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 pathophys iology of ischemia/reperfusion injury, but direct proof for this is st ill sparse. We tested whether protection of high-energy phosphate meta bolism contributes to the beneficial effects of ET(A) receptor antagon ists during ischemia/reperfusion. In isolated, buffer-perfused rat hea rts, isovolumic function was measured by a left ventricular (LV) ballo on, and P-31 nuclear magnetic resonance spectra were continuously reco rded. Two protocols were performed: (a) 15-min control, 30-min total, global ischemia, and 15-min reperfusion; and (b) 15-min control, 15-mi n total, global ischemia, and 30-min reperfusion. Treatment with BQ610 (1.75 mu g/min) or saline was started during control and continued th roughout the protocol. BQ610 did not affect function or energy metabol ism 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-diastoli c pressure (EDP) remained lower (after 30-min ischemia 26 +/- 2 vs. 35 +/- 2 mm Hg). In addition, recovery of mechanical function in BQ610-t reated hearts was accelerated during reperfusion. BQ610 did not affect ATP but significantly accelerated and increased creatine phosphate (5 1 +/- 7 vs. 37 +/- 3%) recovery on reperfusion after 30-min ischemia. BQ610-treated hearts subjected to 15-min ischemia also showed lower ED P during ischemia and accelerated recovery of mechanical function duri ng reperfusion. However, in this case, there were no differences in hi gh-energy phosphate concentrations between treated and untreated heart s. We conclude that the protective action of BQ610 on mechanical funct ion during ischemia/reperfusion injury can be but is not consistently associated with beneficial effects on cardiac high-energy phosphate me tabolism.