Sreenivas Reddy

Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity.

Hypertension is often associated with insulin resistance, and several chemically diverse agents that increase insulin sensitivity attenuate the development of experimental hypertension. We undertook the present study to determine whether attenuation of hypertension by pioglitazone, a thiazolidinedione derivative that increases insulin sensitivity without increasing insulin secretion, is specifically related to its effect on insulin-mediated glucose uptake. Pioglitazone administered daily by oral gavage (20 mg/kg per day) for 3 weeks attenuated the development of hypertension in both the Dahl salt-sensitive (DS) rat (an insulin-resistant model of hypertension) and the one-kidney, one clip rat (a model of hypertension not associated with insulin resistance). Based on euglycemic insulin clamp studies in conscious animals, the glucose clearance rate was increased (P < .05) in pioglitazone-treated DS rats (36 +/- 3 mg/kg per minute) compared with control DS rats (27 +/- 1 mg/kg per minute). However, pioglitazone did not affect the glucose clearance rate in one-kidney, one clip hypertensive rats. Metformin, an unrelated agent that also improves glucose tolerance, had no significant effect on blood pressure or glucose clearance rate in either DS or one-kidney, one clip rats. Thus, the hypotensive effect of pioglitazone is not invariably associated with its capacity to improve insulin-induced glucose utilization.

Increasing Insulin Sensitivity Lowers Blood Pressure in the Fructose-Fed Rat

In the rat, simple carbohydrate feeding induces insulin resistance, and insulin resistance is associated with impaired endothelium dependent vasodilation. To determine if increasing insulin sensitivity corrects this defect of endothelial function, we evaluated the effects of an insulin-sensitizing agent, pioglitazone, on arterial pressure and in vitro vascular reactivity in three groups of Sprague Dawley rats: 1) control; 2) 60% fructose diet for 4 weeks; 3) 60% fructose diet plus pioglitazone (20 mg/kg daily, by oral gavage). Direct mean arterial pressure did not differ in Groups 1 (120 mm Hg +/- 2) and 2 (121 +/- 2) and was lower (P < .05) in Group 3 (112 +/- 2). In vitro uptake of tritiated glucose by adipocytes in response to insulin was reduced (P < .05) by fructose and increased (P < .01) by pioglitazone. In strips of thoracic aorta, norepinephrine-induced vasoconstriction and nitroprusside induced vasodilation did not differ among groups. However, in response to graded dose of acetylcholine, vasodilation was reduced (P < .05) by fructose; this was normalized by pioglitazone. In all groups, N(G)-nitro-L-arginine methyl ester (L-NAME) completely blocked acetylcholine-induced vasodilation. Thus, pioglitazone increased insulin sensitivity, lowered blood pressure, and normalized acetylcholine-induced vasodilation in insulin resistant, fructose-fed rats. Increasing insulin sensitivity may lower arterial pressure by augmenting endothelium dependent vasodilation.

Prematurity in mice leads to reduction in nephron number, hypertension, and proteinuria

The nephron number at birth is a quantitative trait that correlates inversely with the risk of hypertension and chronic kidney disease later in life. During kidney development, the nephron number is controlled by multiple factors including genetic, epigenetic, and environmental modifiers. Premature birth, which represents more than 12% of annual live births in the United States, has been linked to low nephron number and the development of hypertension later in life. In this report, we describe the development of a mouse model of prematurity-induced reduction of nephron number. Premature mice, delivered 1 and 2 days early, have 17.4 ± 2.3% (n = 6) and 23.6 ± 2% (n = 10) fewer nephrons, respectively, when compared with full-term animals (12,252 ± 571 nephrons/kidney, n = 10). After 5 weeks of age, the mice delivered 2 days premature show lower real-time glomerular filtration rate (GFR, 283 ± 13 vs 389 ± 26 μL/min). The premature mice also develop hypertension (mean arterial pressure [MAP], 134 ± 18 vs 120 ± 14 mm Hg) and albuminuria (286 ± 83 vs 176 ± 59 μg albumin/mg creatinine). This mouse model provides a proof of concept that prematurity leads to reduced nephron number and hypertension, and this model will be useful in studying the pathophysiology of prematurity-induced nephron number reductions and hypertension.

Dietary sodium chloride increases blood pressure in obese Zucker rats.

In the rat, elevated arterial pressure is not consistently associated with obesity. The purpose of this study was to compare measurements of blood pressure, cardiac output, and total peripheral resistance in obese and lean Zucker rats on different NaCl intakes. Obese and lean rats drank either water or isotonic NaCl for 18 days. Tail systolic blood pressures of saline-drinking obese rats were higher than all other groups (p less than 0.05). NaCl intake did not affect blood pressure in lean rats, and blood pressures of water-drinking obese rats did not differ from those of lean controls. In a subsequent experiment, direct arterial pressures and cardiac outputs (thermodilution) were measured in separate groups of conscious rats that had been maintained on a 1% or 4% NaCl intake for 12 weeks. Arterial pressure was higher (p less than 0.01) in obese rats fed 4% NaCl (130 +/- 4 mm Hg) than in obese rats fed 1% NaCl (118 +/- 2 mm Hg) or than in lean rats fed either NaCl intake (118 +/- 3 mm Hg and 116 +/- 3 mm Hg, respectively). Cardiac output of obese rats was higher than that of lean rats (p less than 0.01); however, the NaCl-induced increase of blood pressure was accounted for by an increase of peripheral resistance (p less than 0.01). Thus, in contrast to the lean Zucker rat, arterial pressure of the obese Zucker rat is increased by a high dietary intake of NaCl.

A high sucrose, high linoleic acid diet potentiates hypertension in the Dahl salt sensitive rat.

Insulin resistance can be induced by diets high in simple carbohydrates or fatty acids. To determine whether these nutrients also affect arterial pressure in genetic models of salt sensitive and salt resistant hypertension, Dahl salt sensitive (S) and salt resistant (R) rats were each fed the following isocaloric diets containing 3% NaCl for 4 weeks (10 rats/group): 1) control; 2) high sucrose (60%); 3) high linoleic acid (LA, provided as 10% safflower oil); and 4) high sucrose plus high LA. Tail systolic blood pressures (SBP) were measured weekly, and at 4 weeks, direct mean arterial pressures (MBP) were measured in conscious animals. Insulin sensitivity was assessed by in vitro uptake of tritiated glucose by adipocytes in response to graded doses of insulin. Weight gain did not differ among groups. High sucrose alone and high LA alone did not affect blood pressure in either strain. However, SBP and MBP were increased (P < .05) by the high sucrose plus high LA diet in Dahl-S but not in Dahl-R rats. Sucrose alone and LA alone decreased (P < .05) insulin sensitivity in Dahl-S and Dahl-R rats. In both strains, sucrose plus LA decreased insulin sensitivity to a greater extent (P < .05) than sucrose alone or LA alone. Thus, the sucrose plus LA diet decreased insulin sensitivity in both Dahl-S and Dahl-R rats, whereas blood pressure was increased only in Dahl-S rats. The phenotype of elevated arterial pressure is influenced both by a genetic-nutrient interaction and by an interaction among specific nutrients resulting in insulin resistance.

Differential Nephron HO-1 Expression following Glomerular Epithelial Cell Injury

Background: In proteinuria of glomerular origin there is upregulation of heme-oxygenase (HO), the rate-limiting enzyme of heme degradation, in the nephron in a segment-specific manner. To better characterize this phenomenon, we employed a model of proteinuria resulting from disruption of the glomerular capillary permeability barrier to protein by administration of the glomerular epithelial cell toxin puromycin aminonucleoside (PAN) to rats. In this model, we assessed nephron distribution of the expression of the inducible HO isoform, HO-1, and the role of free radicals in modulating HO-1 expression. Methods: Rats were injected with either vehicle (dimethyl sulfoxide) or PAN or the spin trap free radical stabilizer α-phenyl-N-tert butyl nitrone (PBN), or with both PAN and PBN. Ten days following the PAN injection, urine protein, creatinine, nitric oxide (NO) and malonyldialdehyde (MDA) were measured. Kidney sections and protein lysates were assessed for changes in HO-1 expression by immunohistochemistry and Western blot analysis. Results: In control animals (DMSO or PBN alone) there was no proteinuria and very weak or absent HO-1 staining in nephron segments. PAN treatment induced proteinuria and increased urine MDA excretion. In these animals, there was a robust HO-1 expression mainly in tubules and in glomerular parietal but not visceral epithelial cells. Unilateral ureteral obstruction to interrupt glomerular filtration in animals treated with PAN abrogated tubular HO-1 expression in the kidney ipsilateral to the obstruction. Administration of PBN to PAN-treated animals reduced proteinuria and MDA excretion while it markedly augmented tubular HO-1 expression. This augmentation was prominent in tubular cells of the inner cortex/outer medulla. Conclusions: These observations indicate that upregulation of nephron HO-1 following disruption of the glomerular permeability barrier occurs at sites downstream of this barrier and is mediated by a filtered HO-1 inducer(s). Scavenging of free radicals potentiates the effect of this inducer and unmasks nephron segments most and least capable of upregulating HO-1.

Attenuation of experimental hypertension by dietary linoleic acid is model dependent.

OBJECTIVE The purpose of this study was to evaluate the interaction of a linoleic acid enriched diet with NaCl on the development of hypertension in Dahl salt sensitive (Dahl-S) rats and in two-kidney, one-clip Sprague Dawley rats. METHODS In both experimental models, separate groups of animals were fed either linoleic acid enriched (provided as safflower oil) or control (containing coconut oil) diets for 5 weeks. Diets were further subdivided on the basis of either a low NaCl (0.3%) or a high NaCl (3.0%) content. Tail systolic blood pressure, direct mean intra-arterial pressure, and cardiac output were measured in chronically instrumented, conscious rats. RESULTS In Dahl-S, on both NaCl intakes, and in two-kidney, one-clip rats on a high NaCl diet, safflower oil had no effect on arterial pressure. In contrast, in two-kidney, one-clip rats fed the low NaCl diet, both indirect tail systolic blood pressures and direct mean arterial pressure were lower (p<0.01) in animals on the linoleic acid enriched diet; total peripheral resistance was also decreased (p<0.01). CONCLUSION Safflower oil has a hypotensive effect only in the two-kidney, one-clip rat on a low NaCl, but not on a high NaCl intake, and not in Dahl-S rats. Additional studies are required to identify the mechanism(s) for the hypotensive effect of safflower oil and to define the relationship of this animal study to human hypertension.