Fujita K, Matsumura Y, Kita S, Hisaki K, Takaoka M, Morimoto S
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Japan.
Hypertension. 1994 Aug;24(2):227-33. doi: 10.1161/01.hyp.24.2.227.
We investigated the intrarenal conversion of big endothelin-1 (ET-1) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the peptide was 50-fold less than that of ET-1. The big ET-1 (2 x 10(-8) mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect. The effect of kelatorphan (10(-4) mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with phosphoramidon. When ET-1 was exogenously added to the perfusate, phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the phosphoramidon-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels in renal tissues but not in the perfusate can account for the functional conversion of big ET-1 to ET-1 and for the local proteolytic degradation of ET-1 in the kidney.
我们在离体灌注大鼠肾脏中研究了大内皮素-1（big ET-1）向内皮素-1（ET-1）的肾内转化。big ET-1引起灌注压呈浓度依赖性升高，该肽的升压摩尔效力比ET-1低50倍。big ET-1（2×10⁻⁸ mol/L）诱导的升压作用伴随着灌注液和肾组织中免疫反应性内皮素水平的升高。金属蛋白酶抑制剂磷酰胺素（10⁻⁴ mol/L）显著抑制big ET-1诱导的升压作用以及肾组织中免疫反应性内皮素的蓄积。另一方面，磷酰胺素轻微但显著地增强了ET-1诱导的升压效应。中性内肽酶24.11的特异性抑制剂凯拉托品（10⁻⁴ mol/L）对ET-1诱导的升压效应的作用与磷酰胺素相同。当向灌注液中外源性添加ET-1时，磷酰胺素或凯拉托品显著增加了灌注后肾组织中免疫反应性内皮素水平，而不影响免疫反应性内皮素从灌注液中的消失速率。因此，肾脏中对磷酰胺素敏感的ET-1转化酶似乎有助于big ET-1向ET-1的功能性局部转化，并且中性内肽酶24.11可能负责肾脏中ET-1的蛋白水解降解。此外，肾组织而非灌注液中的免疫反应性内皮素水平可以解释big ET-1向ET-1的功能性转化以及肾脏中ET-1的局部蛋白水解降解。
