Richard V, Hogie M, Clozel M, Löffler B M, Thuillez C
Laboratoire de pharmacologie, VACOMED, IFRMP, faculté de médecine et CHU de Rouen, hôpital de Bois-Guillaume.
Arch Mal Coeur Vaiss. 1995 Aug;88(8):1213-6.
Although it is clear that vascular endothelial cells synthesize and release endothelin (ET), the contribution of this vasconstrictor peptide to the regulation of vascular tone appears limited in normal conditions. One possibility to explain this moderate effect is that continuous production of nitric oxide (NO) may permanently inhibit the release and the vasoconstrictor effects of ET. In these conditions, inhibition of NO synthesis might unmask a vasopressor response to ET. Thus, we tested whether bosentan (3 mg/kg i.v.), a non-peptide antagonist of ETA and ETB receptors, or BQ-123 (3 mg/kg), an antagonist of ETA receptors, affected the hypertensive response induced by the NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME 3 mg/kg) or NG-nitro L-arginine (3 mg/kg) in anesthetized, normotensive rats. Bosentan or BQ-123 did not affect blood pressure. L-NAME significantly increased mean arterial pressure (% increase from baseline: 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; p < 0.05) or by BQ-123 (14 +/- 5%; p < 0.01). In contrast, bosentan did not affect the pressor response to phenylephrine. The response to L-NAME (3 mg/kg) was also reduced by bosentan in ganglion-blocked (chlorisondamine: 2.5 mg/kg; controls 89 +/- 10; bosentan: 45 +/- 7%) or pithed rats (controls: 165 +/- 9; bosentan 85 +/- 12%; p < 0.01). Bosentan also inhibited the pressor response to NG-nitro L-arginine (3 mg/kg-1) in normal (controls 24 +/- 5, bosentan 10 +/- 3%; p < 0.01) or ganglion-blocked rats (controls 86 +/- 13; bosentan 25 +/- 8; p < 0.01). Finally, L-NAME induced a modest increase in plasma levels of ET-1 (controls: 26.8 +/- 4.1; L-NAME: 38.5 +/- 3.3 pg/ml; p < 0.05). Thus, acute inhibition of NO synthesis unmasks a tonic vasopressor influence of ET.
虽然血管内皮细胞合成并释放内皮素（ET）这一点很明确，但在正常情况下，这种血管收缩肽对血管张力调节的作用似乎有限。解释这种适度作用的一种可能性是，一氧化氮（NO）的持续产生可能会永久性抑制ET的释放及其血管收缩作用。在这些情况下，抑制NO合成可能会揭示出对ET的升压反应。因此，我们测试了波生坦（静脉注射3mg/kg），一种ETA和ETB受体的非肽拮抗剂，或BQ-123（3mg/kg），一种ETA受体拮抗剂，是否会影响由NO合酶抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME 3mg/kg）或Nω-硝基-L-精氨酸（3mg/kg）在麻醉的正常血压大鼠中诱导的高血压反应。波生坦或BQ-123不影响血压。L-NAME显著升高平均动脉压（相对于基线的升高百分比：25±5%），而波生坦（13±3%；p<0.05）或BQ-123（14±5%；p<0.01）可使其降低。相比之下，波生坦不影响对去氧肾上腺素的升压反应。在神经节阻断（氯筒箭毒碱：2.5mg/kg；对照组89±10；波生坦组：45±7%）或去脑大鼠（对照组：165±9；波生坦组85±12%；p<0.01）中，波生坦也可降低对L-NAME（3mg/kg）的反应。波生坦还可抑制正常（对照组24±5，波生坦组10±3%；p<0.01）或神经节阻断大鼠（对照组86±13；波生坦组25±8；p<0.01）对Nω-硝基-L-精氨酸（3mg/kg-1）的升压反应。最后，L-NAME使血浆ET-1水平适度升高（对照组：26.8±4.1；L-NAME组：38.5±3.3pg/ml；p<0.05）。因此，急性抑制NO合成揭示了ET的一种持续性升压影响。
