Fujihara C K, De Nucci G, Zatz R
Department of Clinical Medicine, University of São Paulo Medical School, Brazil.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S466-9.
Exogenous endothelin (ET) promotes powerful vasoconstriction in systemic and renal microcirculation. However, the physiologic role of endogenous ET on the moment-to-moment regulation of the circulation remains unclear. We investigated the effects of acute administration of FR139317, a nonpeptide inhibitor specific for the ETA receptor shown in preliminary experiments to reverse the established vasoconstrictor effects of exogenous ET. Renal and glomerular functional parameters were determined in eight anesthetized adult male Munich-Wistar rats receiving a standard diet (0.5% Na) before and after bolus injection of FR139317, 10 mg/kg. To assess the physiologic role of ET in sodium depletion, eight rats received a low-salt (0.06% Na) diet for 2 weeks before acute FR139317 treatment. Eight additional salt-restricted rats received a bolus injection of the angiotensin II inhibitor losartan, 10 mg/kg i.v., as a positive control. FR139317 exerted no detectable microcirculatory effect in rats receiving standard diet. In sodium-depleted rats, losartan lowered blood pressure by 12 mm Hg, raised heart rate by 20 beats/min, and decreased renal vascular resistance by 33%. By contrast, FR139317 had only slight hemodynamic effects, although it increased heart rate by 15 beats/min. These results suggest that ET does not participate, at least via ETA receptors, in the regulation of renal and systemic microcirculation in the rat. However, it may be involved in the circulatory adaptations to chronic sodium depletion. A regulatory role for ET via ETB receptors is also possible.
外源性内皮素（ET）可在全身和肾微循环中引起强烈的血管收缩。然而，内源性ET在循环系统实时调节中的生理作用仍不清楚。我们研究了急性给予FR139317（一种对ETA受体具有特异性的非肽类抑制剂，在初步实验中显示可逆转外源性ET已确立的血管收缩作用）的效果。在8只接受标准饮食（0.5%钠）的麻醉成年雄性慕尼黑-威斯塔大鼠中，在静脉推注10mg/kg的FR139317前后，测定肾和肾小球功能参数。为评估ET在钠耗竭中的生理作用，8只大鼠在急性FR139317治疗前接受2周的低盐（0.06%钠）饮食。另外8只限盐大鼠接受静脉推注10mg/kg的血管紧张素II抑制剂氯沙坦作为阳性对照。FR139317在接受标准饮食的大鼠中未产生可检测到的微循环效应。在钠耗竭的大鼠中，氯沙坦使血压降低12mmHg，心率提高20次/分钟，肾血管阻力降低33%。相比之下，FR139317仅产生轻微的血流动力学效应，尽管它使心率提高了15次/分钟。这些结果表明，ET至少通过ETA受体不参与大鼠肾和全身微循环的调节。然而，它可能参与了对慢性钠耗竭的循环适应。ET通过ETB受体发挥调节作用也是有可能的。
