Immune suppression attenuates hypertension and renal disease in the Dahl salt-sensitive rat

Experiments were performed to determine the importance of activation or infiltration of immune cells in the kidney during the development of hypertension and renal disease in Dahl salt-sensitive rats (SS/Mcw) fed a 4.0% NaCl diet. Compared with vehicle-treated rats, chronic administration of mycophenolate mofetil ([MMF] 30 mg/kg per day, IP), an immunosuppressive agent that has cytostatic effects on T and B cells, decreased cell-specific markers of T and B cells by 50% to 60% in the kidneys of SS/Mcw rats (n=5 per group). Further studies were performed on Dahl SS/Mcw rats, which were instrumented with chronic indwelling catheters and studied after 3 weeks on the 4.0% NaCl diet. Rats were administered MMF or 5% dextrose vehicle daily during the 3-week period of high NaCl intake. Mean arterial blood pressure in the rats administered MMF (122+/-2 mm Hg; n=11) was significantly decreased compared with vehicle-treated rats (139+/-4 mm Hg; n=9). Furthermore, the rate of protein (112+/-13 mg per day) and albumin excretion (15+/-3 mg per day) in the MMF-treated rats was significantly lower than the protein and albumin excretion rate in vehicle-treated rats (167+/-25 and 31+/-7 mg per day, respectively). Creatinine clearance and body weight were not different between the groups, averaging 0.52+/-0.08 mL/min per gram kidney weight and 322+/-10 g, respectively, in the MMF-treated group. These experiments indicate that the activation of the immune system or renal infiltration of immune cells plays an important role in the development of hypertension and renal disease in Dahl SS/Mcw rats consuming an elevated NaCl diet.     

Antioxidant treatment prevents renal damage and dysfunction and reduces arterial pressure in salt-sensitive hypertension

The goal of this study was to test the hypothesis that oxidative stress in Dahl salt-sensitive (SS) rats on a high-sodium intake contributes to the progression of renal damage, the decreases in renal hemodynamics, and the development of hypertension. We specifically studied whether antioxidant therapy, using vitamins C and E, could help prevent renal damage and glomerular filtration rate (GFR) and renal plasma flow reductions and attenuate the increases in arterial pressure. Thirty-three 7- to 8-week old Dahl SS/Rapp strain rats were placed on either a high-sodium (8%) or a low-sodium (0.3%) diet with or without vitamin E (111 IU/d) in the food and 98 mg/d vitamin C in the drinking water for 5 weeks. Rats were equipped with indwelling arterial and venous catheters at day 21. By day 35 in the rats with high-sodium diet, vitamin C and E treatment significantly decreased renal cortical and medullary O2*- release, mean arterial pressure, urinary protein excretion, glomerular necrosis, and renal tubulointerstitial damage. At this time, GFR significantly decreased in the high-sodium diet group (1.6+/-0.2 mL/min) when compared with either the high-sodium plus vitamins C and E (2.9+/-0.2 mL/min) or the low-sodium diet group (2.9+/-0.3 mL/min). In SS rats on high-sodium diet, renal plasma flow decreased 40%, and this reduced flow was restored by vitamin treatment. In Dahl salt-sensitive hypertension, increased oxidative stress plays an important role in the renal damage, decreases in renal hemodynamics, and increases in arterial pressure that occur. Antioxidant treatment with vitamins C and E improves renal dysfunction, lessens renal injury, and decreases arterial pressure in Dahl salt-sensitive hypertension.     

High dietary protein exacerbates hypertension and renal damage in Dahl SS rats by increasing infiltrating immune cells in the kidney

The present study evaluated the influence and mechanism of action of dietary protein intake in Dahl SS hypertension and renal disease. Rats were fed isocaloric diets with low (6%), normal (18%), or high (30%) amounts of protein and 0.4% NaCl from 5 to 12 weeks of age; the NaCl content of the diets was then increased to 4.0% NaCl from 12 to 15 weeks of age. Rats fed the high-protein diet developed the highest mean arterial blood pressure and urine albumin-to-creatinine ratio when fed the 4.0% NaCl diet (153 ± 7 mm Hg and 8.0 ± 2.4, respectively) compared to rats fed normal protein (132 ± 3 mm Hg, 1.2 ± 0.3) or low-protein (132 ± 6 mm Hg, 0.3 ± 0.1) diets. Significantly greater numbers of infiltrating T lymphocytes were observed in kidneys of SS rats fed the high-protein diet (18.9 ± 3 × 10? cells) than in rats fed the low-protein diet (9.1 ± 3 × 10? cells). Furthermore, treatment of SS rats fed the high-protein diet with the immunosuppressant agent mycophenolate mofetil (20 mg/kg per day, ip) significantly reduced the number of infiltrating T cells in the kidneys (from 18.9 ± 2.7 to 10.6 ± 2.0 × 10? cells) while decreasing blood pressure (from 133 ± 3 to 113 ± 4 mm Hg) and the albumin/creatinine ratio (from 10.9 ± 2.3 to 5.4 ± 1.2). These results demonstrate that restriction of protein intake protects the Dahl SS rats from hypertension and kidney disease and indicates that infiltrating immune cells play a pathological role in Dahl SS rats fed a high-protein diet. Moreover, the results show that hypertension in Dahl SS rats is sensitive to both NaCl and protein intake.     

N-Acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension

BACKGROUND: Salt-sensitive hypertension in humans and experimental animals causes progressive increases in renal damage and dysfunction. The Dahl salt-sensitive (S) rat closely mimics human salt-sensitive hypertension. AIM: Our goal was to test the hypothesis that enhancing the glutathione system with dietary N-acetylcysteine administration in Dahl S rats on a high sodium intake for 5 weeks will attenuate the increases in arterial pressure, the decreases in renal hemodynamics and the increases in renal damage that normally occur in S rats on high sodium. METHODS: Forty-four 7- to 8-week-old Dahl S/Rapp strain rats were maintained on a high sodium (8%), high sodium + N-acetylcysteine (4 g/kg per day), or low sodium (0.3%) diet for 5 weeks. Rats had arterial and venous catheters implanted at day 21. RESULTS: By day 35 in the high-sodium rats, N-acetylcysteine treatment significantly increased the renal reduced-to-oxidized glutathione ratio, glomerular filtration rate, and renal plasma flow, and decreased renal cortical and medullary O2 release, urinary protein excretion, renal tubulointerstitial damage and glomerular necrosis. At this time, mean arterial pressure increased to 183 +/- 1 mmHg, and N-acetylcysteine reduced this arterial pressure to 121 +/- 4 mmHg. By day 35 in S high-sodium rats, N-acetylcysteine had caused a 91% decrease in glomerular necrosis and an 83% decrease in tubulointerstitial damage. CONCLUSIONS: In Dahl S rats on high sodium intake, arterial pressure increases significantly and renal injury is pronounced. Treatment with N-acetylcysteine enhances the renal glutathione system, improves renal dysfunction and markedly decreases arterial pressure and renal injury in Dahl salt-sensitive hypertension.     

NADPH oxidase in the renal medulla causes oxidative stress and contributes to salt-sensitive hypertension in Dahl S rats

Dahl salt-sensitive (SS) rats exhibit increased renal medullary oxidative stress and blood pressure salt-sensitivity compared with consomic, salt-resistant SS-13BN rats, despite highly similar genetic backgrounds. The present study examined potential sources of renal medullary superoxide in prehypertensive SS rats fed a 0.4% NaCl diet by assessing activity and protein levels of superoxide producing and scavenging enzymes. Superoxide production was nearly doubled in SS rats compared with SS-13BN rats as determined by urinary 8-isoprostane excretion and renal medullary oxy-ethidium microdialysate levels. Medullary superoxide production in tissue homogenates was greater in SS rats, and the NADPH oxidase inhibitor diphenylene iodonium preferentially reduced SS levels to those found in SS-13BN rats. Dinitrophenol, a mitochondrial uncoupler, eliminated the remaining superoxide production in both strains, whereas inhibition of xanthine oxidase, NO synthase, and cycloxygenase had no effect. L-arginine, NO synthase, superoxide dismutase, catalase, and glutathione peroxidase activities between SS and SS-13BN rats did not differ. Chronic blood pressure responses to a 4% NaCl diet were then determined in the presence or absence of the NADPH oxidase inhibitor apocynin (3.5 microg/kg per minute), chronically delivered directly into the renal medulla. Apocynin infusion reduced renal medullary interstitial superoxide from 1059+/-130 to 422+/-80 (oxyethidium fluorescence units) and mean arterial pressure from 175+/-4 to 157+/-6 mm Hg in SS rats, whereas no effects on either were observed in the SS-13(BN). We conclude that excess renal medullary superoxide production in SS rats contributes to salt-induced hypertension, and NADPH oxidase is the major source of the excess superoxide.     

Tonic excitatory input to the rostral ventrolateral medulla in Dahl salt-sensitive rats

The goal of the present study was to test the hypothesis that the balance of tonic excitation and inhibition of vasomotor neurons in the rostral ventrolateral medulla (RVLM) driven by excitatory amino acid (EAA)-mediated inputs to the RVLM is shifted toward excitation in Dahl salt-sensitive (DS) rats compared with Dahl salt-resistant (DR) rats. Glutamate and the EAA antagonist kynurenic acid were microinjected into the RVLM of chloralose-anesthetized DS and DR rats maintained on diets containing either 0.3% NaCl or 8.0% NaCl. DS rats had a higher arterial pressure than DR rats, and this difference was greatly exaggerated by high dietary salt intake. Bilateral injection of kynurenic acid (2.7 nmol) into the RVLM decreased mean arterial pressure by 16+/-2 mm Hg in DS rats fed a diet containing 0.3% NaCl, and this effect was significantly larger in DS rats fed the high-salt diet (40+/-2 mm Hg). In contrast, injections of kynurenic acid into the RVLM did not significantly decrease arterial pressure in DR rats fed either diet. In DR rats, the pressor response elicited by the injection of glutamate into the RVLM was potentiated in rats fed the high-salt diet. The glutamate-evoked pressor response was greater in DS rats compared with DR rats, and the response in DS rats was not influenced by the salt content of the diet. These data suggest that tonically active EAA inputs to the RVLM may contribute to salt-sensitive hypertension in the Dahl model.     

Oxidative stress in Dahl salt-sensitive hypertension

The role of oxidative stress in the long-term regulation of arterial pressure, renal hemodynamics, and renal damage was studied in Dahl salt-sensitive rats. Twenty-eight Dahl S/Rapp strain rats, equipped with indwelling arterial and venous catheters, were subjected to a 3-week intravenous infusion of either low Na (0.9 mmol/d) or high Na (20.6 mmol/d) or the superoxide dismutase mimetic, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), at 125 micromol x kg(-1) x h(-1) plus low Na or high Na. After 21 days, mean arterial pressure was 140+/-3 mm Hg in the high-Na group, 118+/-1 mm Hg (P<0.05) in the high-Na/Tempol group, and unchanged in the low-Na/Tempol and low-Na groups. Tempol did not change renal blood flow, glomerular filtration rate, or glomerular cross-sectional area in rats subjected to the high-Na intake but did decrease urinary protein excretion, the percentage of sclerotic glomeruli, and the kidney weight to body weight ratio. In 15 additional Dahl S rats subjected to high or low Na intake for 3 weeks, renal cortical and medullary O2*- release increased significantly in the high-Na group when compared with the low-Na group. Tempol decreased both renal cortical and medullary O2*- release in the high- and low-Na rats, but the decrease in O2*- release was greater in high-Na rats. The data suggest that oxidative stress contributes to Dahl salt-sensitive hypertension and the accompanying renal damage.     

Impaired myogenic responsiveness of renal microvessels in Dahl salt-sensitive rats.

The mechanisms mediating abnormal renal autoregulation in Dahl salt-sensitive (DS) rats have not been fully defined. In the present study, we assessed myogenic responsiveness of interlobular arteries (ILAs), afferent arterioles (AAs), and efferent arterioles in isolated perfused hydronephrotic Dahl rat kidneys. Dahl rats were divided into four groups according to strain (Dahl salt-resistant [DR] or DS rats) and dietary sodium manipulation (rats fed low or high salt diets). Systolic blood pressure was elevated only in DS rats fed the high salt diet (202 +/- 4 mm Hg, p less than 0.05). Myogenic responses were obtained by stepwise elevation of renal arterial pressure. Vessel diameters were determined by computer-assisted videomicroscopy. Preglomerular microvessels of DS and DR rats responded differently to changes in renal arterial pressure. AAs and ILAs manifested diminished myogenic responsiveness to increasing renal arterial pressure in DS rats compared with DR rats (p less than 0.05). Both AAs and ILAs in DS rats manifested a higher threshold pressure for eliciting myogenic responses and a decrease in maximal pressure-induced vasoconstriction. The sensitivity of the AA myogenic response to nifedipine was enhanced in DS rats compared with DR rats (p less than 0.05). For rats fed the high salt diet, preglomerular vessels exhibited reduced myogenic responsiveness in both strains. In contrast to preglomerular microvessels, efferent arterioles from all four groups of rats failed to exhibit pressure-induced vasoconstriction. Our data suggest that diminished myogenic responsiveness of AAs and ILAs in DS rats contributes to impaired renal autoregulation in this strain.     

Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats

BACKGROUND: Dahl salt-sensitive (Dahl S) rats exhibit many phenotypic traits associated with salt-sensitive hypertension in man. Specifically, they are salt-sensitive, insulin-resistant and hyperlipidemic. They also develop endothelial dysfunction, cardiac injury and glomerulosclerosis. Insulin resistance is linked to hypertension, renal and cardiac damage and endothelial dysfunction. Thus, an agent that has diuretic action and can improve insulin resistance, like recombinant glucagon-like peptide-1(7-36)amide (rGLP-1), may have an antihypertensive effect. OBJECTIVE: To determine whether chronic administration of rGLP-1 attenuates the development of hypertension, endothelial dysfunction and/or hypertension-induced renal and cardiac end organ damage in Dahl S rats. METHODS: Mean arterial pressure (MAP) and urinary excretion of protein and albumin were measured in Dahl S rats before and after they were fed a 8% NaCl diet and infused with rGLP-1 (1 micro g/kg per min, i.v.) or vehicle for 14 days. At the end of the study, the degree of renal and cardiac injury was histologically assessed and endothelium-dependent relaxing function was studied using aortic rings. In other rats, the effects of rGLP-1 on sodium and water balance and plasma glucose and insulin levels for the first 3 days following a step change in sodium intake from a 0.1% NaCl diet to 7.5 mEq/day were determined. RESULTS: rGLP-1 significantly attenuated the development of hypertension in Dahl S rats (136 +/- 7 versus 174 +/- 6 mmHg). This was associated with reduction in proteinuria (46 +/- 7 versus 128 +/- 15 mg/day) and albuminuria (46 +/- 7 versus 86 +/- 18 mg/day) and improvement of endothelial function and renal and cardiac damage. rGLP-1 markedly increased urine flow and sodium excretion for the first 3 days following elevation in sodium intake. It had no significant effects on plasma glucose and insulin concentrations. CONCLUSION: rGLP-1 has antihypertensive and cardiac and renoprotective effects in Dahl S rats fed a high salt diet. The antihypertensive effect of rGLP-1 in Dahl S rats is due mainly to its diuretic and natriuretic effects, rather than an effect to improve insulin-resistance.     

Sexual dimorphism of renal alpha2-adrenergic receptor regulation in Dahl rats.

Male Dahl salt-sensitive hypertensive (S) rats develop hypertension faster than females. We measured renal alpha2-adrenergic receptor density of inbred Dahl salt-sensitive (SS/JR) and salt-resistant (SR/JR) rats, using [3H]-rauwolscine saturation binding studies. Male and female SS/JR rats were gonadectomized or sham-operated at 6 weeks of age and fed a high salt diet for 4 weeks. Additional intact SS/JR and SR/JR rats of both sexes were fed the high salt diet for a longer period of time (7 weeks instead of 4 weeks). Both blood pressure and renal alpha2-adrenergic receptor density were significantly higher in male than female SS/JR rats on high salt diet for 4 weeks. Gonadectomy did not change blood pressure nor did it change renal alpha2-adrenergic receptor density measured at the 4th week of high salt feeding in either male or female SS/JR rats. When the SS/JR rats were fed high salt diet for a longer period (for 7 weeks), blood pressure of female SS/JR reached the level of males, but the density of renal alpha2-adrenergic receptors was still significantly lower than that of males. Both renal alpha2-adrenergic receptor density and blood pressure were higher in male than female SR/JR. We conclude that higher blood pressure in male Dahl SS/JR and SR/JR rats is associated with higher renal alpha2-adrenergic receptor density compared with their female counterparts.     

Stress increases renal nerve activity and decreases sodium excretion in Dahl rats

The effects of a stressful environmental stimulus (air stress) on mean arterial pressure, renal sympathetic nerve activity, and renal function were examined in conscious Dahl salt-sensitive (DS) and Dahl salt-resistant rats (DR) on low (0.4%) and high (8%) NaCl diets. Air stress increased renal sympathetic nerve activity and decreased urine flow rate and urinary sodium excretion in conscious Dahl rats on a high sodium diet, but it had no effect in rats on a low sodium diet. Mean arterial pressure did not change during air stress in any group. Renal denervation prevented the antidiuretic and antinatriuretic responses to air stress in DS and DR on a high NaCl diet. An increased renal tubular reabsorption of sodium and water appeared to mediate the antinatriuretic and antidiuretic responses to air stress, since glomerular filtration rate and renal plasma flow were unchanged. Thus, environmental stress increases renal sympathetic nerve activity and decreases urinary sodium excretion more in Dahl rats on a high NaCl diet than on a low NaCl diet. On a high NaCl diet, these responses are greater in DS than in DR.     

Creation and characterization of a renin knockout rat

The renin-angiotensin system plays an important role in the control of blood pressure (BP) and renal function. To illuminate the importance of renin in the context of a disease background in vivo, we used zinc-finger nucleases (ZFNs) designed to target the renin gene and create a renin knockout in the SS/JrHsdMcwi (SS) rat. ZFN against renin caused a 10-bp deletion in exon 5, resulting in a frameshift mutation. Plasma renin activity was undetectable in the Ren-/- rat, and renin protein was absent from the juxtaglomerular cells in the kidney. Body weight was lower in the Ren-/- rats (than in the Ren+/- or wild-type littermates), and conscious BP on low-salt diet (0.4% NaCl) was 58 ± 2 mm Hg in the Ren-/- male rats versus 117 mm Hg in the Ren+/- littermates, a reduction of almost 50 mm Hg. Blood urea nitrogen (BUN) and plasma creatinine levels were elevated in the Ren-/- strain (BUN 112 ± 7 versus 23 ± 2 mg/dL and creatinine 0.53 ± 0.02 versus 0.26 ± 0.02 mg/dL), and kidney morphology was abnormal with a rudimentary inner renal medulla, cortical interstitial fibrosis, thickening of arterial walls, and abnormally shaped glomeruli. The development of the first rat knockout in the renin-angiotensin system demonstrates the efficacy of the ZFN technology for creating knockout rats for cardiovascular disease on any genetic background and emphasizes the role of renin in BP regulation and kidney function even in the low-renin SS rat.     

Identification of hypertension susceptibility Loci on rat chromosome 12

Previous studies have identified multiple blood pressure and renal disease quantitative trait loci located on rat chromosome 12. In the present study, we narrowed blood pressure loci using a series of overlapping Dahl salt-sensitive/Mcwi (SS)-12 Brown Norway (BN) congenic lines. We found that transferring 6.1 Mb of SS chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12(BN) background significantly elevated blood pressure on 1% NaCl (146 ± 6 versus 127 ± 1 mm Hg; P<0.001) and 8% NaCl diets (178 ± 7 versus 144 ± 2 mm Hg; P<0.001). Compared with the SS-12(BN) consomic, these animals also had significantly elevated albumin (218 ± 31 versus 104 ± 8 mg/d; P<0.001) and protein excretion (347 ± 41 versus 195 ± 12 mg/d; P<0.001) on a 1% NaCl diet. Elevated blood pressure, albuminuria, and proteinuria coincided with greater renal and cardiac damage, demonstrating that SS allele(s) within the 6.1 Mb congenic interval are associated with strong cardiovascular disease phenotypes. Sequence analysis of the 6.1 Mb congenic region revealed 12 673 single nucleotide polymorphisms between SS and BN rats. Of these polymorphisms, 293 lie within coding regions, and 18 resulted in nonsynonymous changes in conserved genes, of which 5 were predicted to be potentially damaging to protein function. Syntenic regions in human chromosome 7 have also been identified in multiple linkage and association studies of cardiovascular disease, suggesting that genetic variants underlying cardiovascular phenotypes in this congenic strain can likely be translated to a better understanding of human hypertension.     

Blood pressure response to hyperinsulinemia in salt-sensitive and salt-resistant rats.

We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 0.3% NaCl diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137 +/- 3 mm Hg versus 119 +/- 3 mm Hg, p < 0.05; plasma norepinephrine, 0.40 +/- 0.02 ng/ml versus 0.27 +/- 0.01 ng/ml, p < 0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an alpha-blocker (bunazosin, 10 mg/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCl), insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model.     

Dietary sodium loading increases arterial pressure in afferent renal-denervated rats

In rats fed high sodium diet, increasing renal pelvic pressure > or =3 mm Hg activates renal mechanosensory nerves, resulting in a renorenal reflex-induced increase in urinary sodium excretion. The low activation threshold of the renal mechanosensory nerves suggests a role for natriuretic renorenal reflexes in the regulation of arterial pressure and sodium balance. If so, interruption of the afferent renal innervation by dorsal rhizotomy (DRX) at T9-L1 would impair urinary sodium excretion and/or increase arterial pressure during high dietary sodium intake. DRX and sham-DRX rats were fed either a high or a normal sodium diet for 3 weeks. Mean arterial pressure measured in conscious rats was higher in DRX than in sham-DRX rats fed a high sodium diet, 130+/-2 vs 100+/-3 mm Hg (P<0.01). However, mean arterial pressure was similar in DRX and sham-DRX rats fed a normal sodium diet, 115+/-1 and 113+/-1 mm Hg, respectively. Steady-state urinary sodium excretion was similar in DRX and sham-DRX rats on high (17.9+/-2.2 and 16.4+/-1.8 mmol/24 h, respectively) and normal (4.8+/-0.3 and 5.0+/-0.4 mmol/24 h, respectively) sodium diets. Studies in anesthetized rats showed a lack of an increase in afferent renal nerve activity in response to increased renal pelvic pressure and impaired prostaglandin E2-mediated release of substance P from the renal pelvic nerves in DRX rats fed either a high or a normal sodium diet, suggesting that DRX resulted in decreased responsiveness of peripheral renal sensory nerves. In conclusion, when the afferent limb of the renorenal reflex is interrupted, a high sodium diet results in increased arterial pressure to facilitate the natriuresis and maintenance of sodium balance.     

Role of endothelin-1 in blood pressure regulation in a rat model of visceral obesity and hypertension

Endothelial dysfunction has been suggested to play an important role in the development of obesity-induced hypertension. Because endothelin release increases in response to endothelial damage, we examined whether endothelin-1 contributes to increased arterial pressure in a model of visceral obesity produced by feeding Sprague-Dawley rats a high-fat (HF) diet (40% fat w/w, n=6) for 12 months. Arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 hours per day and intravenous infusions. After a 5-day control period, rats were infused with the selective endothelin-1 type A receptor (ET-A) blocker ABT-627 (2.5 mg/kg per day, IV) for 9 days, followed by a recovery period. Rats fed a standard chow (normal fat, or NF, group: n=6) for 12 months were also infused with ET-A blocker and were used as controls. Compared with NF rats, HF rats had higher MAP (113+/-4 versus 98+/-2 mm Hg), increased visceral fat (18.7+/-2.0 versus 10.8+/-1.4 g), and 3.2-fold increase in plasma leptin despite similar total body weight gain. Long-term ET-A blockade markedly reduced MAP in HF (-14+/-3 mm Hg) and NF (-14+/-2 mm Hg), but it had no effect on HR, GFR, or PRA. These results indicate that a long-term HF diet may cause visceral obesity and increased MAP, even in the absence of major changes in total body weight. Endothelin-1 appears to play an important role in the maintenance of arterial pressure in rats fed HF and NF diets, but it does not appear to contribute to increased MAP in this model of diet-induced hypertension.