[D-Val22]big ET-1[16-38] inhibits endothelin-converting enzyme activity: a promising concept in the prevention of cerebral vasospasm.
The aim of this study was to investigate whether the blocking of endothelin-converting enzyme (ECE) activity offers a new approach to inhibiting the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) by preventing transformation of big endothelin-1 (big ET-1) to vasoactive endothelin-1 (ET-1). The effect of potential ECE inhibitors was determined in vitro by measurement of isometric contractions, induced by big ET-1, in isolated rat basilar arteries. Intact and de-endothelialized endothelium (E+ and E-, respectively) segments were examined after preincubation with the putative ECE inhibitors: phosphoramidon (10(-4) M), and [22D-Val]big ET-1 [16-38] (10(-5) M and 10(-6) M). Additionally, the effect of [D-Val22]big ET-1 [16-38] was investigated in rabbits after intracisternal application in order to inhibit the contraction of the basilar artery induced by (2x10(-6) M) big ET-1. Application of 10(-4)-M phosphoramidon resulted in a statistically significant decrease in big ET-1-induced contraction in E+ and E- segments; 10(-5)-M and 10(-6)-M [22D-Val]big ET-1 [16-38] in E- segments produced no statistically significant effect. The application of 10(-6)-M [22D-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). In the rabbit group pretreated with [D-Val22]big ET-1 [16-38] (2x10(-5) M) (n=8), the angiographically measured diameter of the basilar artery increased from 0.63+/-0.12 mm to 0.66+/-0.12 mm. In the control group (n=8), this diameter decreased from 0.71+/-0.13 mm to 0.57+/-0.15 mm. This corresponded to an increase in vessel diameter of 5.24+/-9.89% in the treatment group and a decrease of 19.54+/-15.81% in the control group (P=0.002). The present study indicates the existence of functional ECE activity in rat basilar artery, which differs in the endothelium and the smooth muscle layer. These results demonstrate that [D-Val22]big ET-1 [16-38] has a potent ECE-inhibitory effect, preventing cerebral vasospasm in rabbit basilar artery by inhibiting the transformation of big ET-1 to vasoactive ET-1 after intracisternal application in vivo, whereas no inhibitory effect was detectable in rat basilar artery in vitro. Therefore, further studies of the biochemical nature of cerebrovascular ECE activity are required.
Zimmermann
Michael
M
Department of Neurosurgery, University of Frankfurt/Main, Schleusenweg 2-16, 60528 Frankfurt, Germany. Michael.Zimmermann@em.uni-frankfurt.de
Jung
Carla Sabine
CS
Vatter
Hartmut
H
Raabe
Andreas
A
Seifert
Volker
V
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D001488:Basilar Artery / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology* / Q000627:therapeutic use*; D006020:Glycopeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D008666:Metalloendopeptidases; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
D016232:Endothelins; D006020:Glycopeptides; D011480:Protease Inhibitors; C089858:big endothelin-1(16-38), valine(22)-; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon