Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure
Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure
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DOI：
10.1097/00000542-200701000-00021
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发表时间：
2007-01-01
期刊：
影响因子：
8.8
通讯作者：
Kuebler, Wolfgang M.
中科院分区：
文献类型：
--
作者：
Hentschel, Thomas;Yin, Ning;Kuebler, Wolfgang M.
背景：大多数充血性心力衰竭（CHF）患者会出现肺静脉高压，但右心室后负荷常常因肺血管阻力增加而进一步升高。为了研究吸入血管舒张性磷酸二酯酶 3 抑制剂是否可以逆转这一潜在的有害过程，作者研究了吸入或静脉注射米曲酮对 CHF 大鼠模型肺和全身血流动力学的影响。方法：在雄性 Sprague-Dawley 大鼠中，CHF 是通过冠状动脉上束带诱导的，而假手术大鼠作为对照。米力农静脉输注（0.2-1μg（.）kg体重（-1）（.）min（-1））或吸入（0.2-5mg/ml），并测量对肺和全身血流动力学以及肺水含量的影响。 结果：在CHF大鼠中，静脉输注米力农可降低肺动脉血压和全身动脉血压。相反，吸入米曲农主要扩张肺血管，导致肺血管阻力比降低。以 20 分钟的间隔重复吸入米力农可使肺动脉压力稳定降低。当给予0.9% NaCl代替米力农或在假手术大鼠中吸入米力农时，没有检测到血流动力学影响。没有检测到米力农吸入治疗 CHF 的潜在不良反应，例如左心室容量超负荷。此外，反复吸入米力农可显着减轻肺水肿。 结论：如果这些结果能够在人体中得到证实，那么雾化米力农可能为治疗CHF肺静脉高压提供一种新颖、有效、安全的肺部选择性策略。
Background: Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous mitrinone on pulmonary and systemic hemodynamics in a rat model of CHF.Methods: in male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 mu g (.) kg body weight(-1) (.) min(-1)) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured.Results: In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. in contrast, inhalation of mitrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated mitrinone inhalation.Conclusion: If these results can be confirmed in humans, inhalation of nebulized milrinone may present a novel, effective, safe, and pulmonary selective strategy for the treatment of pulmonary venous hypertension in CHF.