内皮素转化酶抑制剂对大内皮素-1诱导的离体大鼠基底动脉收缩的影响。
Effect of endothelin-converting enzyme inhibitors on big endothelin-1 induced contraction in isolated rat basilar artery.
作者信息
Zimmermann M, Jung C S, Vatter H, Raabe A, Seifert V
机构信息
Department of Neurosurgery, Johann Wolfgang Goethe - University Frankfurt/Main, Germany.
出版信息
Acta Neurochir (Wien). 2002 Nov;144(11):1213-9. doi: 10.1007/s00701-002-1000-z.
INTRODUCTION
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).
CONCLUSION
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.
引言
本研究的目的是探讨阻断功能性内皮素转换酶（ECE）活性是否可以通过防止大内皮素-1（big ET-1）转化为血管活性内皮素-1（ET-1），为抑制蛛网膜下腔出血（SAH）后脑血管痉挛的发展提供一种新方法。
方法
在体外，通过测量大ET-1诱导的离体大鼠基底动脉等长收缩，来确定潜在ECE抑制剂的作用。在用假定的ECE抑制剂：磷酰胺素（10⁻⁴ M）、卡托普利（10⁻³ M和10⁻⁴ M）以及[(22)D-缬氨酸]大ET-1（16-38）（10⁻⁵ M和10⁻⁶ M）预孵育后，检查内皮完整（E+）和去内皮（E-）节段。
结果
应用10⁻⁴ M磷酰胺素导致内皮完整（E+）和去内皮（E-）节段中大ET-1诱导的收缩在统计学上显著降低；10⁻³ M卡托普利在E-节段产生了统计学上显著的抑制作用；10⁻⁴ M和10⁻³ M卡托普利在E+节段未显示出统计学上显著的效果；10⁻⁵ M和10⁻⁶ M [(22)D-缬氨酸]大ET-1（16-38）在E-节段未产生统计学上显著的效果。在E+节段应用10⁻⁶ M [(22)D-缬氨酸]大ET-1（16-38）导致收缩增加，浓度-效应曲线（CEC）向左移动表明了这一点。
结论
本研究表明大鼠基底动脉中存在功能性ECE活性，其在内皮和平滑肌层有所不同。这种ECE活性可被卡托普利和磷酰胺素抑制，提示其在预防和治疗脑血管痉挛方面具有潜力。然而，大ET-1的结构类似物[(22)D-缬氨酸]大ET-1（16-38）在减少大ET-1诱导的血管收缩方面无效，反而增加了E+血管中的收缩。因此，需要进一步研究与功能相关的脑血管ECE活性的生化性质，以更好地理解并开发其他有效的ECE抑制剂。
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