Shiba R, Yanagisawa M, Miyauchi T, Ishii Y, Kimura S, Uchiyama Y, Masaki T, Goto K
Institute of Basic Medical Sciences, University of Tsukuba, Japan.
J Cardiovasc Pharmacol. 1989;13 Suppl 5:S98-101; discussion S102. doi: 10.1097/00005344-198900135-00024.
The rate of elimination and the fate of endothelin-1 (ET-1) from the circulating blood was studied in urethane-anesthetized rats by intravenous injection of [125I]-labeled ET-1. The vasoconstrictor activities of the iodinated ET-1 were confirmed to be similar to those of native ET-1. Following i.v. bolus injection of 30 pmol/kg of [125I]-ET-1 into the femoral vein, the total radioactivity of the right atrial blood decayed rapidly, with a half-life of 7 min. At 5 min after the injection, the administered radioactivity distributed chiefly to the parenchyma of the lungs, kidneys, and liver. The analysis of the chemical form of labeled peptides from the plasma by reverse-phase high-performance liquid chromatography (HPLC) demonstrated no appreciable amount of degraded forms of [125I]-ET-1 in the blood for up to 60 min. [125I]-ET-1 was also stable for up to 60 min upon incubation in vitro with heparinized rat blood at 37 degrees C. Even when the same amount of labeled ET-1 was injected together with a pressor dose (1,500 pmol/kg) of cold ET-1, the half-life of the radioactivity in the bloodstream was exactly identical to that for [125I]-ET-1 alone. Nevertheless, the pressor response continued for more than 90 min after i.v. bolus injection of 1500 pmol/kg of ET-1 to the rat. These results clearly indicate that the elimination of ET-1 from circulating blood and the ET-1-induced pressor response are not in parallel, and the relatively rapid disappearance of ET-1 from the bloodstream is mostly due to the removal of the peptide by the parenchymal tissues, in the anesthetized rat. The long-lasting pressor action of ET-1 may be ascribed to our previous finding that the dissociation of ET-1 from its specific binding sites on vascular smooth muscle cells is extremely slow.
通过静脉注射[¹²⁵I]标记的内皮素-1（ET-1），在氨基甲酸乙酯麻醉的大鼠中研究了循环血液中ET-1的消除速率及其去向。碘化ET-1的血管收缩活性经证实与天然ET-1相似。将30 pmol/kg的[¹²⁵I]-ET-1经股静脉静脉推注后，右心房血液中的总放射性迅速衰减，半衰期为7分钟。注射后5分钟，注入的放射性主要分布于肺、肾和肝的实质组织。通过反相高效液相色谱（HPLC）分析血浆中标记肽的化学形式表明，在长达60分钟的时间内，血液中未检测到明显量的[¹²⁵I]-ET-1降解形式。[¹²⁵I]-ET-1在37℃下与肝素化大鼠血液体外孵育长达60分钟时也保持稳定。即使将相同量的标记ET-1与升压剂量（1500 pmol/kg）的冷ET-1一起注射，血流中放射性的半衰期与单独注射[¹²⁵I]-ET-1时完全相同。然而，在给大鼠静脉推注1500 pmol/kg的ET-1后，升压反应持续超过90分钟。这些结果清楚地表明，循环血液中ET-1的消除与ET-1诱导的升压反应并不平行，在麻醉大鼠中，ET-1从血流中相对快速的消失主要是由于实质组织对该肽的清除。ET-1的持久升压作用可能归因于我们之前的发现，即ET-1从血管平滑肌细胞上的特异性结合位点解离极其缓慢。
