An experiment of nature: genetic l-arginine deficiency and NO insufficiency

Nitric oxide (NO) is derived from the oxidation of the semiessential amino acid L-arginine by the NO synthases. Evidence supporting a central role for L-arginine in the NO synthase pathway comes from several observations. First, NO synthesis by cultured endothelial cells depends upon L-arginine content of the media (1). In addition, NO synthesis is blocked by L-arginine analogues (2), such as NG-monomethyl-L-arginine. Asymmetric dimethylarginine (ADMA), an endogenous compound known to inhibit NO synthases (3), and L-glutamine, which inhibits the generation of L-arginine from L-citrulline by argininosuccinate synthetase (4), also impair endothelial NO synthesis (5). Conversely, supplemental L-arginine improves endothelial function (6) and reverses endothelial dysfunction (7). In this issue of the JCI, Kamada and colleagues (8) report the results of vascular studies of an individual with a rare genetic disorder of L-arginine metabolism that lends further support to the critical role of L-arginine in NO synthesis. The authors describe a patient with a rare autosomal recessive disorder, lysinuric protein intolerance, characterized by a defect in dibasic amino acid transport caused by mutations in the SLC7A7 gene. The subject is a compound heterozygote carrying two different putative null alleles. The transporter is normally expressed in intestinal and renal epithelial cells, and deficient expression leads to impaired dietary uptake of exogenous L-arginine and impaired renal tubular reabsorption of filtered L-arginine. As a result, plasma L-arginine concentration in the patient is considerably lower than normal (reduced by 79%). In view of the effect of this genetic experiment of nature on plasma L-arginine concentrations and the importance of L-arginine on vascular NO production, Kamada et al. assessed NO-dependent endothelial function in this patient before and after intravenous L-arginine supplementation. They found that his serum level of nitrogen oxides (NOx) and his flow–mediated brachial artery vasodilator response were each approximately 70% lower than in controls. Intravenous infusion of L-arginine caused an increase in NOx levels and restored normal flow–mediated vasodilator responses in this patient, whose coronary arteriogram was normal. Exercise treadmill testing and positron emission tomography (using [13N]-ammonia) of the heart both showed evidence of myocardial ischemia, which could be ameliorated by intravenous administration of L-arginine. In addition to these abnormalities in vasomotor function, an earlier report showed that this patient also had a reduced circulating platelet count, increased plasma levels of the thrombin-antithrombin III complex, and elevated plasma fibrin(ogen) degradation products. Importantly, intravenous L-arginine increased the platelet count and reduced the levels of thrombin-antithrombin III complex and fibrin(ogen) degradation products (9), as well. Taken together, these complementary clinical studies confirm that endogenous L-arginine is essential for endothelial NO synthesis and demonstrate that a naturally occurring deficiency of endothelial NO production is associated with endothelial dysfunction, manifest as abnormal vasomotor tone and a prothrombotic state. Significantly, replenishing the substrate by intravenous administration of L-arginine restores normal endothelial function. These data support the view that endothelial NO derived from L-arginine maintains tissue perfusion by its vasodilator and antithrombotic effects.