Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus Downloaded from

Abstract

. Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 288: L727-L733, 2005. First published December 17, 2004; doi:10.1152/ajplung.00409.2004.-Nitric oxide (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 41-2272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery on 14 fetal lambs (125-130 days gestation; term ϭ 147 days) 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 (PVR) 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 threefold above baseline and reduced PVR by 75% (P Ͻ 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, compared with sildenafil, a phosphodiesterase 5 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 of 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. physiology; lung; vasodilator HIGH RESISTANCE AND LOW BLOOD flow characterize the normal fetal pulmonary circulation. Pulmonary vascular resistance (PVR) decreases dramatically during the normal transition from the fetal to neonatal circulation at birth. Mechanisms that explain the pulmonary vasodilatation at birth are incompletely understood but include alveolar ventilation (12), increase in Pa O 2 (9, 40), and the synthesis of vasoactive mediators such as nitric oxide (NO) NO mediates vasodilatation by stimulating soluble guanylate cyclase (sGC) in vascular smooth muscle cells. sGC is a hemoprotein with a heterodimer of ␣-and ␤-subunits (19). Enzyme activation by the binding of NO results in the conversion of guanosine triphosphate (GTP) to cGMP. cGMP modulates the activity of cGMP-dependent kinases, cGMP-regulated phosphodiesterases, and cGMP-regulated ion channels, which are involved in the regulation of many physiological functions (14). cGMP signaling is downregulated by phosphodiesterase 5 (PDE5) activity, which lowers intracellular cGMP content through degradation of cGMP to . In addition to NO, pharmacological agents have been developed to directly activate sGC. YC-1, a synthetic benzylindazole derivative, increases sGC activity in a NO-independent manner, enhances the sensivity of sGC toward NO, and inhibits PDE5 activity (14, 39). Recent studies showed that BAY 41-2272, a high-affinity YC-1 analog, caused marked vasodilation in the postnatal circulations Persistent pulmonary hypertension of the newborn (PPHN) is a pathological condition related to endothelial injury and decrease in NO production (24). Although inhaled NO (iNO) is effective in treating newborns with PPHN, 30 -40% of the patients do not respond to iNO and require ECMO therapy due to high PVR and hypoxemia (26, In addition, past studies of fetal pulmonary vasoreactivity have demonstrated that many endothelium-dependent vasodilator stimuli such as increased O 2 , shear stress, and pharmalogical agents cause only transient vasodilatio