Abstract-Although obesity is a risk factor for hypertension, the relationship between these 2 conditions is not well understood. Therefore, we examined some parameters of hypertension and cardiovascular disease in a dietary model of obesity. Male Sprague-Dawley rats were provided either a control diet (C) or a diet containing 32% kcal as fat (similar to a Western diet) for 1, 3, or 10 weeks. Rats in the latter group diverged based on body weight gain into obesity-prone (OP) and obesity-resistant (OR) groups. Systolic blood pressure in OP rats was significantly higher after 10 weeks of the diet (149Ϯ4.8 mm Hg) compared with both OR and C groups (131Ϯ3.7 and 129Ϯ4.5 mm Hg, respectively). The aortic wall area of OP rats was significantly increased, indicating arterial hypertrophy, and a 2-fold increase in plasma renin activity was found in OP rats compared with OR and C rats. The lipid profile showed a significant increase in plasma and VLDL triglycerides of OP versus OR and C groups as early as 3 weeks on the diet. Plasma and LDL-cholesterol levels were increased in the OP group versus the OR and C groups after 3 weeks of the diet, but the difference was blunted after 10 weeks. Lipid peroxidation (thiobarbituric acid-reactive substances) in OP rats was increased 2-fold in LDL and 1.5-fold in aortic wall compared with OR rats, suggesting an increased oxidative stress in these animals. Periodic acid-Schiff staining of the kidney showed mesangial expansion and focal sclerosis that were more prominent in OP rats than in OR rats. The results suggest that hypercholesterolemia, but not hypertriglyceridemia, is linked to the diet; that hypertension and renin-angiotensin system activation are associated with obesity; and that lipid peroxidation and renal damage are the results of both factors. (Hypertension. 2000;35:1009-1015.)besity is a complex, multifactorial disease that is often associated with diabetes, cardiovascular diseases, and stroke. Among other factors, obesity is an important contributor to essential hypertension in humans. Data from the Framingham Heart Study suggest that Ϸ78% of essential hypertension in men and Ϸ65% of essential hypertension in women can be directly attributed to obesity. 1 However, the mechanisms that link obesity with high blood pressure and altered renal function have not been fully elucidated. One problem in the study of the mechanisms of obesity hypertension has been the lack of a suitable animal model. The ideal model would not only have the features of human hypertension but also allow the study of sequential changes in cardiovascular and kidney function that occur with weight gain. The genetic models of obesity may or may not develop hypertension or do not mimic the changes observed in humans. For example, Zucker rats have decreased plasma renin activity (PRA) 2 as opposed to the high PRA observed in humans. 3 In contrast, diet-induced obese animal models appear to be the most relevant with regard to human obesity. Some of these models, such as the obese dog 4 or obese rabbit 5 fed...

Abstract-The mechanisms underlying the development of hypertension in obesity are not yet fully understood. We recently reported the development of hypertension in a rat model of diet-induced obesity. When Sprague-Dawley rats (nϭ60) are fed a moderately high fat diet (32 kcal% fat) for 10 to 16 weeks, approximately half of them develop obesity (obesity-prone [OP] group) and mild hypertension (158Ϯ3.4 mm Hg systolic pressure), whereas the other half (obesity-resistant [OR] group) maintains a body weight equivalent to that of a low fat control group and is normotensive (135.8Ϯ3.8 mm Hg). We examined the potential role of oxidative stress in the development of hypertension in this model. Lipid peroxides measured as thiobarbituric acid-reactive substances showed a significant increase in the LDL fraction of OP rats (2.8Ϯ0.32 nmol malondialdehyde/mg protein) compared with OR and control rats (0.9Ϯ0.3 nmol malondialdehyde/mg protein). Also, aortic and kidney thiobarbituric acid-reactive substances showed a significant (3-and 5-fold) increase in OP rats after 16 weeks of diet. In addition, superoxide generation by aortic rings, measured by lucigenin luminescence, showed a 2-fold increase in the OP group compared with both the OR and control groups. In addition, free isoprostane excretion and nitrotyrosine in the kidney showed an increase in OP rats only. The urine and plasma nitrate/nitrite measured by the LDH method showed a 1.8-fold decrease in OP rats compared with OR rats. However, endothelial NO synthase expression in the kidney cortex and medulla assessed by reverse transcriptasepolymerase chain reaction showed a strong increase in the OP rats versus OR and control rats (endothelial NO synthase/␤-actin ratio 1.3Ϯ0.04 in OP rats versus 0.44Ϯ0.02 in OR rats), suggesting a possible shift toward superoxide production by the enzyme. Collectively, the data show a decreased NO bioavailability in OP animals that is due in part to the increased oxidative stress. Key Words: diet Ⅲ nitric oxide Ⅲ obesity Ⅲ oxidative stress Ⅲ kidney Ⅲ lipids O besity is an important contributor to essential hypertension in humans. Data from the Framingham Heart Study suggest that Ϸ78% of essential hypertension in men and Ϸ65% in women can be directly attributed to obesity. 1 However, the mechanisms that link obesity with high blood pressure (BP) have not been fully elucidated. There are data that indicate increased oxidative stress in human essential hypertension 2,3 as well as in obese hypertensive patients. 4 Also, the involvement of the superoxide radical in BP regulation has been reported for several animal models of hypertension, such as the spontaneously hypertensive rat, 5,6 Dahl rat, 7 and angiotensin II-infused rat. 8 Romero's group (Haas et al 9 and Reckelhoff et al 10 ) has recently reported that subpressor doses of angiotensin II are able to generate oxidative stress in pigs and rats, which, in turn, is able to induce chronic elevations in BP. The increase in superoxide production in hypertension has been shown to have an impact ...

Using stereological methods in vivo, we have investigated the rarefaction of arterioles and capillaries in male spontaneously hypertensive rats (SHR) and the Wistar-Kyoto controls (WKY) at 6-8, 12-14, and 16-18 wk of age. Under chloralose-urethan anesthesia, the gracilis muscle was isolated for microscopic observation. Vessel length and surface area per unit volume of tissue (density) were determined during three consecutive states: innervation, denervation, and vasodilation with nitroprusside. Arteriolar wall-to-lumen ratio was measured after vasodilation. At 6-8 wk capillary density was reduced in the SHR. At 12-14 wk there was a reduction of arteriole and capillary density under innervated and denervated conditions but not after vasodilation (a state of functional rarefaction). At 16-18 wk there was a reduction of arteriolar and capillary density under all three conditions (a state of anatomical rarefaction). At 12-14 and 16-18 wk there was an elevated level of arteriolar vasoconstriction in the SHR that was masked in any one state by the closure of the smaller arterioles. Arteriolar wall-to-lumen ratio was not elevated in the SHR at any time. Arteriolar closure was not reversed by acute denervation.

Abstract-The objective of this study was to determine the effect of pioglitazone on blood pressure (BP) and oxidative balance in obese, hypertensive, Sprague-Dawley rats and to identify some of the molecular mechanisms involved. After 12 weeks of a moderately high-fat diet, rats diverged into obesity-prone (OP) and obesity-resistant (OR) groups (nϭ6 per group). At the end of the diet, peroxisome proliferator activated receptor-␥ (PPAR␥) mRNA expression and activity in the renal cortex and medulla of OP rats were significantly lower compared with that in OR rats. Pioglitazone treatment increased PPAR␥ expression and activity in OP rats, suggesting a possible direct ligand-related effect of pioglitazone. As opposed to the untreated OP group, which showed moderate hypertension (systolic BPϭ159Ϯ5.3 mm Hg) after 12 weeks, pioglitazone-treated rats were normotensive (systolic BPϭ123.9Ϯ2.7 mm Hg). Insulin production was reduced by 2-fold in the OP group treated with pioglitazone. Urinary isoprostanes and renal lipid peroxides were also reduced in OP rats treated with pioglitazone compared with untreated counterparts. Also, expression of p47phox and gp91phox, both increased in OP versus OR rats, was reduced in the former by pioglitazone treatment. In addition, pioglitazone treatment increased nitrate/nitrite excretion and expression of renal endothelial and neuronal nitric oxide synthase. Collectively, the results show that pioglitazone treatment prevented hypertension and renal oxidative stress both by reducing free-radical production and by increasing nitric oxide production/availability. Key Words: kidney Ⅲ oxidative stress Ⅲ free radicals Ⅲ nitric oxide Ⅲ vitamins O besity is a widespread and increasingly prevalent condition associated with a large number of comorbid diseases, one of the most important of which is obesityinduced hypertension. A pleiotropic class of molecules involved in regulation of gene expression in a variety of metabolic and cardiovascular conditions is the peroxisome proliferator-activated receptors (PPARs). PPARs are ligandactivated transcription factors that form heterodimers with the 9-cis retinoic acid receptor RXR␣. 1 PPAR␥ is one of the three PPAR isoforms and is one of the major regulators of adipogenesis. 2 In addition, PPAR␥ exerts pleiotropic effects on blood pressure, lipid metabolism, and insulin action.Recent genetic analysis showed that 2 dominant-negative mutations in PPAR␥ were associated with severe hypertension in humans. 3,4 Consistent with these findings, thiazolidinendiones, the insulin-sensitizer drugs (pioglitazone, rosiglitazone) that are also high-affinity PPAR␥ ligands, 5 have been shown to lower blood pressure (BP) in a variety of hypertensive animal models 6 -8 as well as in diabetic and nondiabetic, 9 hypertensive humans. However, the mechanism underlying the antihypertensive effects of PPAR␥ agonists is not known. PPAR␥ and RXR have been found constitutively expressed in the inner medullary collecting ducts, thick ascending limb, glomerulus, and renal medullary mic...

This study was designed to characterize in vivo arterial remodeling of male Wistar rat small mesenteric arteries exposed to varying levels of elevated blood flow in the presence of normal arterial pressure. Through a series of arterial ligations, respective ileal artery and second-order branch blood flows acutely increased ∼36 and ∼170% over basal levels. Their respective diameters increased 12 and 38% and their wall area increased 58 and 120% in a time-dependent fashion between 1 and 7 days postligation compared with same-animal control vessels. Medial extracellular connective tissue increased concomitantly with medial wall hypertrophy. Immunostaining for proliferating cell nuclear antigen and nuclear profile analyses suggests that both smooth muscle and endothelial cell hyperplasia contribute to flow-induced vascular remodeling. The initial stimulus in this model is flow-mediated shear stress, with possible augmentation by hoop stress, which is increased ∼7% by the resultant vasodilation. Stable wall thickness-to-lumen diameter ratios at 1, 3, and 7 days, however, suggest chronic hoop stress is tightly regulated and remains constant. The model described herein allows analyses of two arteries with different degrees of flow elevation within the same animal and demonstrates that the magnitude of vessel remodeling in vivo is directly dependent on the duration of flow elevation after abrupt arterial occlusion.

. Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity. Am J Physiol Renal Physiol 285: F619-F628, 2003. First published June 10, 2003 10.1152 10. /ajprenal.00388. 2002 diet is known to induce or aggravate hypertension in animal models of hypertension and in humans. When Sprague-Dawley rats (n ϭ 60) are fed a moderately high-fat diet (32% kcal fat, 0.8% NaCl) for 10 wk, about one-half develop obesity [obesity prone (OP)] and mild hypertension, whereas the other half [obesity resistant (OR)] maintain body weight equivalent to a low-fat control (C) and are normotensive. The aim of this study was to test the effect of high-NaCl diets (2 and 4% NaCl) on the development of hypertension and obesity, oxidative stress, and renal function. Both 2 and 4% NaCl induced an early increase in systolic blood pressure of OP but not OR or C rats. High-salt intake induced an increase in the size and reduction in number of adipocytes, concomitant to a twofold increase in circulating leptin in OP rats. Aortic superoxide generation indicated a 2.8-fold increase in the OP high-salt vs. normalsalt groups, whereas urine isoprostanes were not significantly increased. Also, hydroxynonenal protein adducts in the kidney were highly increased in OP rats on 2 and 4% NaCl, indicating oxidative stress in the renal tissue. Urine albumin was increased threefold in the OP on 2% NaCl and fourfold in the same group on 4% NaCl vs. 0.8% NaCl. Kidney histology indicated a higher degree of glomerulosclerosis in OP rats on high-salt diets. In summary, high-salt diet accelerated the development but did not increase the severity of hypertension; high salt increased oxidative stress in the vasculature and kidney and induced kidney glomerulosclerosis and microalbuminuria. Also, the OP rats on high salt displayed adipocyte hypertrophy and increased leptin production.glomerulosclerosis; kidney; leptin; sodium dietary OBESITY IS A complex, multifactorial disease that is associated with essential hypertension in ϳ78% of men and ϳ65% of women, as indicated by the data from the Framingham Heart Study (25). Another important contributor to hypertension in humans is the excessive consumption of dietary salt, and epidemiological studies have demonstrated a significant but weak relation between salt intake and hypertension (32, 33). Some, but not all, interventional studies have shown that salt restriction may lower blood pressure (BP) (19,33). Some recent studies report correlation among hypertension, salt sensitivity, and insulin resistance in obese humans (38), whereas others fail to observe a significant relationship (8). Animal models of obesity, hypertension, and insulin resistance display differences with respect to salt sensitivity. In Zucker rats, there is a clear correlation between salt intake and the severity of hypertension (4, 47), whereas in chronic hyperinsulinemic Sprague-Dawley (SD) rats, hypertension is not salt sensitive, albeit a shift in pressure-natriuresis relationship was reported (2). One important cont...

SUMMARY Fifty-eight normal subjects and 51 subjects with borderline hypertension underwent microvascular and hemodynamic studies while on an ad libitum diet and during periods of sodium depletion (10 mEq/day) and repletion (200 mEq/day). Hemodynamic measurements included arterial blood pressure, cardiac index, total peripheral resistance, forearm blood flow, vascular resistance, venous compliance, and capillary filtration fraction. Studies of the mlcrocirculation consisted of macrophotography of the buibar conjunctiva with measurement of anteriolar, venular, and capillary density and diameter. During sodium repletion, cardiac index increased significantly in the normal subjects (2.35 ± 0.7 vs 2.44 ± 0.7 L/min/m 2 ; p<0.01) and in the borderline hypertensive subjects (2.50 ± 0.7 vs 2.70 ± 0.8 L/min/m 2 ; p<0.01). However, mean blood pressure rose by more than 5% in only 33 subjects, 13 with normal and 20 with borderline hypertension. When these sodium-sensitive subjects were compared with those whose blood pressure did not rise, the former were found to have significantly higher forearm vascular resistance (32.2 ± 21 vs 17.9 ± 12 mm Hg/ml/min/lOOg; p<0.01), lower forearm blood flow (4.42 ± 2.7 vs 7.47 ± 5.0 ml/min/100 g) and lower conjunctival capillary density (3.72 ± 1.7 vs 5.18 ±2.1 [SD] mm/mm 2 ; p< 0.05). These results indicate that sodium sensitivity In humans is accompanied by elevation of forearm vascular resistance and attenuation of the microcirculatton. (Hypertension 9: 398-406, 1987) KEY WORDS • hypertension microcirculation sodium • vascular resistance * hemodynamics T HE conclusion that certain individuals are sodium-sensitive is supported by two main lines of evidence, experimental and epidemiological. Meneely et al. 1 found that rats fed a high sodium diet displayed a wide spectrum of blood pressure responses: some became severely hypertensive, some remained normotensive, and others manifested intermediate levels of blood pressure elevation. After several generations of selective inbreeding, Dahl et al. were able produce strains of genetically sodium-sensitive and sodium-resistant rats. Received December 16, 1985; accepted December 10, 1986. While studies within populations have not shown a direct relationship between individual sodium intake and blood pressure, possibly because of a saturation effect, studies of human populations have also supported the concept of individual susceptibility to the hypertensive effects of sodium. Several surveys have demonstrated a positive relationship between sodium intake and the prevalence of hypertension.3 However, normotensive persons can be found even in populations ingesting large quantities of sodium, suggesting that some humans are sodium-resistant while others are sodium-sensitive. 4 A number of investigators have observed abnormalities in the vascular resistance of patients with early, mild hypertension that might underlie sodium sensitivity. "12 The purpose of the present study was to identify persons whose blood pressure rises with increases in ...

This experiment was designed to investigate the effect of converting enzyme inhibition on functional and structural vascular alterations in one-kidney, one clip hypertensive rats and in normotensive rats. Starting 1 day before surgery, 100 mg/kg/day captopril was given chronically to half of the hypertensive and normotensive groups in their drinking water. With use of intravital microscopy in the cremaster muscle, arteriolar dimensions were measured 4 weeks later, both before and after topical application of 10~3 M adenosine. Mean blood pressure was 124 ±4 mm Hg in control rats and 103 ±5 mm Hg in captopril-treated control rats (p<0.05). Mean blood pressure was significantly elevated to 183±5 mm Hg in captopril-treated one-kidney, one clip hypertensive rats and 193 ±5 mm Hg in one-kidney, one clip hypertensive rats. With use of histological techniques, a marked reduction of medial-intimal area of the abdominal aorta was found in captopril-treated control rats (24%), and hypertrophy of the aortic wall in one-kidney, one clip hypertensive rats was decreased 26% by captopril. Structural diameter reductions occurred in large arterioles of the captopril-treated control and hypertensive groups and the nontreated hypertensive group. In spite of a significant increase in wall-to-lumen ratio of first-order arterioles in all captopril-treated rats, captopril decreased cross-sectional wall area of these vessels 37% in hypertensive and 20% in control rats, respectively. Measured by stereological techniques, small arteriolar density decreased 30% in captopril-treated hypertensive rats and 17% in captopril-treated control rats. Therefore, smaller arteriolar lumens, decreased aortic and arteriolar cross-sectional wall area, and arteriolar rarefaction after converting enzyme inhibition, in spite of rising or falling blood pressure, are evidence that vascular growth was inhibited in vivo. {Hypertension 1990;15:68-77) T he influence of angiotensin II (Ang II) on vascular structure has been widely studied. Ang II has been shown to stimulate DNA and protein synthesis in cardiovascular tissue 1 and induce hypertrophy without cellular proliferation in cultured rat aortic smooth muscle cells (SMCs) maintained in a defined serum-free medium.2 Ang II also increased growth rates and cell size in cultured human SMCs grown in the presence of serum. However, all of these were in vitro studies. In vivo, captopril not only lowered blood pressure, but was more effective than hydralazine and propranolol in preventing increases in aortic SMC content, medial SMC weight, and percentage of polyploid SMCs in spontaneously hypertensive rats (SHR).4 SMC volume was also reduced in captopril-treated SHR and Wistar-Kyoto (WKY) rats. 4 In mesenteric arteries, captopril induced a long-lasting decrease in wallto-lumen (W/L) ratio in SHR and simultaneously induced long-lasting decreases in myocardial and aortic wall hypertrophy that persisted up to 7 weeks after treatment withdrawal.5 Recently, converting enzyme inhibition in two-kidney, one clip hypertensiv...