Zhao L, Mason N A, Morrell N W, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov M M, Aldashev A, Wilkins M R
Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Circulation. 2001 Jul 24;104(4):424-8. doi: 10.1161/hc2901.093117.
This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice.
In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O(2) for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean+/-SD mm Hg]: normoxia 16.0+/-2.1 versus hypoxia 25.0+/-4.8) was almost abolished by sildenafil (normoxia 16.0+/-2.1 versus hypoxia 18.0+/-3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg. kg(-1). d(-1)) throughout 3 weeks of exposure to hypoxia (10% O(2)) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3+/-9.9 versus 29.9+/-9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling.
Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.
本研究调查了磷酸二酯酶5抑制剂西地那非对人和小鼠肺血管低氧反应的影响。
在一项随机双盲研究中，10名健康志愿者在呼吸11%氧气30分钟前1小时口服100毫克西地那非或安慰剂。用留置的右心导管测量肺动脉压（PAP）。安慰剂治疗期间低氧导致平均PAP急性升高56%（平均PAP[平均值±标准差毫米汞柱]：常氧16.0±2.1与低氧25.0±4.8），而西地那非几乎消除了这种升高（常氧16.0±2.1与低氧18.0±3.6），对体循环血压无显著影响。在野生型和内皮型一氧化氮合酶（eNOS）缺陷小鼠的离体灌注肺中，西地那非显著减弱急性低氧性肺血管收缩。在暴露于低氧（10%氧气）3周的整个过程中，野生型小鼠口服该药（25毫克·千克-1·天-1），右心室收缩压显著降低（安慰剂与西地那非：43.3±9.9与29.9±9.7毫米汞柱，P<0.05），同时右心室肥厚略有减轻，肺血管重塑受到抑制。在eNOS突变小鼠中，西地那非减轻了右心室收缩压的升高，但对右心室肥厚或血管重塑无显著影响。
西地那非减轻人和小鼠低氧诱导的肺动脉高压，为治疗这种疾病提供了一种新方法。eNOS-NO-cGMP途径参与了对西地那非的反应，但cGMP的其他生化来源也起作用。即使eNOS活性受损，西地那非也具有有益的肺血流动力学效应。
