Endogenous nitric oxide synthase inhibitors are responsible for the L‐arginine paradox

Abstract

L-Arginine, the substrate of nitric oxide (NO) synthases (NOSs), is found in the mammalian organism at concentrations by far exceeding K M values of these enzymes. Therefore, additional L-arginine should not enhance NO formation. In vivo, however, increasing L-arginine concentration in plasma has been shown repeatedly to increase NO production. This phenomenon has been named the L-arginine paradox; it has found no satisfactory explanation so far. In the present work, evidence for the hypothesis that the endogenous NOS inhibitors methylarginines, asymmetric dimethylarginine being the most powerful (IC 50 1.5 W WM), are responsible for the L-arginine paradox is presented. ß

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

“…One of the most studied effects of free MA released upon proteolysis is that of free MA on nitric oxide [2]. Physiological levels of nitric oxide produced by endothelial cells influence relaxation of vascular smooth muscle cells.…”

“…Physiological levels of nitric oxide produced by endothelial cells influence relaxation of vascular smooth muscle cells. L-Arginine is the substrate for nitric oxide synthases (NOS), and its plasma levels always exceed their K m values [2].…”

“…Protein arginine N-methyltransferases catalyse the conversion of protein-bound arginine to NMMA, which may be further methylated by protein arginine N-methyltransferases I and II to form ADMA and SDMA, respectively. Free NMMA and ADMA are inhibitors of NOS, with different potencies for different isoforms, and both are competitive inhibitors of arginine transport, whereas SDMA only inhibits the transport of arginine [2,3], whose precise role at concentrations found in vivo remains to be defined [4].…”

“…These conditions include hypertension and dyslipidaemia [2,5], hyperhomocysteinaemia and renal failure [6,7], and diabetes [8], all conditions with insulin resistance [5,7,8]. Since insulin stimulates endothelial nitric oxide production, thereby increasing blood flow as one of its actions in enhancing glucose disposal, impaired nitric oxide synthesis is expected to contribute to insulin resistance.…”

“…MA levels, when elevated, are relevant to their inhibitory properties in vitro and in vivo. For example, ADMA inhibits neural NOS with K i 0.4 μmol/l, K ii 1.6 μmol/l and IC 50 of 1.5 μmol/l [2]. However, the mechanism(s) that mediate elevations of plasma methylarginines are not completely understood.…”