Hemodynamic effects of combined L-nitro-arginine and indomethacin to promote closure of patent ductus arteriosus in preterm baboons

Patent ductus arteriosus (PDA) is a major complication of prematurity and its incidence increases with decreasing gestational age. Indomethacin-induced constriction of the ductus is often transient and is also less successful with decreasing gestational age. We have previously shown that both nitric oxide and prostaglandins play significant roles in maintaining ductus patency in vitro using vessels from newborns. Therefore, the effects of prostaglandin inhibition alone or in combination with nitric oxide inhibition were examined in the current studies. Preterm baboons were delivered by c-section at 125 days gestational age (67% fullterm), treated with exogenous surfactant at birth, and mechanically ventilated for 6 days. Five animals were treated with daily doses of prophylactic indocin (INDO) (0.1 mg/kg/dose) starting at 24 hrs and six additional animals received prophylactic indocin plus a 4 day continuous infusion of L-nitro-arginine (L-NA) starting at 50 hrs (6 mg/kg/hr). By echocardiography. 3/5 treated with INDO alone had transient closure with all but one reopening by echo at 6 days. In contrast, 6/6 treated with INDO + L-NA had functional closure of their PDA and all remained closed by echo at 6 days. At necropsy after 6 days, 0/5 treated with INDO alone achieved visual anatomic closure while 4/6 treated with INDO + L-NA had visual anatomic closure and the remaining 2 had only pinpoint openings of the lumens of their ductus. Treatment with L-NA had mild effects on oxygenation which were resolved within 24 hrs of starting the infusion. Urine output was excellent and similar in both groups. However, L-NA increased systemic BP significantly with mean BPs (±SEM) of 46.2±7.8 mm Hg (L-NA + INDO) vs. 29.8±2.7 mm Hg (INDO alone) at 6d. In 4 animals tested, mean BP initially increased by 31% with L-NA versus only 10% following 20 mcg/kg/min of dopamine for 1 hr (prior to the start of the L-NA infusion). However, systemic flow velocity integrals measured by echocardiography increased 54% with dopamine and decreased 30% with L-NA suggesting that the major effect of L-NA was on peripheral resistance. In conclusion, nitric oxide inhibition appears to promote persistent closure of the PDA in preterm baboons of borderline viability and may have significant effects on peripheral vascular resistance.