dipropylenetriamine-nonoate and Hypertension--Pulmonary

A single dose of NONOate attenuates pulmonary hypertension (PH) induced by group B Streptococcus (GBS) infusion and this is accompanied by a decrease in systemic vascular resistance (SVR).. The objective of the study was to determine whether two doses of the NONOate sustain the attenuation in GBS-induced PH without further systemic compromise.. 15 anesthetized newborn piglets were randomized to receive placebo (n = 8) or two doses of nebulized DPTA/NO (n = 7) at 15 and 75 min after GBS-induced PH. Pulmonary artery (Ppa) and systemic (Psa) pressures, cardiac output (CO) and arterial blood gases were obtained at baseline and every 15 min until 180 min during GBS infusion.. Ppa and pulmonary vascular resistance (PVR) decreased significantly after the first dose of nebulized DPTA/NO and this effect was maintained after the second dose. Psa and SVR decreased after the first dose of DPTA/NO to values close to baseline and no further changes in systemic circulation were observed with repeated treatment. PVR/SVR increased with GBS infusion, but decreased after the first dose of DPTA/NO and remained significantly lower for 180 min. CO was significantly higher in the DPTA/NO group. Changes in Ppa, PVR, Psa, SVR, and CO with GBS infusion were not modified by placebo infusion. PaCO(2), base deficit, and pH did not differ between groups. PaO(2) was significantly lower in the DPTA/NO group after the second dose.. These data demonstrated that GBS-induced PH is attenuated with two doses of DPTA/NO without significant systemic effect. The vasodilatory effect is more pronounced in the pulmonary than in the systemic vasculature, as suggested by lower PVR/SVR in the DPTA/NO group. We speculate that NONOates may have a clinical application in the management of PH in neonates.

Topics: Administration, Inhalation; Alkenes; Animals; Animals, Newborn; Disease Models, Animal; Drug Administration Schedule; Hypertension, Pulmonary; Nebulizers and Vaporizers; Nitric Oxide; Nitric Oxide Donors; Streptococcal Infections; Streptococcus agalactiae; Swine; Treatment Outcome

NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus (GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4-10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 x 10(8) CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p <0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p <0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates.

Topics: Adult; Alkenes; Animals; Animals, Newborn; Hemodynamics; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide; Random Allocation; Streptococcal Infections; Streptococcus agalactiae; Swine

NONOates, novel NO donors, are complexes of NO with nucleophiles which spontaneously and nonenzymatically release NO in aqueous solution. This study sought to determine the cardiopulmonary effects of the nebulized NONOate dipropylenetriamine (DPTA)/NO in newborn piglets with acute hypoxia-induced pulmonary hypertension. Twenty sedated and mechanically ventilated piglets (4-10 days old) exposed to hypoxia (Fi(O2) = 0.14) were randomly assigned to receive nebulized saline as placebo (PL) or DPTA/NO (75 mg) after 30 min of hypoxia. Pulmonary artery (P(pa)) and wedge pressures, systemic (P(sa)) and right atrial pressures, cardiac output (CO) and arterial blood gas were measured at baseline and every 15 min for 2 h. Methemoglobin levels were measured at baseline and 1 h after drug nebulization. Data (means +/- SD) were analyzed by repeated-measures analysis of variance. Acute hypoxia resulted in an increase in P(pa) and pulmonary vascular resistance (PVR), which was significantly attenuated by DPTA/NO nebulization as compared to the PL group (p < 0.0001). Changes in P(sa), CO, systemic vascular resistance (SVR), arterial blood gas and methemoglobin levels were not different between groups. In contrast to the increase in PVR/SVR observed during hypoxia in the PL group, there was a significant decrease in this ratio after NONOate administration (p < 0.0001). These data show that acute hypoxic pulmonary hypertension in newborn piglets is markedly attenuated by NONOate nebulization. This response is predominantly in the pulmonary vasculature as the PVR/SVR was significantly lower in the treated group. We speculate that NONOates may have clinical application in the treatment of persistent pulmonary hypertension of the newborn.

Topics: Acute Disease; Alkenes; Animals; Animals, Newborn; Blood Gas Analysis; Blood Pressure; Disease Models, Animal; Hypertension, Pulmonary; Hypoxia; Nebulizers and Vaporizers; Nitric Oxide Donors; Random Allocation; Respiratory Function Tests; Swine

To determine the selective vasodilatory effects of two inhaled "NONOate" aerosols in a closed chest pig model of acute pulmonary hypertension (APH).. APH was induced by IV infusion of the prostaglandin H(2)/thromboxane A(2) receptor agonist (U46619). Aerosolized diethylenetriamine nitric oxide (NO) adduct (DETA/NO, n = 4), dipropylenetriamine NO adduct (DPTA/NO, n = 4) [60 micro mol each], or placebo (n = 4) was delivered via the trachea. Hemodynamic parameters and blood samples were measured before and after inhalation therapy.. Compared to control animals, pulmonary vascular resistance and pulmonary arterial pressure were significantly reduced from 10 to 105 min after DETA/NO administration and from 10 to 45 min after DPTA/NO aerosol administration (p < 0.05). Both aerosols had no significant effect on systemic vascular resistance or systemic BP. Serum nitrite significantly increased after the inhalation of both NONOates (p < 0.01). There was a tendency for reduced intrapulmonary shunting, particularly after treatment with DETA/NO.. Both DETA/NO and DPTA/NO administered as aerosols selectively reduced pulmonary hypertension induced by U46619.

Topics: Aerosols; Alkenes; Analysis of Variance; Animals; Female; Hemodynamics; Hypertension, Pulmonary; Nitric Oxide Donors; Nitroso Compounds; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Swine; Vasodilator Agents