Matsumura Y, Ikegawa R, Suzuki Y, Takaoka M, Uchida T, Kido H, Shinyama H, Hayashi K, Watanabe M, Morimoto S
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Japan.
Life Sci. 1991;49(11):841-8. doi: 10.1016/0024-3205(91)90249-b.
There is increasing evidence that the conversion of big endothelin-1 (big ET-1) to endothelin-1 (ET-1) is specifically inhibited by the metalloproteinase inhibitor phosphoramidon. We investigated the effect of phosphoramidon on delayed cerebral vasospasm from subarachnoid hemorrhage (SAH) using a two-hemorrhage canine model. The magnitude of the vasospasm and the drug effect were determined angiographically. On SAH Day 7, diameter of the basilar artery decreased to about 55% of the control value obtained before SAH (on Day 0). Immunoreactive ET (IR-ET) in the cerebrospinal fluid (CSF) significantly increased after SAH (on Day 7). The intracisternal pretreatment of phosphoramidon potently suppressed the decrease in diameter of the basilar artery after SAH, i.e., observed decrease was only about 20%, compared with the value before SAH. In the phosphoramidon group, IR-ET in CSF markedly increased (on SAH Day 2), but the increased levels of IR-ET significantly declined on SAH Day 7. These results clearly indicate that phosphoramidon effectively prevents delayed cerebral vasospasm. Whether the prevention is due to the inhibition of conversion of big ET-1 to ET-1 is now under study.
越来越多的证据表明，金属蛋白酶抑制剂磷酰胺素可特异性抑制大内皮素-1（big ET-1）向内皮素-1（ET-1）的转化。我们使用双次出血犬模型研究了磷酰胺素对蛛网膜下腔出血（SAH）后迟发性脑血管痉挛的影响。通过血管造影术确定血管痉挛的程度和药物效果。在SAH第7天，基底动脉直径降至SAH前（第0天）对照值的约55%。SAH后（第7天），脑脊液（CSF）中的免疫反应性ET（IR-ET）显著增加。蛛网膜下腔内预先给予磷酰胺素可有效抑制SAH后基底动脉直径的减小，即与SAH前的值相比，观察到的减小仅约为20%。在磷酰胺素组中，CSF中的IR-ET在SAH第2天显著增加，但在SAH第7天，IR-ET的增加水平显著下降。这些结果清楚地表明，磷酰胺素可有效预防迟发性脑血管痉挛。这种预防是否是由于抑制big ET-1向ET-1的转化目前正在研究中。
