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1 Pediatric Heart Lung Center, University of Colorado Health Sciences Center, Denver, CO, USA; Faculte de medecine, Universite de Lille 2, Lille, France
2 Pediatric Heart Lung Center, University of Colorado Health Sciences Center, Denver, CO, USA
3 CHRU de Lille, Hopital Jeanne de Flandre, Lille, France
* To whom correspondence should be addressed. E-mail: Steven.Abman{at}UCHSC.edu.
NO-cGMP signaling plays a critical role during the transition of the pulmonary circulation at birth. BAY 41-2272 is a novel NO-independent direct stimulator of soluble guanylate cyclase that causes vasodilation in systemic and local circulations. However, the hemodynamic effects of BAY 41-2272 have not been studied in the perinatal pulmonary circulation. We hypothesized that BAY 41-272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery in fourteen fetal lambs (125-130d gestation; term = 147d), and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for drug infusion. Pulmonary vascular resistance was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA blood flow. BAY 41-2272 caused dose-related increases in pulmonary blood flow up to 3-fold above baseline and reduced PVR by 75% (p<0.01). Prolonged infusion of BAY 41-2272 caused sustained pulmonary vasodilation throughout the 120 min infusion period. The pulmonary vasodilator effect of BAY 41-2272 was not attenuated by N
-nitro-L-arginine, a NO-synthase inhibitor. In addition, when compared to sildenafil, a PDE5 inhibitor, the pulmonary vasodilator response to BAY 41-2272 was more prolonged. We conclude that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation independent on NO release. We speculate that BAY 41-2272 may have therapeutic potential for pulmonary hypertension associated with failure to circulatory adaptation at birth, especially in the setting of impaired NO production.
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