Richard V, Hogie M, Clozel M, Löffler B M, Thuillez C
Department of Pharmacology, Rouen University Medical School, France.
Circulation. 1995 Feb 1;91(3):771-5. doi: 10.1161/01.cir.91.3.771.
Continuous production of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effects of endothelin. Thus, inhibition of NO synthesis might unmask a vasopressor response to endothelin. To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ETA and ETB endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME).
Anesthetized rats received increasing doses of L-NAME (0.1 to 3 mg.kg-1) in the absence or the presence of bosentan (3 mg.kg-1 IV 15 minutes before L-NAME). Bosentan itself did not affect blood pressure. L-NAME induced a dose-dependent increase in mean arterial pressure (percent increase from baseline after 3 mg.kg-1, 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; P < .05) or by the selective ETA antagonist BQ-123 (3 mg.kg-1: controls, 25 +/- 4%; BQ-123, 14 +/- 5%; P < .01). In contrast, bosentan did not affect the pressor response to phenylephrine (1 to 100 micrograms.kg-1). The response to L-NAME (3 mg.kg-1) was also reduced by bosentan in ganglion-blocked (chlorisondamine 2.5 mg.kg-1: controls, 89 +/- 10%; bosentan, 45 +/- 7%) or pithed rats (controls, 165 +/- 9%; bosentan, 85 +/- 12%; P < .01). Bosentan also inhibited the pressor response to another inhibitor of NO synthesis, NG-nitro L-arginine (3 mg.kg-1) in normal (controls, 24 +/- 5%; bosentan, 10 +/- 3%; P < .01) or ganglion-blocked (controls, 86 +/- 13%; bosentan, 25 +/- 8%; P < .01) rats. Finally, L-NAME induced a modest increase in plasma levels of endothelin-1 (controls, 26.8 +/- 4.1 pg.mL-1; L-NAME, 38.5 +/- 3.3 pg.mL-1; P < .05).
These experiments demonstrate that inhibition of NO synthesis unmasks a tonic pressor influence of endothelin, suggesting that this peptide could play a major role in pathophysiological situations associated with an impaired formation of NO.
内皮细胞持续产生一氧化氮（NO）可永久性抑制内皮素的合成及其血管收缩作用。因此，抑制NO合成可能会揭示出对内皮素的升压反应。为了评估内皮素是否参与了由抑制NO合成所诱导的升压反应，我们测试了波生坦（一种ETA和ETB内皮素受体的非肽类拮抗剂）是否会影响由NO合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）所诱导的高血压反应。
麻醉大鼠在不存在或存在波生坦（在给予L-NAME前15分钟静脉注射3mg·kg-1）的情况下接受递增剂量的L-NAME（0.1至3mg·kg-1）。波生坦本身不影响血压。L-NAME诱导平均动脉压呈剂量依赖性升高（3mg·kg-1后较基线升高的百分比为25±5%），而这一升高被波生坦（13±3%；P<.05）或选择性ETA拮抗剂BQ-123（3mg·kg-1：对照组为25±4%；BQ-123为14±5%；P<.01）所降低。相比之下，波生坦不影响对去氧肾上腺素（1至100μg·kg-1）的升压反应。在神经节阻断（氯筒箭毒碱2.5mg·kg-1：对照组为89±10%；波生坦为45±7%）或脊髓横断的大鼠中（对照组为165±9%；波生坦为85±12%；P<.01），波生坦也降低了对L-NAME（3mg·kg-1）的反应。波生坦还抑制了对另一种NO合成抑制剂NG-硝基-L-精氨酸（3mg·kg-1）在正常（对照组为24±5%；波生坦为10±3%；P<.01）或神经节阻断（对照组为86±13%；波生坦为25±8%；P<.01）大鼠中的升压反应。最后，L-NAME诱导血浆内皮素-1水平适度升高（对照组为26.8± &
