Ohnishi Masato, Wada Atsuyuki, Tsutamoto Takayoshi, Fujii Masanori, Matsumoto Takehiro, Yamamoto Takashi, Takayama Tomoyuki, Wang Xinwen, Kinoshita Masahiko
First Department of Internal Medicine, Shiga University of Medical Science, Tsukinowa, Seta, Otsu, Shiga 520-2192, Japan.
Clin Sci (Lond). 2002 Aug;103 Suppl 48:241S-244S. doi: 10.1042/CS103S241S.
Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n=5; 270 beats/min) compared with normal dogs (n=5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56+/-0.16 compared with 2.93+/-0.25 litres/min; P<0.01) and systemic vascular resistance had increased (4653+/-374 compared with 3227+/-396 dyn.s.cm(-5); P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95+/-0.83 compared with 2.12+/-0.39 pg/ml; P<0.05) and ADMA (3.27+/-0.49 compared with 1.91+/-0.25 nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r=0.72, P<0.05). Secondly, we chronically administered an ET(A) receptor antagonist, TA-0201 (0.3 mg/kg; n=5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58+/-0.24 litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36+/-0.30 nmol/ml and 2423+/-188 dyn.s.cm(-5) respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ET(A) receptor antagonist can prevent the inhibition of NO production and the increased peripheral vascular resistance observed in CHF.
充血性心力衰竭（CHF）的特征是外周血管阻力增加。内皮素 -1（ET -1）是一种强大的内皮源性血管收缩剂，其在血浆中的浓度升高，并参与CHF中血管张力的调节。内皮源性舒张因子一氧化氮（NO）也调节血管张力，但在CHF中内皮依赖性NO介导的血管舒张作用减弱。内源性NO合酶抑制剂非对称二甲基精氨酸（ADMA）可抑制NO生成和内皮依赖性舒张，其在血浆中的水平升高，并在CHF的内皮功能受损中起作用。然而，目前CHF中ET -1与血管舒张受损之间的关系尚不清楚。我们推测ET -1通过增加CHF中ADMA的生成来抑制NO介导的血管舒张，并且内皮素受体拮抗剂可以阻止血浆ADMA水平的这种升高。在本研究中，我们首先检查了与正常犬（n = 5）相比，由3周快速心室起搏（n = 5；270次/分钟）诱导的CHF犬模型中循环ADMA水平是否升高。起搏3周后，与正常犬相比，CHF犬的心输出量显著降低（分别为1.56±0.16与2.93±0.25升/分钟；P<0.01），全身血管阻力增加（分别为4653±374与3227±396 dyn.s.cm(-5)；P<0.01）。CHF犬的血浆ET -1（分别为4.95±0.83与2.12±0.39 pg/ml；P<0.05）和ADMA（分别为3.27±0.49与1.91±0.25 nmol/ml；P<0.05）水平均显著升高。血浆ET -1与ADMA水平之间观察到显著正相关（r = 0.72，P<0.05）。其次，我们对起搏的CHF犬长期给予ET(A)受体拮抗剂TA -0201（0.3 mg/kg；n = 5）。药物给药从起搏第8天开始并持续整个实验。与未用TA -0201治疗的CHF犬相比，TA -0201显著增加心输出量（2.58±0.24升/分钟；P<0.01），并抑制血浆ADMA水平和全身血管阻力的升高（分别为2.36±0.30 nmol/ml和2423±188 dyn.s.cm(-5)；每项P<0.05）。总之，ET -1部分通过增加CHF中内源性NO合酶抑制剂的水平来参与血管张力的调节，并且ET(A)受体拮抗剂可以防止CHF中观察到的NO生成抑制和外周血管阻力增加。
