706-6 Endothelin-1 Receptor Antagonists BQ123 and BQ610 Delay Ischemic Contracture, Preserve High-Energy Phosphate Metabolism and Improve Systolic Function During Ischemia/Reperfusion

Using specific Endothelin-l (ET-1) antagonists BQ123 and BQ61 0, we tested whether endogenous ET-1 contributes to ischemia/reperfusion injury in isolated, Langendorff-perfused rat hearts. BQ123 (7 μg/min) and BQ610 (1.75 μg/min) did not affect mechanical function or coronary flow and shifted the dose-response curve for ET-1 significantly to the right. Isovolumic rat hearts were pre-treated with BQ123, BQ610 or saline for 10 min, and were subjected to 30 min ischemia followed by reperfusion. At 15 min ischemia, the increase of left ventricular resting pressure (mmHg) was significantly reduced by BQ 123(17 ± 3*; n = 11) and B0610(17 ± 3*; n = 12) compared to saline (45 ± 7; n = 12). During reperfusion, recovery of left ventricular developed pressure (mmHg) was improved with BQ123 (23 ± 7*) and BQ61 0 (20 ± 3*) compared to saline (10 ± 3). In hearts pre-treated with BQ610, highenergy phosphate metabolism was continuously recorded with 31P-NMR spectroscopy (7T Bruker NMR System). ATP content (% of control) at 30 min ischemia was higher with BQ610 (20 ± 3*; n = 11) compared to saline (5 ± 2; n = 8), and creatine phosphate recovery (% of control) was improved with BQ610 during reperfusion (76 ± 7*vs 54 ± 6 with saline). Thus, endogenous ET-1 contributes to ischemia/reperfusion injury. Specific ET-1 antagonists attenuate functional and metabolic consequences of ischemia/reperfusion injury without affecting pre-ischemic workload.*p < 0.05 vs. saline