Aerosol delivery of diethylenetriamine/nitric oxide, a nitric oxide adduct, causes selective pulmonary vasodilation in perinatal lambs

Postnatal adaptation of the pulmonary circulation is mediated partly by endothelium-derived nitric oxide (NO). Recent studies have demonstrated that inhaled NO causes selective and sustained vasodilation in infants with persistent pulmonary hypertension of the newborn. Because the short half-life of NO limits its clinical application, we hypothesized that aerosol delivery of an NO-adduct, diethylenetriamine (DETANO), can cause sustained and selective pulmonary vasodilation. To test the acute effects of DETANO, we studied the pulmonary vascular response of late-gestation fetal lambs (n = 8; age = 138 days; term = 147) to aerosolized DETANO in the presence of an endothelium-derived NO inhibitor, nitro-1-arginine. To determine whether DETANO has a sustained effect, fetal lambs were ventilated with FiO(2) 0.10 before and 15 minutes after they were treated with aerosolized DETANO. Fetal lambs were acutely prepared. Nitro L-arginine (1 mg/min x 30 minutes) was infused into the left pulmonary artery before ventilation with FiO(2) 1.00 for 30 minutes, followed by continued ventilation with FiO(2) 0.10 for 10 minutes. This represented the control period. Ventilation was continued with FiO(2) 1.00, and aerosolized DETANO was given in doses of 0.1, 0.4, and 1.0 mg. Fifteen minutes after the last dose of DETANO was administered, animals were ventilated with FiO(2) 0.10. In the control period, during ventilation with FiO(2) 0.10, left pulmonary artery flow was 122 +/- 33 mL/min and decreased to 104 +/- 22 mL/min. Aerosol delivery of DETANO increased left pulmonary artery flow to 176 +/- 26 mL/min (P <.05) and had no effect on aortic pressure or heart rate. After DETANO was administered, ventilation with FiO(2) 0.10 did not cause any change in left pulmonary artery flow. We conclude that DETANO can cause selective fetal pulmonary vasodilation. Aerosol delivery of DETANO may increase the clinical applications of NO.