The objective of this study was to investigate the role of endogenous nitric oxide, formed from L-arginine, in the regulation of pulmonary circulation in vivo, with special reference to the hypoxic pressor response. In artificially ventilated open-chest rabbits, pulmonary vascular resistance at normoxic ventilation (FIO2 = 21%) was 78 +/- 16 cmH2O ml-1 min 1000-1 (mRUL). Hypoxic ventilation (FIO2 = 10%) increased pulmonary vascular resistance to 117 +/- 17 mRUL. N omega-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase, increased pulmonary vascular resistance at normoxic ventilation to 192 +/- 28 mRUL and during hypoxic ventilation to 462 +/- 80 mRUL. During N omega-nitro-L-arginine methylester infusion there was also an increase in mean arterial blood pressure as well as a decrease in cardiac output that was even more pronounced during hypoxic ventilation. L-arginine reversed the effect of N omega-nitro-L-arginine methylester on pulmonary vascular resistance at normoxic ventilation to 140 +/- 26 mRUL and at hypoxic ventilation to 239 +/- 42 mRUL. In spontaneously breathing closed-chest rabbits, N omega-nitro-L-arginine methylester evoked a marked decrease in arterial PO2 and increases in respiration frequency and central venous pressure, while blood pH, PCO2 and base excess remained unchanged. Taken together these findings indicate that endogenous nitric oxide, formed from L-arginine, might be a regulator of ventilation-perfusion matching at normoxic ventilation, and that nitric oxide acts as an endogenous modulator of the hypoxic pressor response.

Concentrations of endogenous nitric oxide (NO) were measured in premature (n = 18) and term infants (n = 7). Nasal gas was aspirated continuously and after timed occlusions, 15 s and 60 s, by a fast-response chemiluminescence analyser. The sampling flow rate was 20 ml min-1. Typical NO recordings consisted of plateaux and postocclusive peaks. In term infants peak NO concentrations (60 s occlusion) were 2.71 +/- 0.44 parts per million (ppm) within 10 min after birth, increasing (p < 0.05) to 3.81 +/- 0.25 ppm at 4-7 d postnatally. Peak NO values (15 s occlusion) averaged 1.22 +/- 0.16 ppm in premature infants (postconceptional age 25-37 weeks, body weight 623-2844 g) and the NO concentrations increased significantly with postconceptional age (p < 0.05). Nasal excretion rate, estimated from plateau NO concentrations and sampling flow rate, was 0.10 +/- 0.01 nmol min-1 kg-1 in both groups. We conclude that premature and term newborn infants excrete considerable amounts of NO in the upper airways, with hitherto not fully known functions.

Endogenously produced nitric oxide (NO) was monitored in exhaled air from ovalbumin-sensitized and pentobarbital anaesthetized guinea-pigs. Stable levels of nitric oxide were detected in exhaled air over a 30-min control period in each experiment (9.2 +/- 1.4 parts per billion, [ppb]). Insufflation pressure and NO in exhaled air immediately increased, in a dose dependent manner, in response to challenge with nebulized allergen (Ovalbumin, 0.1-10 mg). Indomethacin (5 mg kg-1) augmented the allergen-induced increases in insufflation pressure and NO. Fifteen min after the challenge the insufflation pressure remained elevated while NO in exhaled air had dropped below control levels. The increase in insufflation pressure induced by inhalation of PGF2 alpha (5 micrograms) was accompanied by an increase in nitric oxide in exhaled air, which however was significantly less than the increase in NO induced by allergen challenge. The results suggest a role for NO mechanisms in asthma.

Objective-To study the short-term effects of inhaled nitric oxide in infants and young children with congenital heart disease. Setting-A supraregional referral centre for children with congenital heart disease. Patients and methods-22 infants and children aged 3-32 months (median age 5 months) with congenital heart disease undergoing preoperative cardiac catheterisation. AlU but one infint had intracardiac shunt lesions and 13 had increased pulmonary vascular resistance. Conclusion-The present study shows that in infants with congenital heart disease inhaled nitric oxide reduced pathologically increased pulmonary vascular resistance without affecting systemic circulation and without important side effects with brief exposure. (Br HeartrJ 1994;71:282-286) Increased pulmonary vascular resistance with pulmonary hypertension is a frequent complication in congenital heart disease,' and postoperative pulmonary hypertensive crisis is a major problem that may account for a substantial part of the postoperative mortality and morbidity.2 Until the discovery of the biological effects of nitric oxide (NO) there was no selective treatment to produce pulmonary vasodilatation. NO is a major endothelium derived relaxing factor3" that regulates blood flow and modulates the hypoxic pressor response in the lung.6 It is also present in exhaled air of human.7 Because it is rapidly inactivated by haemoglobin,8 the dilating effects of inhaled NO should be confined to the pulmonary vascular bed. The selective pulmonary vasodilating effect of inhaled NO in hypoxic pulmonary hypertension was shown in lambs9 and in healthy volunteers.'0 Inhaled NO was of benefit in the treatment of persistent pulmonary hypertension of the newbornm 12 and in the adult respiratory distress syndrome.'3 Recently Roberts et al showed that pulmonary vascular resistance was reduced by NO during cardiac catheterisation in infants with congenital heart disease'4 and we have also reported a dramatic effect in one case of postoperative pulmonary hypertension." NO, however, can cause methaemoglobinemia,'6 and in the presence of oxygen NO forms nitrogen dioxide, which is toxic in the lungs even in very low concentrations.'7-'9 No severe side effects were seen during or after the administration of NO at concentrations below 80 ppm in adults'0 13 but experience is still limited. In infants and children there is even less experience and the aim of this study was to investigate further the effects and side effects of brief inhalation of NO in infants and children with congenital heart defects. Patients and methodsWe studied 22 infants and children aged 3-32 months (median age 5 months) with congenital heart disease who had routine preoperative cardiac catheterisation (table). All but one had shunt lesions, and 10 had atrioventricular septal defects. Twelve also had Down's syndrome. Pethidine (2 mg/kg), promethazine (0-5 mg/kg), and chlorpromazine (0 5 mg/kg) were used for sedation. One hour before catheterisation a topical anaesthetic containing prilocaine and ...

Intravital microscopy of rabbit tenuissimus muscle was used for studies of endogenous nitric oxide as a microvascular regulator in vivo. Derivatives of arginine were administered in order to modulate the formation of nitric oxide from L-arginine. N omega-nitro-L-arginine methylester (L-NAME) (1-100 mg kg-1 i.v.) dose-dependently reduced microvascular diameters. A concomitant blood pressure increase and a decrease in heart rate was observed. The blood pressure increase induced by L-NAME (30 mg kg-1) was reversed by L-arginine (1 g kg-1) but not D-arginine. Vasodilation in response to topical acetylcholine (0.03-3 microM) was significantly inhibited by L-NAME (30 mg kg-1), whereas vasodilation by sodium nitroprusside (300 nM) was not affected. Vasomotor nerve-induced vasodilatation, induced by stimulation of the tenuissimus nerve after neuromuscular blockade by pancuronium in animals pretreated with guanethidine, was significantly attenuated by L-NAME, an effect also reversed by L-arginine. The vasodilatation in response to active contractions of the muscle induced by motor nerve stimulation as well as the vasodilator response elicited by graded perfusion pressure reductions were unaffected by L-NAME or NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) administered topically. Our results indicate that endogenous nitric oxide formed from L-arginine is a modulator of microvascular tone in vivo. Furthermore, the results suggest that endogenous nitric oxide is required for vasomotor nerve-induced vasodilatation, whereas it does not appear to play a role in myogenic vasodilatation or functional hyperaemia in this tissue.