[D-Val22]big ET-1[16?38] inhibits endothelin-converting enzyme activity: a promising concept in the prevention of cerebral vasospasm

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Abstract
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 (2×10–6 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] (2×10–5 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.

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