Deruelle Philippe, Grover Theresa R, Abman Steven H
Pediatric Heart Lung Center, University of Colorado School of Medicine, Denver, Colorado, USA.
Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L798-806. doi: 10.1152/ajplung.00119.2005. Epub 2005 Jun 17.
Persistent pulmonary hypertension of the newborn (PPHN) is partly due to impaired nitric oxide (NO)-cGMP signaling. BAY 41-2272 is a novel direct activator of soluble guanylate cyclase, but whether this drug may be an effective therapy for PPHN is unknown. We hypothesized that BAY 41-2272 would cause pulmonary vasodilation in a model of severe PPHN. To test this hypothesis, we compared the hemodynamic response of BAY 41-2272 to acetylcholine, an endothelium-dependent vasodilator, and sildenafil, a selective inhibitor of PDE5 in chronically instrumented fetal lambs at 1 and 5 days after partial ligation of the ductus arteriosus. After 9 days, we delivered the animals by cesarean section to measure their hemodynamic responses to inhaled NO (iNO), sildenafil, and BAY 41-2272 alone or combined with iNO. BAY 41-2272 caused marked pulmonary vasodilation, as characterized by a twofold increase in blood flow and a nearly 60% fall in PVR at day 1. Effectiveness of BAY 41-2272-induced pulmonary vasodilation increased during the development of pulmonary hypertension. Despite a similar effect at day 1, the pulmonary vasodilator response to BAY 41-2272 was greater than sildenafil at day 5. At birth, BAY 41-2272 dramatically reduced PVR and augmented the pulmonary vasodilation induced by iNO. We concluded that BAY 41-2272 causes potent pulmonary vasodilation in fetal and neonatal sheep with severe pulmonary hypertension. We speculate that BAY 41-2272 may provide a novel treatment for severe PPHN, especially in newborns with partial response to iNO therapy.
新生儿持续性肺动脉高压（PPHN）部分归因于一氧化氮（NO）-环磷酸鸟苷（cGMP）信号传导受损。BAY 41-2272是一种新型的可溶性鸟苷酸环化酶直接激活剂，但这种药物是否可能成为PPHN的有效治疗方法尚不清楚。我们假设BAY 41-2272会在重度PPHN模型中引起肺血管舒张。为了验证这一假设，我们比较了BAY 41-2272与乙酰胆碱（一种内皮依赖性血管舒张剂）以及西地那非（一种PDE5选择性抑制剂）在动脉导管部分结扎后1天和5天的慢性植入胎儿羔羊中的血流动力学反应。9天后，我们通过剖宫产分娩动物，以测量它们对吸入NO（iNO）、西地那非和单独使用或与iNO联合使用的BAY 41-2272的血流动力学反应。BAY 41-2272引起了明显的肺血管舒张，其特征是第1天时血流量增加两倍，肺血管阻力（PVR）下降近60%。在肺动脉高压发展过程中，BAY 41-2272诱导的肺血管舒张效果增强。尽管在第1天有类似的效果，但在第5天，BAY 41-2272的肺血管舒张反应大于西地那非。出生时，BAY 41-2272显著降低PVR，并增强了iNO诱导的肺血管舒张。我们得出结论，BAY 41-2272在患有重度肺动脉高压的胎儿和新生羊中引起有效的肺血管舒张。我们推测BAY 41-2272可能为重度PPHN提供一种新的治疗方法，特别是对于对iNO治疗有部分反应的新生儿。
