Effect of EndothelinA-Receptor Antagonist BQ-123 and Phosphoramidon on Cerebral Vasospasm

Abstract

Summary: The present study was designed to determine whether an endothelinA (ETA)-receptor antagonist BQ-123 (cyclo[Dtrp, Dasp, pro-D-Val-Leu]) or an ET-converting enzyme inhibitor phosphoramidon may prevent development of cerebral vasospasm after subarachnoid hemorrhage (SAH). A “double hemorrhage” canine model of the disease was used (n = 17 dogs), and the degree of vasospasm of the basilar artery was assessed by angiography. Mongrel dogs of either sex were divided into three experimental groups: animals treated with daily intracisternal injections of BQ-123 (10-4M; n = 6) or phosphoramidon (2 × 10-4M; n = 6) and control animals treated with saline solution (n = 5). Diameter of basilar arteries in animals treated with saline solution was reduced by SAH to 56 ± 7% of control diameter. BQ-123 and phosphoramidon did not significantly affect SAH-induced vasospasm (diameters were 62 ± 0% and 56 ± 10% of control diameters for BQ-123 and phosphoramidon, respectively). In contrast, in isolated canine basilar arteries BQ-123 (10-5M) selectively inhibited concentration-dependent contractions to ET-1 (10-11-3 × 10-8M; n = 5). Levels of immunoreactive ET in plasma and cerebrospinal fluid were not affected by development of vasospasm. These results suggest that intracisternal injections of ETA-receptor antagonist or phosphoramidon cannot prevent SAH-induced cerebral vasospasm and that ET-1 may not be the major mediator responsible for the decrease in cerebral arterial diameter associated with SAH.