NO activity through guanylate cyclase and phosphodiesterase modulation is impaired in fetal lambs with congenital diaphragmatic hernia

Background: Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypertension and death. Administration of nitric oxide (NO) alone remains ineffective in CDH cases. We investigated in near full-term lambs with and without CDH the role of Guanylate Cyclase (GC), the enzyme activated by NO, in increasing cyclic 3'-5'-guanylosine monophosphate (cGMP) and the role of Phosphodiesterase V (PDE V), the enzyme degrading cGMP. Methods: CDH was surgically created in fetal lambs at 85 days of gestation. Pulmonary hemodynamics were assessed by means of pressure and blood flow catheters (135 days). In vitro, we tested drugs on rings of isolated pulmonary vessels. Results: In vivo, sodium nitroprusside (SNP), a direct NO donor, T-1032 and Zaprinast, both PDE V blockers, reduced pulmonary vascular resistance (PVR) in CDH and non CDH animals. The activation of GC by SNP and the inhibition of PDE V by T-1032 were less effective in CDH animals. In vitro, the stimulation of GC by YC-1 (a benzyl indazole derivative) and the inhibition of PDE V by T-1032 were less effective in pulmonary vascular rings from CDH animals. The YC-1 induced vasodilation in rings from CDH animals was higher when associated with the PDE V inhibitor T-1032. Conclusions: GC and PDE V play a role in controlling pulmonary vascular tone in fetal lambs with or without CDH. Both enzymes seem to be impaired in fetal lambs with CDH.