Kaasjager K A, Koomans H A, Rabelink T J
Department of Nephrology and Hypertension, University Hospital Utrecht (The Netherlands).
Hypertension. 1997 Jul;30(1 Pt 1):15-21. doi: 10.1161/01.hyp.30.1.15.
The potential role of endothelin-1 (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of hypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET-1 levels from 2.5+/-0.4 to 11.6+/-1.0 pmol/L (P<.05). Blood pressure rose by approximately 10 mm Hg (P<.05). Cardiac index decreased by 21+/-22%, whereas calculated systemic vascular resistance increased by 27+/-6% (P<.05). Renal blood flow decreased from 1051+/-94 to 707+/-60 mL/min at the end of the ET-1 infusion (P<.05), and calculated renal vascular resistance increased from 118+/-19 to 189+/-19 mm Hg x min/L (P<.05). Sodium excretion decreased from 227+/-39 to 111+/-15 micromol/min (P<.05). Both enalapril and nifedipine treatment prevented the systemic effects of ET-1 infusion in these subjects. However, during enalapril treatment, despite renal predilatation, ET-1 reduced renal blood flow (from 1119+/-132 to 701+/-75 mL/min, P<.05) and increased renal vascular resistance (from 111+/-16 to 187+/-28 mm Hg x min/L, P<.05) to the same levels as during ET-1 infusion alone. Nifedipine pretreatment attenuated the ET-1-induced fall in renal blood flow (from 1088+/-93 to 907+/-68 mL/min) and increase in renal vascular resistance (from 105+/-9 to 133+/-10 mm Hg x min/L). Although neither drug modulated the antinatriuretic effect of ET-1, nifedipine increased basal sodium excretion (P<.05), which compensated for the decrease during ET-1 infusion. In conclusion, essential hypertensive subjects are sensitive to the vasoconstrictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in attenuating the renal constrictor effects of ET-1.
内皮素-1（ET-1）在人类原发性高血压中的潜在作用仍存在争议。我们最近报道，在血浆ET-1发生病理生理升高时，会出现强烈的钠潴留和肾血管收缩。除了这种血管收缩作用外，ET-1还具有促有丝分裂特性，在高血压的病理生理过程中发挥作用。另一方面，一些数据反驳了ET-1在高血压中起重要作用的观点。因此，我们对9名原发性高血压患者进行了研究，通过全身输注ET-1（0.5 ng/kg每分钟，持续60分钟，然后1.0 ng/kg每分钟，持续60分钟，最后2.0 ng/kg每分钟，持续60分钟）来挑战这些患者，以研究ET-1的收缩作用。此外，我们研究了口服血管紧张素转换酶抑制剂依那普利（20 mg，每日两次）或钙通道阻滞剂硝苯地平（60 mg，每日一次）是否能调节ET-1的这些作用。输注ET-1使血浆ET-1水平从2.5±0.4升高至11.6±1.0 pmol/L（P<0.05）。血压升高约10 mmHg（P<0.05）。心脏指数下降21±22%，而计算得出的全身血管阻力增加27±6%（P<0.05）。在ET-1输注结束时，肾血流量从1051±94降至707±60 mL/分钟（P<0.05），计算得出的肾血管阻力从118±19升至189±19 mmHg·分钟/L（P<0.05）。钠排泄量从227±39降至111±15 μmol/分钟（P<0.05）。依那普利和硝苯地平治疗均能预防这些患者中ET-1输注的全身效应。然而，在依那普利治疗期间，尽管肾血管有预扩张，但ET-1仍使肾血流量减少（从1119±132降至701±75 mL/分钟，P<0.05），并使肾血管阻力增加（从111±16升至187±28 mmHg·分钟/L，P<0.05），达到与单独输注ET-1时相同的水平。硝苯地平预处理减轻了ET-1引起的肾血流量下降（从1088±93降至907±68 mL/分钟）和肾血管阻力增加（从105±9升至133±10 mmHg·分钟/L）。尽管两种药物均未调节ET-1的利钠作用，但硝苯地平增加了基础钠排泄量（P<0.05），这补偿了ET-1输注期间的减少。总之，原发性高血压患者对ET-1的血管收缩作用敏感。依那普利和硝苯地平均可预防ET-1的全身效应，但硝苯地平在减轻ET-1的肾血管收缩作用方面似乎更有效。
