after 30-min ischemia. BQ610-treated hearts subjected to 15-min ischemia also showed lower EDP during ischemia and accelerated recovery of mechanical function during reperfusion. However, in this case, there were no differences in high-energy phosphate concentrations between treated and untreated hearts. We conclude that the protective action of BQ610 on mechanical function during ischemia/reperfusion injury can be but is not consistently associated with beneficial effects on cardiac high-energy phosphate metabolism.
Illing
B
B
Medizinische Universitätsklinik, Würzburg, Germany.
Horn
M
M
Han
H
H
Hahn
S
S
Bureik
P
P
Ertl
G
G
Neubauer
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D016232:Endothelins / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017725:Ventricular Pressure / Q000187:drug effects
D016232:Endothelins; D009842:Oligopeptides; D010725:Phosphocreatine; C087220:BQ 610; D000255:Adenosine Triphosphate