Effect of endothelin-converting enzyme inhibitors on big endothelin-1 induced contraction in isolated rat basilar artery.
BACKGROUND
The aim of this study was to investigate whether blocking functional endothelin-converting enzyme (ECE) activity may offer a new approach to inhibit the development of cerebral vasopasm after subarachnoid hemorrhage (SAH) by preventing transformation of big Endothelin-1 (big ET-1) to vasoactive Endothelin-1 (ET-1).


METHODS
In vitro, the effect of potential ECE inhibitors was determined by measurement of isometric contractions, induced by big ET-1, in isolated rat basilar arteries. Endothelium intact (E+) and de-endothelialized (E-) segments were examined after pre-incubated with the putative ECE inhibitors: Phosphoramidon (10(-4) M), Captopril (10(-3) M and 10(-4) M) and [(22)D-Val] big ET-1 (16-38) (10(-5) M and 10(-6) M).


RESULTS
Application of 10(-4) M Phosphoramidon resulted in a statistically significant decrease in big ET-1 induced contraction in endothelium intact (E+) and de-endothelialized (E-) segments; 10(-3) M Captopril in E- segments caused a statistically significant inhibitory effect; 10(-4) M and 10(-3) M Captopril in E+ segments showed no statistically significant effect; 10(-5) M and 10(-6) M [(22)D-Val] big ET-1 (16-38) in E- segments produced no statistically significant effect. The application of 10(-6) M [(22)D-Val] big ET-1 (16-38) in E+ segments caused increased contractions as shown by the shift to the left of the concentration-effect curve (CEC).


CONCLUSIONS
The present study indicates the existence of functional ECE activity in rat basilar artery, which is different in the endothelium and the smooth muscle layer. This ECE-activity could be inhibited by Captopril and Phosporamidon, suggesting a potency for prevention and therapy of cerebral vasospasm. However, the structural analogue of big ET-1, [(22)D-Val] big ET-1 (16-38), was ineffective in reducing big ET-1 induced vasoconstriction and rather increased contraction in E+ vessels. Therefore further studies of the biochemical nature of the functional relevant cerebrovascular ECE activity are required for better understanding and development of other efficient ECE inhibitors.
Zimmermann
M
M
Department of Neurosurgery, Johann Wolfgang Goethe - University Frankfurt/Main, Germany.
Jung
C S
CS
Vatter
H
H
Raabe
A
A
Seifert
V
V
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001488:Basilar Artery / Q000187:drug effects / Q000503:physiopathology; D002216:Captopril / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D020301:Vasospasm, Intracranial / Q000503:physiopathology*
D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D006020:Glycopeptides; D011498:Protein Precursors; C089858:big endothelin-1(16-38), valine(22)-; D002216:Captopril; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon