Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage

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✓ 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.

Article Information

Address for Dr. Caner: Baskent University Hospital, Ankara, Turkey.Address reprint requests to: Kevin S. Lee, Ph.D., Department of Neurological Surgery, Box 420, University of Virginia, Health Sciences Center, Charlottesville, Virginia 22908.

© AANS, except where prohibited by US copyright law.

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Figures

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    Graphs depicting the effects of endothelins (ETs), CGS 26303, and CGS 24592 on transclivally exposed rabbit basilar arteries. Topical application of ET-1 or Big ET-1 elicits large constrictions of the arteries (A and B). Topical application of the ET-converting enzyme (ECE) inhibitor, CGS 26303, does not inhibit the constrictor response to ET-1 (C), but does inhibit the constrictor response to Big ET-1 (D). Topical application of CGS 24592 does not inhibit the constrictor response to Big ET-1 (E). Intravenous administration of CGS 26303 partially inhibits the response to topical Big ET-1, but not to topical ET-1 (F). All values are expressed as means ± standard errors of the means. CGS 26303 = active inhibitor of ECE; CGS 24592 = inhibitor of endopeptidase, but not ECE.

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    Bar graph displaying the effect of CGS 26303 on subarachnoid hemorrhage—induced cerebral vasospasm. The average luminal areas (means ± standard errors of the means) of cross sections of basilar arteries are shown for groups of animals treated with vehicle or the endothelin-converting enzyme inhibitor, CGS 26303. Treatment with CGS 26303 significantly inhibited spastic response in the vessels (p < 0.01; Student's t-test). The dotted line near the top of the graph indicates the average luminal diameter of control (those which have not experienced subarachnoid hemorrhage) animals in a previous study from this laboratory.7

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