Whole Body Arginine Metabolism and Nitric Oxide Synthesis in Newborns with Persistent Pulmonary Hypertension

Abstract

ABSTRACT: Despite the potential relevance of the L-arginine-nitric oxide (NO) pathway in the pathophysiology of pulmonary hypertension, no in vivo studies of the kinetics of arginine and NO have been conducted previously in this population. The terminal guanidino N-atom of L-arginine is the precursor for NO, which is oxidized to the stable inorganic nitrogen oxides, nitrite (NO₂^-) and nitrate (NO₃^-). Thus, synthesized NO is detected in serum or urine as NO₂^- and NO₃^-. The purpose of this investigation was to compare studies of whole body arginine metabolism twice in nine patients with persistent pulmonary hypertension of the newborn (PPHN), using a primed constant i.v. infusion of L-[guanidino-¹⁵N₂,5,5²H₂]arginine and L-[5,5,5²H₃]leucine, first during acute pulmonary vasoconstriction and again during convalescence, and thereby to characterize quantitative aspects of whole body arginine kinetics and NO production, as estimated from the rate of transfer of the ¹⁵N-guanidino-label of arginine to urinary nitrate (¹⁵NO₃^-). Arginine flux rates were 84.1 ± 8.6 μmol-kg.^-1h^-1 (mean ± SEM) during acute pulmonary hypertension and increased to 125 ± 13.2 (p < 0.05) during convalescence, whereas leucine fluxes were unchanged (168.5 ± 15 versus 178.8 ± 10.2 μmol.kg.^-1h^-1), and comparable to those reported in healthy newborns. During convalescence total urinary nitrate excreted increased by 66% (p < 0.05), urinary ¹⁵NO₃^- increased from 0.29 ± 0.07 to 0.74 ± 0.15 μmol.d^-1 (p < 0.05), and the rate of plasma arginine conversion to NO increased from 10.3 ± 2.2 to 45.6 ± μmol.d^-1 (p < 0.05). This study indicates a decreased plasma arginine utilization for whole body NO synthesis during the acute vasoconstrictive state of PPHN and suggests that arginine availability may become an important factor in NO formation.

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