Weimann J, Ullrich R, Hromi J, Fujino Y, Clark M W, Bloch K D, Zapol W M
Departments of Anesthesia and Critical Care, Respiratory Care, and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Anesthesiology. 2000 Jun;92(6):1702-12. doi: 10.1097/00000542-200006000-00030.
Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction.
In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6).
Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation.
Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.
5型磷酸二酯酶（PDE5）可水解肺中的环磷酸鸟苷，从而调节一氧化氮（NO）/环磷酸鸟苷介导的肺血管舒张。PDE5抑制剂已被用于治疗肺动脉高压。在本研究中，我们检测了已被批准用于治疗勃起功能障碍的新型选择性PDE5抑制剂西地那非的肺血管舒张和全身血管舒张特性。
在通过静脉输注血栓素类似物U46619诱导的急性肺动脉高压清醒羔羊模型中，我们测量了经鼻胃管给予12.5、25和50 mg西地那非对肺和全身血流动力学的影响（n = 5）。我们还比较了西地那非（n = 7）和另一种PDE5抑制剂扎普司特（n = 5）对百万分之2.5、10和40吸入NO的肺血管舒张作用的影响。最后，我们检测了静脉输注L-NAME（内源性NO生成抑制剂）对50 mg西地那非诱导的肺血管舒张的影响（n = 6）。
西地那非累积剂量（12.5、25和50 mg）分别使肺动脉压降低21%、28%和42%，肺血管阻力分别降低19%、23%和45%。仅在最大累积西地那非剂量后，全身动脉压降低了12%。西地那非和扎普司特均未增强吸入NO扩张肺血管的能力。扎普司特而非西地那非在停止吸入NO后显著延长了肺血管舒张的持续时间。输注L-NAME消除了西地那非诱导的肺血管舒张。
在急性肺动脉高压绵羊模型中，西地那非是一种选择性肺血管舒张剂。西地那非通过NO依赖机制诱导肺血管舒张。与扎普司特不同，西地那非不会延长吸入NO的肺血管舒张作用。
