Down-regulation of renal glutathione synthesis by systemic nitric oxide synthesis inhibition in spontaneously hypertensive rats

Nitric oxide stimulates in vitro the synthesis of glutathione, an abundant thiol with a number of functions such as detoxification of xenobiotics and reactive oxygen species. In order to study this relationship in an animal m odel of hypertension, we treated spontaneously hypertensive rats (SHR) eith er with a nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl e ster (L-NAME) or with a nitric oxide donor isosorbide-5-mononitrate (IS-5-M N). Inhibition of nitric oxide synthesis led to malignant hypertension and to a marked decrease in glutathione synthesis through down-regulation of th e rate-limiting enzyme gamma-glutamylcysteine synthetase (GCS). The reducti on in GCS activity was further augmented in SHR on a high sodium diet. Rena l GCS activity in untreated SHR was 234 +/- 14 and 240 +/- 18 nmol/min/mg p rotein (mean +/-SD) on a low and high sodium diet, respectively. When L-NAM E was included in the diet, the activities dropped to 173 +/- 28 and 123 +/ - 28 for the low and high sodium diets, respectively. IS-5-MN attenuated th e rise in blood pressure induced by sodium chloride, but did not affect the GCS activity. The mechanism of GCS stimulation by nitric oxide is not know n, but our results combined with the literature suggest that a relatively h igh concentration of nitric oxide is needed. BIOCHEM PHARMACOL 59;4:441-443 , 2000. (C) 2000 Elsevier Science Inc.