Two different approaches to restore renal nitric oxide and prevent hypertension in young spontaneously hypertensive rats: L-citrulline and nitrate

Nitric oxide (NO) deficiency mediates oxidative stress in the kidney and is involved in the development of hypertension. NO synthesis occurs via 2 pathways: nitric oxide synthase (NOS) dependent and NOS-independent. We tested whether the development of hypertension is prevented by restoration of NO by dietary l-citrulline or nitrate supplementation in young spontaneously hypertensive rats (SHRs). Male SHRs and normotensive Wistar Kyoto control rats (WKYs)s age 4 weeks were assigned to 4 groups: untreated SHRs and WKYs, and SHRs and WKYs that received 0.25% l-citrulline for 8 weeks. In our second series of studies, we replaced l-citrulline with 1 mmol/kg/d sodium nitrate. All rats were sacrificed at age 12 weeks. We found an increase in the blood pressure of SHRs was prevented by dietary supplementation of l-citrulline or nitrate. Both treatments restored NO bioavailability and reduced oxidative stress in SHR kidneys. l-Citrulline therapy reduced levels of l-arginine and asymmetric dimethylarginine (ADMA) - an endogenous inhibitor of NOS - and increased the l-arginine-to-ADMA ratio in SHR kidneys. Nitrate treatment reduced plasma levels of l-arginine and ADMA concurrently in SHRs. Our findings suggest that both NOS-dependent and -independent approaches in the prehypertensive stage toward augmentation of NO can prevent the development of hypertension in young SHRs.