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

Hakan H. Caner, Aij Lie Kwan, Adam Arthur, Arco Y. Jeng, Rodney W. Lappe, Neal F. Kassell, Kevin S. Lee

Research output: Contribution to journalArticle

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Abstract

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 inhibit 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 systematically 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.

Original languageEnglish (US)
Pages (from-to)917-922
Number of pages6
JournalJournal of Neurosurgery
Volume85
Issue number5
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Intracranial Vasospasm
Endothelin-1
Subarachnoid Hemorrhage
Basilar Artery
Muscle Spasticity
Peptides
Vasoconstrictor Agents
Constriction
Endothelin-Converting Enzymes
Video Microscopy
Metalloproteases
Enzyme Inhibitors
Vasoconstriction
Intravenous Administration

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage. / Caner, Hakan H.; Kwan, Aij Lie; Arthur, Adam; Jeng, Arco Y.; Lappe, Rodney W.; Kassell, Neal F.; Lee, Kevin S.

In: Journal of Neurosurgery, Vol. 85, No. 5, 01.01.1996, p. 917-922.

Research output: Contribution to journalArticle

Caner, Hakan H. ; Kwan, Aij Lie ; Arthur, Adam ; Jeng, Arco Y. ; Lappe, Rodney W. ; Kassell, Neal F. ; Lee, Kevin S. / Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage. In: Journal of Neurosurgery. 1996 ; Vol. 85, No. 5. pp. 917-922.
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