Vasodilatory effect of the stable vasoactive intestinal peptide analog RO 25-1553 in murine and rat lungs.
Vasodilatory effect of the stable vasoactive intestinal peptide analog RO 25-1553 in murine and rat lungs.
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DOI：
10.1371/journal.pone.0075861
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kuebler WM
中科院分区：
文献类型：
--
作者：
Yin J;Wang L;Yin N;Tabuchi A;Kuppe H;Wolff G;Kuebler WM
基于其支气管扩张和抗炎作用，血管活性肠肽（VIP）的稳定类似物已被提议作为慢性阻塞性肺病（COPD）的新疗法。我们推测 VIP 类似物可能会提供额外的好处，因为它们在肺部发挥血管舒张特性，并在离体和体内模型中测试了这一假设。在离体灌注小鼠肺和体内大鼠模型中，肺血管因缺氧而预收缩，并测定了循环 VIP 类似物 RO 25-1553 的全身（离体）或吸入（体内）给药引起的血流动力学变化。在小鼠肺部，RO 25-1553 降低了常氧条件下的内在血管阻力，并减弱了急性缺氧引起的肺动脉压力的增加。一致地，吸入RO 25-1553（1 mg·mL−1，持续3分钟）引起对体内缺氧反应的肺动脉压升高的广泛且持续（> 60分钟）的抑制，这与吸入西地那非的效果相当。这种效应并非归因于 RO 25-1553 的全身心血管效应，而是归因于肺血管阻力的肺部特异性降低，而心输出量和全身动脉血流动力学不受影响。未检测到吸入 RO 25-1553 对肺气体交换、通气-灌注匹配或肺液含量的不良影响。我们的研究结果表明，吸入稳定的 VIP 类似物 RO 25-1553 可在肺循环中诱导有效且持续的血管舒张作用，且没有可检测到的不良反应。 RO 25-1553 的治疗性吸入除了对 COPD 具有抗炎和支气管扩张作用外，还可能对血管有益，但鉴于在最近的一系列临床试验中，血管扩张剂治疗 COPD 继发性肺动脉高压的总体效果不佳，因此需要谨慎。
Stable analogs of vasoactive intestinal peptide (VIP) have been proposed as novel line of therapy in chronic obstructive pulmonary disease (COPD) based on their bronchodilatory and anti-inflammatory effects. We speculated that VIP analogs may provide additional benefits in that they exert vasodilatory properties in the lung, and tested this hypothesis in both ex vivo and in vivo models. In isolated perfused mouse lungs and in an in vivo rat model, pulmonary blood vessels were preconstricted by hypoxia and hemodynamic changes in response to systemic (ex vivo) or inhaled (in vivo) administration of the cyclic VIP analog RO 25-1553 were determined. In mouse lungs, RO 25-1553 reduced intrinsic vascular resistance at normoxia, and attenuated the increase in pulmonary artery pressure in response to acute hypoxia. Consistently, inhalation of RO 25-1553 (1 mg·mL−1 for 3 min) caused an extensive and sustained (> 60 min) inhibition of the pulmonary arterial pressure increase in response to hypoxia in vivo that was comparable to the effects of inhaled sildenafil. This effect was not attributable to systemic cardiovascular effects of RO 25-1553, but to a lung specific reduction in pulmonary vascular resistance, while cardiac output and systemic arterial hemodynamics remained unaffected. No adverse effects of RO 25-1553 inhalation on pulmonary gas exchange, ventilation-perfusion matching, or lung fluid content were detected. Our findings demonstrate that inhaled delivery of the stable VIP analog RO 25-1553 induces a potent and sustained vasodilatory effect in the pulmonary circulation with no detectable adverse effects. Therapeutic inhalation of RO 25-1553 may provide vascular benefits in addition to its reported anti-inflammatory and bronchodilatory effects in COPD, yet caution is warranted given the overall poor results of vasodilator therapies for pulmonary hypertension secondary to COPD in a series of recent clinical trials.
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DOI：
10.1164/ajrccm.164.2.2006129
发表时间：
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影响因子：
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