Newborn pigs with chronic
hypoxia-induced
pulmonary hypertension (PH) have evidence of
endothelial nitric oxide synthase (eNOS) uncoupling. In this model, we showed that
therapies that promote eNOS coupling, either
tetrahydrobiopterin (BH4), a NOS cofactor, or l-
citrulline, a NO-
l-arginine precursor, inhibit PH. We wanted to determine whether cotreatment with l-
citrulline and a BH4 compound,
sapropterin dihydrochloride, improves NO signaling and chronic
hypoxia-induced PH more markedly than either alone. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received sole treatment with l-
citrulline or BH4, or were cotreated with l-
citrulline and BH4, from day 3 through day 10 of
hypoxia.
Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios and NO production. In untreated hypoxic piglets, pulmonary vascular resistance (PVR) was higher and NO production and eNOS dimer-to-monomer ratios were lower than in normoxic piglets. Compared with the untreated hypoxic group, PVR was lower in hypoxic piglets cotreated with l-
citrulline and BH4 and in those treated with l-
citrulline alone but not for those treated solely with BH4. NO production and eNOS dimer-to-monomer ratios were greater for all three treated hypoxic groups compared with the untreated group. Notably, greater improvements in PVR, eNOS dimer-to-monomer ratios, and NO production were found in hypoxic piglets cotreated with l-
citrulline and BH4 than in piglets treated with either alone. Cotreatment with l-
citrulline and BH4 more effectively improves NO signaling and inhibits chronic
hypoxia-induced PH than either treatment alone. Combination
therapies may offer enhanced therapeutic capacity for challenging clinical conditions, such as chronic neonatal PH.