Wenzel R R, Rüthemann J, Bruck H, Schäfers R F, Michel M C, Philipp T
Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital Essen, Essen, Germany.
Br J Clin Pharmacol. 2001 Aug;52(2):151-7. doi: 10.1046/j.0306-5251.2001.01422.x.
Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear.
We studied the effects of the ETA-selective antagonist BQ-123 and the ETB-selective antagonist BQ-788 (both 10(-10)-10(-8) M) on ET-1 (10(-16)-10(-10) M), angiotensin II (AT, 10(-16)-10(-10) M) and noradrenaline (NA, 10(-16)-10(-10) M) induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler flowmetry and double injection technique.
BQ-123 caused a dose-dependent vasodilatation (maximum effect: + 949 +/- 84 AUC-PU, P < 0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: -388 +/- 96 AUC-PU, P < 0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10(-14) M: + 814 +/- 93 AUC-PU vs ET alone, P < 0.001), followed by noradrenaline (maximum effect at 10(-16) M: +580 +/- 107 AUC-PU vs NA alone, P < 0.01) and angiotensin II (maximum effect at 10(-14) M: + 493 +/- 111 AUC-PU vs AT alone, P < 0.001).
ETA-selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.
内皮素 -1（ET -1）是一种由血管内皮产生的强效血管收缩剂。ET与人体交感神经系统和肾素 - 血管紧张素系统介质之间的相互作用尚不清楚。
我们使用激光多普勒血流仪和双注射技术，研究了ETA选择性拮抗剂BQ - 123和ETB选择性拮抗剂BQ - 788（均为10⁻¹⁰ - 10⁻⁸ M）对25名健康男性志愿者体内人皮肤微循环中ET -1（10⁻¹⁶ - 10⁻¹⁰ M）、血管紧张素II（AT，10⁻¹⁶ - 10⁻¹⁰ M）和去甲肾上腺素（NA，10⁻¹⁶ - 10⁻¹⁰ M）诱导的血管收缩的影响。
BQ - 123引起剂量依赖性血管舒张（最大效应：+ 949 ± 84 AUC - PU，P < 0.001），而BQ - 788诱导轻度血管收缩（最大效应：-388 ± 96 AUC - PU，P < 0.01）。在存在BQ - 123而非BQ - 788的情况下，在任何测试的激动剂剂量下，ET -1、AT和NA引起的血管收缩明显减少；对ET -1的影响最为显著（10⁻¹⁴ M时的最大效应：+ 814 ± 93 AUC - PU，与单独使用ET相比，P < 0.001），其次是去甲肾上腺素（10⁻¹⁶ M时的最大效应：+580 ± 107 AUC - PU，与单独使用NA相比，P < 0.01）和血管紧张素II（10⁻¹⁴ M时的最大效应：+ 493 ± 111 AUC - PU，与单独使用AT相比，P < 0.001）。
ETA选择性拮抗作用在健康受试者体内抑制对AT和NA的血管收缩。这种有益作用可能对包括高血压在内的心血管疾病患者的治疗有用，特别是在与交感神经阻滞剂和肾素 - 血管紧张素系统抑制剂联合治疗时。
