SYSTEMIC ADMINISTRATION OF AN INHIBITOR OF ENDOTHELIN-CONVERTING ENZYME FOR ATTENUATION OF CEREBRAL VASOSPASM FOLLOWING EXPERIMENTAL SUBARACHNOID HEMORRHAGE

The potent vasoconstrictor peptide, endothelin-1 (ET-1), has been impl icated in the pathophysiology of cerebral vasospasm that occurs after subarachnoid hemorrhage (SAH). This peptide is synthesized as a large prepropeptide that requires a series of modifying steps for its activa tion. The last of these steps involves the proteolytic conversion of a relatively inactive propeptide, Big ET-1. to its active, 21-amino aci d peptide form. The enzyme responsible for converting Big ET-1 to ET-1 is a metalloprotease called endothelin-converting enzyme (ECE). In th e present study the authors examined the effects of a newly developed inhibitor of ECE on responses to ET peptides in the normal basilar art ery and on pathophysiological constriction in the spastic basilar arte ry after SAH. In the first series of experiments the authors examined normal basilar arteries in the rabbit, which were exposed transclivall y and measured on-line using videomicroscopy. Intravenous administrati on or topical application of an active inhibitor of ECE, CGS 26303, bl ocked vasoconstrictor responses to topically applied Big ET-1 but not to ET-1. In contrast, topical application of a structurally related co mpound that does not inhibit ECE, CGS 24592, was ineffective in blocki ng vasoconstriction that was elicited by a topical application of Big ET-1. These findings indicate that CGS 26303 when administered systemi cally is capable of blocking the conversion of Big ET-1 to ET-1 in the basilar artery without affecting the ability of the vessel to respond to ET-1. In the second series of experiments the authors examined the effects of the ECE inhibitor on cerebral vasospasm after experimental SAH. Intraperitoneal administration of CGS 26303 via osmotic minipump s significantly attenuated the delayed spastic response of the basilar artery to an intracisternal injection of autologous blood. This study provides the first evidence that systemic administration of an inhibi tor of ECE is capable of preventing cerebral vasospasm after SAH. The results reinforce a growing body of evidence that ETs play a critical role in the development of spastic constriction after SAH. Moreover, t he findings indicate that blocking the conversion of Big ET-1 to its a ctive ET-1 form using CGS 26303 may represent a feasible strategy for ameliorating cerebral vasospasm.