Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios.

Objective: We determined whether inhaled nitric oxide (NO) could improve systemic oxygenation in human neonates with hypoplastic lungs.

Methods: A multicenter nonrandomized investigation was performed to study the efficacy of short-term NO inhalation. Inhaled NO was administered at 80 ppm to nine neonates without evidence of structural cardiac disease by echocardiography.

Use of ATP-MgCl2 in the evaluation and treatment of children with pulmonary hypertension secondary to congenital heart defects.

Background: Pulmonary hypertension results in increased morbidity and mortality in children after surgical repair of congenital heart defects. Various vasodilators have been unsuccessful in providing preferential pulmonary vasodilation in these patients. Identification of a more preferential pulmonary vasodilator would improve the assessment, management, and outcome of these children.

Developmental effects of endothelin-1 on the pulmonary circulation in sheep.

Endothelin-1 (ET-1) is a polypeptide that has potent hemodynamic effects on the pulmonary circulation. To determine whether there are changes in these effects with increasing postnatal age, we investigated the effects of ET-1 (250 ng/kg) at rest and during pulmonary hypertension in eight lambs (< 1 wk old) and 11 juvenile sheep (6-12 mo old). At rest, ET-1 did not change pulmonary arterial pressure in lambs, but increased pulmonary arterial pressure by 64.

Chronic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs.

Persistent pulmonary hypertension of the newborn (PPHN) is associated with chronic intrauterine events. Acute nitric oxide (NO) inhibition attenuates the normal increase in pulmonary blood flow at birth. We investigated whether chronic NO inhibition in utero causes persistent pulmonary hypertension.

The role of endothelin and endothelin receptor subtypes in regulation of fetal pulmonary vascular tone.

The physiologic role of endothelin-1 (ET-1) and its receptors in regulating fetal pulmonary vascular tone is unknown. We therefore investigated the role of ET-1 and its receptors in the regulation of fetal pulmonary vascular tone using BQ 123 (an ETa receptor antagonist) and 4 Ala ET-1 (an ETb receptor agonist). In six fetal sheep in utero, we found that injections of ET-1 (250 ng/kg fetal weight) into the left pulmonary artery increased left pulmonary blood flow (21.

HA1004, an intracellular calcium antagonist, selectively attenuates pulmonary hypertension in newborn lambs.

HA1004, an isoquinolinesulfonamide and a cyclic nucleotide-dependent protein kinase inhibitor, is an intracellular calcium antagonist that produces vascular smooth muscle (VSM) relaxation in vitro. We studied the hemodynamic effects of intravenous (i.v.

Diethylamine/nitric oxide (NO) adduct, an NO donor, produces potent pulmonary and systemic vasodilation in intact newborn lambs.

Nitric oxide (NO), a labile humoral factor produced by vascular endothelial cells, is a potent vasodilator and an important mediator of pulmonary vascular tone. Nucleophile/NO adducts are a new class of compounds that spontaneously and predictively release NO. We investigated the hemodynamic effects of intravenous (i.

Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb.

The vascular endothelium mediates, in part, pulmonary vascular tone. Because endothelin-1 (ET-1), a paracrine hormone produced by vascular endothelial cells, has vasoactive properties, we investigated the hemodynamic effects of intrapulmonary injections of ET-1 in eight intact newborn lambs at rest and during pulmonary hypertension. At rest, ET-1 (50-1,000 ng/kg) did not change pulmonary arterial pressure.

Hyperoxia and alkalosis produce pulmonary vasodilation independent of endothelium-derived nitric oxide in newborn lambs.

Supplemental oxygen and alkalosis are the most effective treatments used to lower pulmonary arterial pressure in children with pulmonary hypertensive disorders. However, their mechanisms of action are unknown. Endothelium-derived nitric oxide (EDNO) is an important mediator of pulmonary vascular tone and produces potent pulmonary vasodilation during pulmonary hypertension.

M&B 22948, a cGMP phosphodiesterase inhibitor, is a pulmonary vasodilator in lambs.

To investigate the hypothesis that pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in the vascular smooth muscle cell concentration of cGMP, we studied the hemodynamic effects of M&B 22948, a selective guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor, in eight intact newborn lambs. At rest, M&B 22948 (1.0-2.

Endothelin-1 does not mediate acute hypoxic pulmonary vasoconstriction in the intact newborn lamb.

The mechanisms by which acute alveolar hypoxia induces pulmonary vasoconstriction remain unclear. Previous studies suggest that hypoxia-induced vasoconstriction is endothelium-dependent and is associated with the release of endothelin-1 (ET-1), a potent vasoactive paracrine hormone produced by vascular endothelial cells. The vasoconstrictive effects of ET-1 are likely to be mediated by ETA receptors located on vascular smooth-muscle cells.

EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs and oxygenation. Inhibition of prostaglandin synthesis prevents pulmonary vasodilation during rhythmic distension of the lungs but not during oxygenation. Because endothelium-derived relaxing factor (EDRF) modulates pulmonary vascular tone at birth, at rest, and during hypoxia in older animals, we hypothesized that EDRF may modulate pulmonary vascular tone during oxygenation in fetal lambs.

K+ channel pulmonary vasodilation in fetal lambs: role of endothelium-derived nitric oxide.

To define the role and mechanism of action of K+ channels in regulating fetal pulmonary vascular tone, we studied the hemodynamic effects of pinacidil (a K+ channel activator) and glibenclamide (a K+ channel blocker). The effects of pinacidil were compared with those of acetylcholine [an endothelium-derived relaxing factor- (EDRF) dependent pulmonary vasodilator] and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP, an EDRF-independent pulmonary vasodilator) before and after treatment with N omega-nitro-L-arginine [a competitive inhibitor of an EDRF, endothelium-derived nitric oxide (EDNO), synthesis], or L-arginine (the substrate for the formation of EDNO). In 14 unanesthetized fetal lambs in utero, catheters were inserted into the fetal pulmonary artery, descending aorta, left atrium, and superior vena cava to measure pressures and administer drugs.

EDRF inhibition augments pulmonary hypertension in intact newborn lambs.

There is increasing evidence that resting pulmonary vascular tone is mediated by the release of endothelium-derived relaxing factors (EDRF). However, the importance of EDRF release during pulmonary hypertension is unknown. Therefore, in eight newborn lambs we studied the effects of both N omega-nitro-L-arginine (an inhibitor of EDRF synthesis) and L-arginine (a precursor of EDRF synthesis) during pulmonary hypertension induced either by the intravenous infusion of U-46619 (a thromboxane A2 mimic) or by hypoxia.

L-Arginine, a precursor of EDRF in vitro, produces pulmonary vasodilation in lambs.

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects.

In vivo attenuation of endothelium-dependent pulmonary vasodilation by methylene blue.

In vitro evidence suggests that resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in vascular smooth muscle concentrations of guanosine 3',5'-cyclic monophosphate (cGMP). We investigated this hypothesis in vivo in 19 mechanically ventilated intact lambs by determining the hemodynamic effects of methylene blue (a guanylate cyclase inhibitor) and then by comparing the hemodynamic response to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimic) or methylene blue. Methylene blue caused a significant time-dependent increase in pulmonary arterial pressure.

N omega-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs.

To investigate the role of endothelium-derived relaxing factor (EDRF) in the regulation of resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation, we studied the hemodynamic effects of N omega-nitro-L-arginine (a new stereospecific EDRF inhibitor) in 10 spontaneously breathing lambs and then compared the hemodynamic responses to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimetic) or N omega-nitro-L-arginine. N omega-nitro-L-arginine caused a significant dose-dependent increase in pulmonary arterial pressure. Pretreatment with L-arginine blocked this increase, but pretreatment with D-arginine did not, suggesting that N omega-nitro-L-arginine is a competitive inhibitor of L-arginine for EDRF production.

Effects of vasoactive drugs on thromboxane A2 mimetic-induced pulmonary hypertension in newborn lambs.

Isoproterenol, dobutamine, dopamine, and nitroprusside are four vasoactive drugs used to decrease pulmonary arterial pressure and increase cardiac output in newborns, infants, and children with sepsis. Thromboxane A2 likely produces some of the hemodynamic changes in sepsis, and U46619, a thromboxane A2 mimetic, produces similar changes in lambs. We studied the hemodynamic effects of these four vasoactive drugs in 10 spontaneously breathing newborn lambs during an infusion of U46619.

Selective pulmonary vasodilation with ATP-MgCl2 during pulmonary hypertension in lambs.

We investigated the effects of infusions of ATP-MgCl2 on the circulation in 11 spontaneously breathing newborn lambs during pulmonary hypertension induced either by the infusion of U-46619, a thromboxane A2 mimetic, or by hypoxia. During pulmonary hypertension induced by U-46619, ATP-MgCl2 (0.01-1.