Prié S, Stewart D J, Dupuis J
Department of Medicine, Montreal Heart Institute, Quebec, Canada.
Circulation. 1998 Jun 2;97(21):2169-74. doi: 10.1161/01.cir.97.21.2169.
Nitric oxide (NO) and endothelin (ET) have been implicated in the pathogenesis of pulmonary hypertension (PH). Chronic ETA antagonist therapy reduces PH in monocrotaline (MCT)-treated rats. Interactions between the L-arginine-NO pathway and the ET system have been described. We therefore studied the effect of long-term treatment with an oral ETA antagonist (LU 135252) on NO-related vasodilation in isolated lungs from control rats and rats with MCT-induced PH.
Three weeks after MCT injection, PH was associated with an increase in right ventricular pressure (from 27.4 +/- 0.9 to 66.6 +/- 4.1 mm Hg) and a decrease in endothelium-independent vasodilation in response to sodium nitroprusside (10(-10) to 10(-5) mol/L; delta Emax, from 11.1 +/- 0.9 to 2.7 +/- 0.3 mm Hg). Endothelium-dependent vasodilation in response to acetylcholine (10(-9) to 10(-4) mol/L) and the calcium ionophore A23187 (10(-9) to 10(-7) mol/L) remained unaffected. Treatment with LU 135252 did not significantly affect the endothelium-dependent and -independent vasodilations in control rats. However, in MCT-treated rats, LU 135252 therapy significantly reduced right ventricular pressure (39.7 +/- 2.1 mm Hg), potentiated acetylcholine-induced vasodilatation (delta Emax, from 1.6 +/- 0.2 to 3.7 +/- 0.4 mm Hg), and improved the responses to sodium nitroprusside (delta Emax, from 2.7 +/- 0.3 to 5.6 +/- 0.6 mm Hg). LU 135252 did not significantly alter the non-receptor-mediated endothelium-dependent vasodilation to A23187 or pulmonary constitutive NO synthase activity.
MCT PH is associated with a reduced smooth muscle responsiveness to NO but a maintained endothelium-dependent vasodilatory potency. Long-term ETA antagonist therapy not only restores smooth muscle responsiveness to NO but also increases endothelium-dependent dilation in response to acetylcholine. This mechanism may contribute to the therapeutic benefit of ETA antagonists in PH.
一氧化氮（NO）和内皮素（ET）与肺动脉高压（PH）的发病机制有关。慢性ETA拮抗剂治疗可降低用野百合碱（MCT）处理的大鼠的肺动脉高压。已经描述了L-精氨酸-NO途径与ET系统之间的相互作用。因此，我们研究了口服ETA拮抗剂（LU 135252）长期治疗对来自对照大鼠和MCT诱导的肺动脉高压大鼠的离体肺中与NO相关的血管舒张的影响。
MCT注射三周后，肺动脉高压与右心室压力升高（从27.4±0.9升高至66.6±4.1 mmHg）以及对硝普钠（10^-10至10^-5 mol/L；最大舒张反应变化量，从11.1±0.9降至2.7±0.3 mmHg）的非内皮依赖性血管舒张降低有关。对乙酰胆碱（10^-9至10^-4 mol/L）和钙离子载体A23187（10^-9至10^-7 mol/L）的内皮依赖性血管舒张未受影响。LU 135252治疗对对照大鼠的内皮依赖性和非内皮依赖性血管舒张无显著影响。然而，在MCT处理的大鼠中，LU 135252治疗显著降低了右心室压力（39.7±2.1 mmHg），增强了乙酰胆碱诱导的血管舒张（最大舒张反应变化量，从1.6±0.2升至3.7±0.4 mmHg），并改善了对硝普钠的反应（最大舒张反应变化量，从2.7±0.3升至5.6±0.6 mmHg）。LU 135252未显著改变对A23187的非受体介导的内皮依赖性血管舒张或肺组成型NO合酶活性。
MCT肺动脉高压与平滑肌对NO的反应性降低但内皮依赖性血管舒张能力维持有关。长期ETA拮抗剂治疗不仅恢复了平滑肌对NO的反应性，还增加了对乙酰胆碱的内皮依赖性舒张。这种机制可能有助于ETA拮抗剂在肺动脉高压治疗中的益处。
