Effect of an endothelin-1 antagonist, BQ-485, on cerebral oxygen metabolism after complete global cerebral ischemia in dogs

Endothelin-1 (ET-1) plays an important role in the physiologic or pathophysiologic regulation of cerebral circulation. To evaluate the effects of the newly synthesized ET(A) receptor-selective antagonist, BQ-485 (N-perhydroazepin-1-ylcarbonyl-Leu-D-Trp-D-Trp-OH), on the cerebral metabolism of oxygen during the delayed cerebral hypoperfusion that follows global cerebral ischemia, we occluded the ascending aorta and caval veins of 10 beagle dogs for 12.5 min. The animals were randomized into two groups. BQ-485 was given directly into the carotid artery at 0.03 mg/kg per min for 30 min, starting 15 min after reperfusion in the treatment group (n = 5). Isotonic saline was infused in the control group (n = 5). A fiberoptic catheter was inserted into the superior sagittal sinus to monitor its oxygen saturation (S-ssO2) continuously. Arterial O-2 content (Ca-o2): and sagittal sinus O-2 content (C-ssO2) were monitored before and at 0.5, 1, 2, 4, 6 and 8 h after the ischemic insult. BQ-4X5 significantly prevented the expected decrease in S-SSO2 and increase in the cerebral O-2 utilization coefficient at 4, 6 and 8 h after the ischemic insult (P < 0.05). Thus, BQ-485 ameliorated the mismatch between O-2 supply and demand in the delayed hypoperfusion phase. We conclude that ET may be involved in the pathogenesis of delayed cerebral hypoperfusion after cardiac arrest. (C) 1997 Elsevier Science Ireland Ltd.