The role of nitric oxide and the renin-angiotensin system in salt-restricted dahl rats

To elucidate the role of nitric oxide (NO) and reninangiotensin system (RAS) in the development of saltsensitive hypertension, we investigated the pressor responses and renal histologic changes after long-term inhibition of endogenous NO synthesis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats under salt-restricted conditions that exaggerate RAS activation. Male DS and DR rats (6 weeks old) were fed with a low-salt (0.3%) diet for 5 weeks. N^G-nitro-L-arginine (L-NA: dissolved in 60 mg/L deionized water), an arginine analogue acting as a NO-inhibitor, was also administered for 5 weeks. L-NA administration induced a gradual increase in systolic blood pressure (SBP) in both strains, and the pressor response in DS rats was apparently more enhanced relative to that in DR rats. Urinary nitrate plus nitrite (u-NOx) excretion was decreased by L-NA, with a significant negative correlation between SBP and u-NOx excretion in DS rats but not in DR rats. Plasma renin activity and urinary aldosterone level were significantly increased in L-NA-treated DS rats on week 5. Marked histologic changes with uria and urinary N-acetyl-β-glucosaminidase excretion were found in L-NA-treated DS rats but not DR rats. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that angiotensin II type I receptor (AT₁R) mRNA level was significantly lower in DS rats than in DR rats at week 2 and that L-NA administration significantly reduced glomerular AT₁R level of DS rats at week 5, possibly because of downregulation. Our results showed that, even under sodium restriction, the pressor response and renal injury induced by chronic NO inhibition were markedly more enhanced in DS rats than in DR rats, which indicates that depletion of NO participates in both the development of hypertension and glomerular injury in DS rats through a potential activation of RAS irrespective of sodium loading. These data suggest that endogenous NO is an essential determinant of salt-sensitive hypertension in DS rats.