Response of nitric oxide pathway to L-arginine infusion at the altitude of 4,350 m. J-C. Schneider, I. Blazy, M. Déchaux, D. Rabier, N.P. Mason, J-P. Richalet. #ERS Journals Ltd 2001. ABSTRACT: It was hypothesized that hypoxia may inhibit nitric oxide (NO) production by reducing the availability of endothelial NO synthase (NOS III) substrate.To evaluate the effect of L-arginine on the NO release in high altitude, 11 subjects were infused with L-arginine (0.5 g?kg -1 ) during 30 min in normoxia and after 36 h at 4,350 m (hypoxia). The L-citrulline and cyclic guanosine monophosphate (cGMP) concentrations were measured to investigate NO synthesis and guanylyl cyclase activity respectively. L-citrulline concentration, arterial oxygen saturation (Sa,O 2 ), systemic blood pressure, heart rate and acute mountain sickness (AMS) score were measured at rest and 15, 30 and 45 min after starting infusion.The results showed that baseline L-citrulline was lower in hypoxia (pv0.05). L-arginine infusion increased L-citrulline concentration in both conditions. However, in hypoxia L-citrulline concentration remained lower than in normoxia (pv0.05). The concentration of cGMP was lower in hypoxia (pv0.05). In hypoxia, Sa,O 2 increased from 15 min after the start of the infusion to 45 min (pv0.05). Blood pressure and heart rate were not affected by L-arginine infusion.Subjects who experienced symptoms of AMS showed a slight decrease in AMS score with L-arginine.The decreased L-citrulline suggests a hypoxia-induced impairment of nitric oxide synthase III or a decrease in L-arginine availability. The improvement of arterial oxygen saturation by pretreatment with L-arginine could be ascribed to an enhancement of the ventilation/perfusion ratio. Collectively, these results are consistent with a decrease in nitric oxide production in hypoxia that could be antagonized by supplying nitric oxide synthase cosubstrate. Exposure to high altitude causes hypoxaemia, which is often accompanied by the clinical manifestations of acute mountain sickness (AMS) and may lead to the development of pulmonary hypertension and high altitude pulmonary oedema (HAPE). Several factors are incriminated: hypoxic pulmonary vasoconstriction (HPV), water retention, and permeability alterations [1]. Increased release of vasoconstrictors, such as endothelin or catecholamines, at high altitude may be partially responsible for HPV [2]. However, impairment of nitric oxide (NO) synthesis by pulmonary endothelial cells occurs in the pulmonary hypertensive process suggesting that the increase in pulmonary vascular tone could have its origin in a decline of endothelium-dependent relaxation [3]. NO is synthesized in pulmonary artery endothelial cells by the action of the endothelial constitutive NO synthase isoform (NOS III) on the cationic amino acid L-arginine (Arg). NO is produced from the terminal guanidino-nitrogen of Arg upon conversion to L-citrulline by NOS III in a reaction that requires molecular oxygen and cofactors. Direct measurement of NO release from vascular ...

Endothelin-1 (Et1), like angiotensin II, is implicated in postnatal maturation and development. The present study was designed to identify Et1 receptors and subtype Et1 receptors present in rat kidney between 1 and 30 days of postnatal life. On day 1, high-affinity and high-density Et1 binding sites were identified in rat kidney. The dissociation constant and maximum binding for ET1 to membranes from whole kidney were 0.073 +/- 0.05 nM and 1,345.9 +/- 73 fmol/mg protein, respectively. On day 30, affinity and receptor density were markedly decreased. The dissociation constant and maximum binding were 0.147 +/- 0.021 nM (P < 0.01) and 633.2 +/- 56.4 fmol/mg protein (P < 0.001), respectively. Using BQ 123 (EtA-selective antagonist) and sarafotoxin S6c (EtB-selective agonist), the two Et1 receptor subtypes EtA and EtB were identified in 1- and 30-day-old rat kidney. BQ 123 selectively recognized EtA receptors with high affinity (2.9 +/- 0.44 on day 1 and 4.0 +/- 0.5 nM on day 30) and sarafotoxin S6c bound with higher affinity EtB receptors (0.871 +/- 0.14 on day 1 and 0.717 +/- 0.12 nM on day 30). Between birth and day 30, the EtA binding capacity was decreased (304 +/- 27 vs. 752 +/- 202 fmol/mg protein, P < 0.05), whereas EtB binding was not affected (514 +/- 87 vs. 656 +/- 171 fmol/mg protein, NS). The decrease in the total number of Et1 receptors during the 1st month of life may be due to the concomitant decrease in the number of EtA receptors. Increased Et1 receptor density in early postnatal life suggests an influence of Et1 on immature kidney circulation and/or kidney growth.

The aim of this work was to investigate the presence of inactive renin (IR) in plasma of normal infants and children and nephrectomized children and to study the plasma IR response to stimulation of the renin-angiotensin system (orthostasis) in children. The study was performed in 10 normal infants (2 days to 1 yr old), 28 normal children (1-15 yr old), 8 nephrectomized children (8-14 yr old), and 7 normal adults (20-40 yr old). IR was calculated as the difference in renin activity in trypsin-treated (1500 micrograms/ml) plasma, e.g. total renin (TR), and in untreated plasma, e.g. active renin (AR). IR was not detectable in most infants in the supine position, but their AR values were high (8.8-30 ng/ml X h). Moreover, in some of these infants, trypsin appeared to degrade renin activity, since TR values were lower than AR values. IR was detectable in 3 infants and 27 children, but their AR values were in a lower range (0.3-10 ng/ml X h). Trypsin degradation of renin activity was not found in either children or adults. With increasing age (2 days to 40 yr), AR decreased while IR and the IR to TR ratio increased significantly (P less than 0.001). A significant (P less than 0.001) inverse relationship was found between the IR and AR values of subjects 2 days to 40 yr old. IR was detectable in all nephrectomized children and represented 25% of normal values, while AR was undetectable (less than 0.1 ng/ml X h). In children in the upright position, IR decreased and AR increased significantly (P less than 0.001) in a reciprocal manner. TR did not change. These data suggest 1) that trypsin degradation of renin activity and absence of trypsin-activated IR are specific to infants with high AR levels, and 2) that IR might be activated in vivo into AR, especially after changes in position in children. IR could be a prorenin playing a physiological role in children.