The goal of this study was to determine the role of inducible nitric oxide synthase (iNOS) in the arterial pressure, renal hemodynamic, renal excretory, and hormonal changes that occur in Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats during changes in Na intake. Thirty-two R and S rats, equipped with indwelling arterial and venous catheters, were subjected to low (0.87 mmol/day) or high (20.6 mmol/day) Na intake, and selective iNOS inhibition was achieved with intravenous aminoguanidine (AG, 12.3 mg. kg(-1). h(-1)). After 5 days of AG, mean arterial pressure increased to 121 +/- 3% control in the R-high Na AG rats compared with 98 +/- 1% control (P < 0.05) in the R-high Na alone rats, and S-high Na rats increased their arterial pressure to 123 +/- 3% control compared with 110 +/- 2% control (P < 0.05) in S-high Na alone rats. AG caused no significant changes in renal hemodynamics, urinary Na or H(2)O excretion, plasma renin activity, or cerebellar Ca-dependent NOS activity. The data suggest that nitric oxide produced by iNOS normally helps to prevent salt-sensitive hypertension in the Dahl R rat and decreases salt sensitivity in the Dahl S rat.

A large percentage of human hypertensive patients are salt sensitive, referring to the dependence of hypertension on sodium intake, but the cause of the salt sensitivity is not known. Although several mechanisms may contribute to salt-sensitive hypertension, the nitric oxide (NO) system appears to play a major role. Studies in humans and Dahl salt-sensitive (S) rats indicate that NO production is decreased during hypertension. Intravenous L-arginine infusion in Dahl S rats increases NO production and prevents salt-sensitive hypertension. In the Dahl salt-resistant (R) rat, NO production by both inducible NO synthase (iNOS) and neuronal NOS (nNOS) help to prevent salt-sensitive hypertension. Experimental evidence is summarized, indicating that the Dahl S rat has a deficient production of NO by nNOS, although NO production by iNOS appears to moderately decrease salt sensitivity. Other evidence about the importance of NO in salt-sensitive hypertension is reviewed, including the role of the renal NO system. These data indicate that NO production may be attenuated in hypertensive patients, which, based on its renal effects, could contribute to salt-sensitive hypertension. However, the role of NO in salt-sensitive hypertension remains to be elucidated.The Dahl salt-sensitive (S) rat has many features in common with human salt-sensitive hypertension. Although several experimental models exhibit salt sensitivity, a model that closely mimics human salt-sensitive essential hypertension is the Dahl S rat. Common traits shared by humans and the S rat include salt sensitivity, 6,7 decreased NO production, 4 insulin resistance, 8 hyperlipidemia, 8 successful treatment with diuretics, 9 and development of progressive glomerulosclerosis.10 Of these traits, decreased NO production may play an especially important role in the etiology of salt sensitivity. Indeed, Luscher et al 11,12 found that endothelium-dependent relaxations in response to acetylcholine, adenosine diphosphate, and thrombin were significantly decreased in aortic rings from Dahl S rats on high sodium intake. They also found that an 8-week treatment of prehypertensive Dahl S rats with antihypertensive therapy prevented the blunted endothelium-dependent vasodilation response to acetylcholine. Role of the Kidney in Dahl Salt-Sensitive HypertensionThe importance of the kidney in Dahl salt-sensitive hypertension was demonstrated by Louis Dahl who transplanted S kidneys into R rats, which caused hypertension in the R recipients.13-15 Also, transplantation of R kidneys into S rats normalized arterial pressure in the hypertensive S recipients in Dahl's studies, [13][14][15] but only partly normalized pressure in S recipients in another study. 16 Although these data implicate that the kidney is important in the development of salt-sensitive hypertension, the renal abnormality that causes salt-sensitive hypertension in the Dahl S rat is not clear.Several abnormalities in Dahl rats may change renal function, including changes in production of 20-HETE 17 and 11␤-steroid hydr...

The present study addressed the effect of interventions aimed to increase NO in the setting of acute renal ischemia/reperfusion (I/R) in uninephrectomized rabbits. In the 60-minute post-I/R period, L-arginine+superoxide (O2.-) dismutase (SOD) synergistically improved the renal functional (69.4% versus 10.4% of the pre-I/R glomerular filtration rate with or without L-arginine+SOD, respectively; p < .01) and histological parameters (82.9% decrease of medullary congestion in L-arginine+SOD, P < .01 versus vehicle) and blocked the I/R-dependent neutrophil accumulation (89.3% reduction). In spite of these results over the short term, a second set of experiments disclosed that the protection by L-arginine+SOD was no longer present at 24 and 48 hours (plasma creatinine in vehicle-treated versus L-arginine+SOD-treated animals [mg/100 mL]: 24 hours after I/R, 9.4 +/- 1.9 versus 8.07 +/- 0.65; 48 hours after I/R, 11.6 +/- 3.6 versus 9.7 +/- 0.9; P = NS in all the cases). Additional experiments were conducted using a milder 30-minute ischemic model, which showed no significant functional or histological protection by using L-arginine+SOD. In conclusion, our experiments disclosed the following: (1) the critical importance of the interaction between NO and O2.- in the acute protective effect of L-arginine (this effect not only improved renal function and histology but also reduced neutrophil accumulation) and (2) the discordance existing between the immediate protection afforded by L-arginine+SOD and the lack of protection observed at 24 and 48 hours. This finding suggests that a punctual intervention on the NO system at the time of I/R is not sufficient to reduce renal damage over the long term.

Abstract-The goal of this study was to determine the role of neuronal nitric oxide synthase (nNOS) in the arterial pressure, renal hemodynamic, and renal excretory changes that occur in Dahl salt-resistant (DR) and salt-sensitive (DS) rats during changes in Na intake. Fifty-three DR and DS rats/Rapp strain of 7 to 8 weeks of age with indwelling arterial and venous catheters were subjected to low (0.87 mmol/d) or high (20.6 mmol/d) Na intake beginning 2 days before the start of the control period. Measurements were made during a 5-day control period followed by a 5-day period of nNOS inhibition with intravenous 7-nitroindazole (7NI, 1.67 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 ) or vehicle infusion. After 5 days of 7NI, mean arterial pressure increased to 120Ϯ6% control in the DR-high Na, 7NI rats compared with 98Ϯ1% control (PϽ0.05) in the DR-high Na alone rats. After 5 days of 7NI, DS-high Na rats, which had a control arterial pressure 31 mm Hg higher than the comparable DR rats, increased their arterial pressure to 114Ϯ3% control, which was not significantly different from the DS-high Na alone pressure of 110Ϯ2% control. No significant changes occurred in glomerular filtration rate, effective renal plasma flow, urinary Na excretion, or urine volume because of 7NI. However, plasma renin activity decreased significantly in DR and DS rats on low Na intake with 7NI infusion. The data demonstrate that the highly salt-resistant DR rat became salt-sensitive during nNOS inhibition with 7NI. However, the arterial pressure of the DS rat was not affected by 7NI. This suggests that nitric oxide produced by nNOS in the DR rat normally helps to prevent salt-sensitive hypertension and that low functional levels of nNOS in the DS rat may contribute to its salt-sensitivity. Key Words: arterial pressure Ⅲ glomerular filtration rate Ⅲ renal hemodynamics Ⅲ sodium Ⅲ renin Ⅲ urine T he arterial pressure of some people with hypertension is very sensitive to changes in Na intake and they have been classified as "salt-sensitive," but the cause of the saltsensitivity is not known. A recent preliminary report showed that salt-sensitive humans release less nitric oxide (NO) during NO agonist administration compared with patients with salt-resistant essential hypertension. 1 In Dahl saltsensitive (DS) rats, our laboratory and others 2,3 showed that NO production is decreased during high Na intake compared with Dahl salt-resistant (DR) rats. L-Arginine administration to DS rats increased NO production and prevented saltsensitive hypertension. 3,4 Therefore, a decrease in NO production may be partly responsible for salt-sensitive hypertension in humans and DS rats. However, the relative importance of the various isoforms of NO synthase in causing saltsensitive hypertension is not known.Recent studies have shown that NO produced by neuronal NO synthase (nNOS) may play a significant role in preventing salt-sensitive hypertension in normal rats. Increases in Na intake caused an increase in renal medullary nNOS protein in Sprague-Dawley (SD) rats. 5 Even though the ...