The Effect of Nω-Nitro-L-Arginine Methylester on Hypoxic Vasoconstriction in the Neonatal Pig Lung

Abstract

ABSTRACT. This study was carried out to determine the influence and site of action of Nu-nitro-L-arginine methylester, an L-arginine analogue, on basal pulmonary vascular tone and hypoxic vasoconstriction in neonatal pig lungs. We studied isolated lungs from pigs, age 14.5 2 0.5 (SD) d and weight 3.6 +: 0.7 kg, perfused with autologous blood a t a constant flow rate. The arterial-venous occlusion method was used to determine sites of action upstream and downstream of the double occlusion pressure (Pd) during baseline, infusion of acetylcholine, and ventilation of the lung with a hypoxic gas mixture. The measurements were then repeated during the three conditions described above after adding Nu-nitro-L-arginine methylester, a competitive inhibitor of nitric oxide synthase, to the blood. During control conditions, the vascular resistance was almost evenly divided upstream and downstream of Pd. Infusion of acetylcholine resulted in downstream dilation, and hypoxia resulted in an increase in both upstream and downstream resistance. After adding Nu-nitro-L-arginine methylester to the blood, there was an increase in both upstream and downstream resistances; acetylcholine infusion resulted in an increase in total vascular resistance, which was entirely due to upstream constriction; and the hypoxia response was much larger both upstream and downstream of Pd. These results suggest that nitric oxide synthase helped maintain a low level of basal pulmonary vascular tone both upstream and downstream of Pd in these neonatal pig lungs; that the vascular effect of acetylcholine was changed from downstream dilation to upstream constriction by Nu-nitro-L-arginine methylester; and that nitric oxide synthase activity modulated both the upstream and downstream vasomotor response to hypoxia. (Pediatr Res 34: 349-353,1993) Abbreviations Ach, acetylcholine NO, nitric oxide NAME, Nw-nitro-L-arginine methylester Pa, pulmonary artery pressure Pd, double occlusion pressure Pv, left atrial pressureThe release of NO from the endothelial cell has been implicated in the maintenance of the normally low resting pulmonary vascular resistance (I-5), but some studies have found no change in pulmonary vascular resistance during basal conditions when the action of NO is inhibited (6, 7). Similarly, the role of NO during the pulmonary vasoconstrictor response to hypoxia remains unclear, with studies suggesting hypoxia-induced inhibition of NO release (4, 8-1 1) or stimulation of NO release (5-7, 12, 13). There is currently no available information on how NO synthase inhibitors, such as NAME, influence the arterial venous distribution of pulmonary vascular resistance or the arterial venous site of action of pulmonary vasomotor stimuli. These questions are of particular importance in the neonate, where the pulmonary vasculature appears to be particularly reactive (14). Furthermore, recent studies (2, 15, 16) have suggested a role for NO in modulating pulmonary vascular resistance in the early neonatal period. Thus, the present study was designed to ...

The Effect of Inhaled Nitric Oxide on the Pulmonary Circulation of the Neonatal Pig

“…For example, Fike reported in neonatal pigs (20)(21)(22)(23). As a positive control in two and Kaplowitz (28) found that injection of papaverine resulted animals at the end of the experiment, 0.3 mg/kg neostigmine in a decrease in PVR in neonatal pig lungs, and we found that was given i.v., which resulted in a doubling of pulmonary resist-infusion of acetylcholine decreased PVR in a similar preparation ance from 4.0 * 1.1 cm H20/mL/s baseline to 7.8 k 2.8 cm (19). These differences between pigs and lambs may suggest H20/mL/s after neostigmine administration.…”

“…After 15 min the measurements described above were repeated. We have previously found that the neonatal pig has a stable hypoxic response over this time period (19). Finally, the pig breathed room air, and after 2 or 3 min, when the pulmonary artery pressure had stabilized at the baseline value, the pig was exsanguinated and the lungs removed for the determination of wet-to-dry weight ratios.…”

Hypoxic Pulmonary Vasoconstriction

“…On the one hand, HPV was enhanced in intact and isolated lungs treated with NOS antagonists (60,78,114,185,214,264,379,449,477,509,512,640,752,1058,1107,1368,1699,1825,1968,2138) and isolated nonprecontracted pulmonary arteries treated with NOS antagonists, Hb (which binds NO), or inhibitors of soluble guanylyl cyclase (393, 1104,1411,1418). Moreover, HPV was exaggerated in transgenic mice with complete or partial eNOS deficiency (495, 1106), but blunted in rat and mouse lungs overexpressing eNOS and/or iNOS (277, 887,896).…”

Lung Circulation

“…Numerous studies have utilized NOS antagonists to investigate the role of NO in maintaining low normal pulmonary vascular tone. In the neonate, studies clearly demonstrate a critical role for NO as a modulator of PVR (143,228,455). In the adult lung, however, contradictory results have been reported.…”