bq-485 and Ischemic-Attack--Transient

Endothelin-1 is a very powerful endogenous vasoconstrictor substance produced by endothelial cells. Its long-lasting vasoconstrictor and hypertensive action has been well documented in several species, including humans.. It is generally accepted that endothelin-1 may contribute to the pathogenesis of a number of cardiovascular diseases. In the cerebral vasculature, endothelin-1 has been proposed as a key mediator of cerebral vasospasm following subarachnoid hemorrhage. Availability of endothelin-1 antagonist provided a pharmacologic tool to test the role of endothelin in the development of vasospasm.. This brief review is focused on the controversial results reported by different groups concerning the possible role of endothelin-1 in narrowing of cerebral arteries exposed to autologous blood.

Topics: Animals; Azepines; Endothelin Receptor Antagonists; Endothelins; Humans; Indoles; Ischemic Attack, Transient; Oligopeptides; Peptides, Cyclic; Subarachnoid Hemorrhage

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 ETA receptor-selective antagonist, BQ-485 (N-perhydroazepin-l-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 (SssO2) continuously. Arterial O2 content (CaO2), and sagittal sinus O2 content (CssO2) were monitored before and at 0.5, 1, 2, 4, 6 and 8 h after the ischemic insult. BQ-485 significantly prevented the expected decrease in SssO2 and increase in the cerebral O2 utilization coefficient at 4, 6 and 8 h after the ischemic insult (P < 0.05). Thus, BQ-485 ameliorated the mismatch between O2 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.

Topics: Analysis of Variance; Animals; Azepines; Brain; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Endothelin Receptor Antagonists; Heart Arrest; Injections, Intra-Arterial; Ischemic Attack, Transient; Oligopeptides; Oxygen Consumption; Random Allocation; Receptor, Endothelin A

Because endothelin-1 has a potent and long-lasting vasoconstrictive action, it has been proposed that it plays some important roles in the pathogenesis of delayed cerebral vasospasm following subarachnoid hemorrhage. We examined the preventive effect of a novel ETA receptor antagonist, BQ-485, on experimental vasospasm using canine two-hemorrhage model of subarachnoid hemorrhage. The IC50 value of BQ-485 on [125I]endothelin-1 binding was 3.4 x 10(-9) M for ETA receptor and 26 x 10(-6) M for ETB receptor. Systemic continuous administration of 120 mg/day of the agent inhibited the narrowing of canine basilar artery on day 7 following experimental subarachnoid hemorrhage (75.0% vs 59.9% (control), p < 0.01). The present results suggest that endothelin-1 and ETA receptor participate in the pathogenesis of delayed cerebral vasospasm.

Topics: Animals; Aorta; Azepines; Binding, Competitive; Cell Membrane; Cerebellum; Cerebral Hemorrhage; Coronary Vessels; Dogs; Endothelin Receptor Antagonists; Endothelins; Ischemic Attack, Transient; Muscle, Smooth, Vascular; Oligopeptides; Receptors, Endothelin; Swine; Vasoconstriction; Vasoconstrictor Agents