Vatter H, Schilling L, Schmiedek P, Ehrenreich H
Department of Neurosurgery, Faculty of Clinical Medicine, Mannheim, Germany.
J Cardiovasc Pharmacol. 1998;31 Suppl 1:S64-7. doi: 10.1097/00005344-199800001-00021.
Endothelin-1 (ET-1) may be involved in the upregulation of cerebroarterial resistance under pathologic conditions, most notably in the development of vasospasm after subarachnoid hemorrhage. Therefore, blocking the contractile action of ET-1 by receptor antagonists may prove to be a new and worthwhile approach. However, decreasing synthesis and release of ET-1 by blocking the endothelin-converting enzyme (ECE) activity may also prove worthwhile. In this study we have therefore investigated the effect of several putative ECE inhibitors in isolated rat basilar artery by measuring isometric contraction after application of big ET-1, the precursor peptide which is not vasoactive in itself. In the presence of phosphoramidon (10(-4) M in segments with an intact endothelium or 5 x 10(-4) M in de-endothelialized segments), there was only a small shift to the right of the concentration-effect curve for big ET-1. Similarly, 10(-3) M thiorphan (a selective inhibitor of the neutral endopeptidase) did not affect big ET-1-induced contraction, both alone and in combination with phosphoramidon (10(-3) M). When the big ET-1 analogue [22Phe]big ET-1[19-37] was applied, an increase in resting tension occurred irrespective of whether or not the endothelium was present. Furthermore, in the presence of 10(-5) M [22Phe]big ET-1[19-37], contraction induced by big ET-1 was not affected in de-endothelialized segments but rather was enhanced in endothelium-intact segments. These results suggest the presence of functional ECE activity in the rat basilar artery wall. However, such activity could not be markedly inhibited with different putative enzyme inhibitors. Therefore, the chemical nature of the cerebroarterial ECE activity must be further elucidated before rational development of efficient ECE inhibitors for treatment of cerebral vasospasm becomes possible.
内皮素-1（ET-1）可能在病理状态下参与脑动脉阻力的上调，最显著的是在蛛网膜下腔出血后血管痉挛的发生过程中。因此，通过受体拮抗剂阻断ET-1的收缩作用可能被证明是一种新的且有价值的方法。然而，通过阻断内皮素转换酶（ECE）的活性来减少ET-1的合成和释放也可能被证明是有价值的。因此，在本研究中，我们通过测量在应用大ET-1（其本身无血管活性的前体肽）后等长收缩，研究了几种假定的ECE抑制剂对离体大鼠基底动脉的作用。在存在磷酰胺（在内皮完整的节段中为10⁻⁴ M，在去内皮节段中为5×10⁻⁴ M）的情况下，大ET-1的浓度-效应曲线仅向右有小的偏移。同样，10⁻³ M的硫丙脯酸（一种中性内肽酶的选择性抑制剂）单独使用或与磷酰胺（10⁻³ M）联合使用时，均不影响大ET-1诱导的收缩。当应用大ET-1类似物[22苯丙氨酸]大ET-1[19 - 37]时，无论是否存在内皮，静息张力都会增加。此外，在存在10⁻⁵ M [22苯丙氨酸]大ET-1[19 - 37]的情况下，大ET-1诱导的收缩在去内皮节段中不受影响，但在内皮完整的节段中反而增强。这些结果表明大鼠基底动脉壁中存在功能性ECE活性。然而，使用不同的假定酶抑制剂并不能显著抑制这种活性。因此，在合理开发用于治疗脑血管痉挛的有效ECE抑制剂成为可能之前，必须进一步阐明脑动脉ECE活性的化学性质。
