The potent
vasoconstrictor peptide,
endothelin-1 (ET-1), has been implicated 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 activation. The last of these steps involves the proteolytic conversion of a relatively inactive propeptide, Big ET-1, to its active, 21-amino
acid peptide form. The
enzyme responsible for converting Big ET-1 to ET-1 is a
metalloprotease called
endothelin-converting enzyme (ECE). In the present study the authors examined the effects of a newly developed inhibitor of ECE on responses to ET
peptides in the normal basilar artery and on pathophysiological constriction in the
spastic basilar artery after SAH. In the first series of experiments the authors examined normal basilar arteries in the rabbit, which were exposed transclivally and measured on-line using videomicroscopy.
Intravenous administration or topical application of an active inhibitor of ECE,
CGS 26303, blocked
vasoconstrictor responses to topically applied Big ET-1 but not to ET-1. In contrast, topical application of a structurally related compound that does not inhibit ECE,
CGS 24592, was ineffective in blocking vasoconstriction that was elicited by a topical application of Big ET-1. These findings indicate that
CGS 26303 when administered systemically 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 minipumps 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 inhibitor 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, the findings indicate that blocking the conversion of Big ET-1 to its active ET-1 form using
CGS 26303 may represent a feasible strategy for ameliorating
cerebral vasospasm.