L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants

Abstract

Effective therapies are urgently needed for infants with forms of pulmonary hypertension that develop or persist beyond the first week of life. The L-arginine nitric oxide (NO) precursor, L-citrulline, improves NO signalling and ameliorates pulmonary hypertension in newborn animals. In vitro studies demonstrate that manipulating L-citrulline transport alters NO production.

Conclusion: Strategies that increase the supply and transport of L-citrulline merit pursuit as novel approaches to managing infants with chronic, progressive pulmonary hypertension.

Keywords: Bronchopulmonary dysplasia; Nitric oxide; Oxidative stress; Premature infants; Pulmonary hypertension.

©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Figures

Figure 1

Model for L-citrulline transport, arginine channelling and nitric oxide (NO) metabolism in pulmonary endothelial cells. Circulating L-citrulline is taken up by the sodium-dependent neutral amino acid transporter, SNAT1, and is delivered to a multi-protein complex containing the urea cycle enzymes, argininosuccinate synthetase, ASS, and argininosuccinate lyase, ASL, endothelial nitric oxide synthase, eNOS, and the chaperone protein, heat shock protein 90, Hsp90, for efficient metabolism of L-citrulline to arginine and arginine to NO and L-citrulline. This model would explain the so called arginine paradox and would predict that citrulline is an effective precursor for NO production.