R A C TDespite 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 (NO,-) and nitrate (NO,-). Thus, synthesized NO is detected in serum or urine as NO,-and NO,-. 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 ~-[~uanidino-~~N,,5,5~H,]ar~inine and L- [5,5,52~,]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 '5~-guanidino-label of arginine to urinary nitrate (ISNO,-). Arginine flux rates were 84.1 ? 8.6 p r n~l -k~. -~h -~ (mean ? SEM) during acute pulmonary hypertension and increased to 125 ? 13.2 ( p < 0.05) during conva-PPHN is an acute vascular maladaptation to extrauterine life, characterized by reactive pulmonary vasoconstriction, causing extrapulmonary shunting of blood across fetal channels and critical hypoxemia. Remodeling of the pulmonary arteries has been observed in some patients with PPHN (1). The etiology of this disorder is uncertain, but a role for altered NO production, a recently discovered key regulator of vascular tone (2-4), Received October 10, 1994; accepted February 27, 1995 Abbreviations PPHN, persistent pulmonary hypertension of the newborn NO, nitric oxide eNOS, nitric oxide synthase AaDO,, alveolo-arterial oxygen gradient ECMO, extracorporeal membrane oxygenation A.P.E., atom percent excess must be considered. NO is produced in the pulmonary and systemic arteries of newborn animals (5) and contributes to the postnatal vasodilation of the pulmonary circulation (6, 7). NO is synthesized in the endothelial cells, through the action of eNOS, and diffuses into subjacent vascular smooth muscle, where it binds to its molecular target, the prosthetic heme group of soluble guanylyl cyclase, forming nitrosyl proteins (8). This process activates guanylyl cyclase, augmenting levels of the second messenger, cGMP (8). Intracellular elevation of cGMP levels activates cGMP-dependent protein kinases, leading to phosphorylation of proteins and inhibition of intracellu-MA 02114. lar calcium release and/or influx through calcium channels.