Fenofibrate lowers blood pressure in two genetic models of hypertension

2000 ◽  
Vol 78 (5) ◽  
pp. 367-371 ◽  
Author(s):  
Raied Khaled Shatara ◽  
Dale W Quest ◽  
Thomas W Wilson
Keyword(s):  
Blood Pressure ◽  
Weight Gain ◽  
High Salt ◽  
Lipid Lowering ◽  
Urine Protein ◽  
High Salt Diet ◽  
Salt Diet ◽  
Urine Protein Excretion ◽  
Protein Excretion ◽  
Sd Rats

Fenofibrate, a commonly used lipid lowering drug, induces the expression of the gene coding for cytochrome P450-4A, whose major product is 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a potassium channel antagonist, could increase or decrease blood pressure (BP). We studied the effects of four weeks of oral fenofibrate on BP, urine output (UVol), plasma renin activity (PRA), and urine protein excretion in young (4-5 weeks) stroke prone spontaneously hypertensive rats (SHRSP), older (25 weeks) SHRSP, Dahl salt sensitive rats (Dahl S) on a high salt diet, Dahl S rats on a normal salt diet, and normotensive Sprague-Dawley (SD) rats. Fenofibrate prevented the increase in BP in 4-5 week old SHRSP, reduced BP in 25 week old SHRSP, but had no effect on BP in normotensive SD rats. Similarly, fenofibrate prevented the increase in BP in Dahl S rats on a high salt diet, but had no effect in Dahl S rats on a low salt diet. Fenofibrate increased UVol (and reduced weight gain) in young SHRSP and tended to increase it in other groups. It also increased PRA 2 to 5-fold in all groups except older SHRSP. Young SHRSP receiving fenofibrate excreted significantly less urine protein than control rats. The drug reduced proteinuria in Dahl S rats on high salt diet, but had no significant effect on proteinuria in other groups. In summary, fenofibrate reduced blood pressure and weight gain, increased UVol and PRA, and reduced urine protein excretion in young SHRSP. Other groups of animals showed these changes to a variable, but directionally similar extent. These findings are consistent with a natriuretic effect of fenofibrate. Key words: hypertension, animal models, natriuresis, fenfibrate, lipid lowering agents.

High-salt diet upregulates kininogen and downregulates tissue kallikrein expression in Dahl-SS and SHR rats

1996 ◽  
Vol 271 (4) ◽  
pp. F824-F830 ◽  
Author(s):  
C. Wang ◽  
C. Chao ◽  
L. M. Chen ◽  
L. Chao ◽  
J. Chao
Keyword(s):  
Blood Pressure ◽  
High Salt ◽  
Transcriptional Level ◽  
Tissue Kallikrein ◽  
Mrna Levels ◽  
Hypertensive Rats ◽  
High Salt Diet ◽  
Salt Loading ◽  
Salt Diet ◽  
Sd Rats

Tissue kallikrein cleaves low-molecular-weight (low-M(r)) kininogen to produce the vasoactive kinin peptide. It has been suggested that hypertensive patients with low urinary kallikrein excretion may have a defect in sodium handling. In this study, we examined the effect of a high-salt diet on the expression of tissue kallikrein and kininogen genes in Dahl salt-sensitive rats (Dahl-SS), spontaneously hypertensive rats (SHR), and normotensive Sprague-Dawley rats (SD) by Northern and Western blot analysis and radioimmunoassay. Control and experimental groups received normal and high-salt diets containing 0.4% and 8% NaCl, respectively, for 6 wk. High-salt diet induced a significant time-dependent increase of blood pressure in both strains of hypertensive rats and a slight but significant increase of blood pressure in normotensive SD rats. Hepatic kininogen mRNA levels of both Dahl-SS and SHR on a high-salt diet increased 2.4-fold and 2.0-fold, respectively, while alpha 1-antitrypsin mRNA levels were not changed in rats receiving high-salt diet. Immunoreactive total kininogen and low-M(r) kininogen (58 kDa) levels in sera increased in response to high-salt diet in both strains of hypertensive rats. In SD rats, the low-M(r) kininogen level in sera was unaltered, whereas total kininogen increased in response to high-salt diet. Tissue kallikrein mRNAs in the kidney and salivary glands of Dahl-SS, SHR, and SD rats were reduced, whereas beta-actin mRNA was not altered by high-salt diet. Similarly, immunoreactive intrarenal kallikrein levels were reduced in these rats in response to high-salt diet. These studies show that increases in blood pressure after salt loading in Dahl-SS and SHR are accompanied by increases in low-M(r) kininogen. Tissue kallikrein gene expression in hypertensive Dahl-SS and SHR and normotensive SD rats is suppressed after salt loading. These findings show that reduced renal kallikrein expression and increased kininogen expression is regulated at the transcriptional level during salt loading.

Abstract 500: The Cardiorenal Effects Of An Angiotensin Receptor Blocker (Valsartan) And Neprilysin Inhibitor (AHU377) Co-administered Daily For 6 Weeks In The Dahl Salt-sensitive Rat Model Of Volume-dependent Hypertension

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Alexander J McNamara ◽  
Laxminarayan G Hegde ◽  
Uwe Klein ◽  
Craig Hill ◽  
Cecile Yu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Weight Gain ◽  
Rat Model ◽  
Renal Injury ◽  
Body Weight Gain ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Neprilysin Inhibitor

The endogenous natriuretic peptide system helps maintain cardiovascular homeostasis by counterbalancing the deleterious effects of renin angiotensin system activation. This study examined whether the co-administration of an ARB (valsartan: VAL) with a NEPi (AHU377: AHU) can reduce cardiorenal disease progression in the Dahl salt-sensitive (Dahl/SS) rat model of volume-dependent hypertension. Methods: Studies were conducted in conscious Dahl/SS hypertensive rats that were maintained on a high salt diet and surgically implanted with telemetry transmitters for monitoring blood pressure. Rats were treated for 6 weeks with either vehicle, VAL (30 mg/kg, PO) or VAL+AHU (30 + 30 mg/kg, PO). Changes in cardiac and renal functions were measured via Left Ventricle (LV) pressure-volume loops and biomarkers (KIM-1, NGAL and osteopontin). Results: Dahl/SS rats maintained on a high salt diet exhibited a progressive decrease in body weight gain, progressive increases in blood pressure and elevation of plasma and urinary biomarkers indicative of cardiac stress or renal injury. VAL and VAL+AHU both improved body weight gain and blunted the progressive hypertension. However, the magnitude of the antihypertensive effect was greater for VAL+AHU (peak change: - 33 ± 3 mmHg) than for VAL alone (peak change: -15 ± 5 mmHg). VAL+AHU treatment provided greater renal protective effects, based on renal biomarkers KIM-1 (286 ± 29 vs. 341 ± 59 ng), NGAL (58 ±9 vs. 108 ± 28 μg) and osteopontin (1637 ± 372 vs 2155 ± 748 ng), than VAL alone. The VAL+AHU treatment group demonstrated a greater normalization in LV function, with improved systolic contractility over VAL alone (preload-adjusted PWR max = 1 ± 0.1 vs. 2 ± 0.5 μWatt/uL). Most notably, the VAL+AHU group exhibited a greater survival rate (94%: 15 of 16) than either the VAL (75%: 12 of 16) or vehicle (70%: 14 of 20) groups. Conclusion: In summary, chronic co-administration of an ARB and NEPi to Dahl/SS rats significantly attenuated progression of hypertension, suppressed increases in biomarkers indicative of renal injury, improved cardiac function and increased overall survival. These results suggest that co-administration of an ARB and NEPi may confer a beneficial therapeutic strategy for the treatment of cardiorenal disease.

scholarly journals Effects of Doenjang, a Traditional Korean Soybean Paste, with High-Salt Diet on Blood Pressure in Sprague–Dawley Rats

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2745 ◽  
Author(s):  
Eun-Gyung Mun ◽  
Jung Eun Park ◽  
Youn-Soo Cha
Keyword(s):  
Blood Pressure ◽  
Reduce Blood Pressure ◽  
Fermented Food ◽  
High Salt ◽  
Fermented Foods ◽  
Sprague Dawley ◽  
High Salt Diet ◽  
Salt Diet ◽  
Sd Rats ◽  
Soybean Paste

Fermented foods in Korea contain a lot of salt. Although salt is reported to exacerbate health trouble, fermented foods have beneficial effects. We hypothesized that doenjang could reduce blood pressure in Sprague–Dawley (SD) rats fed a high-salt diet. Eighteen SD rats were divided into three groups: normal-salt (NS) group, high-salt (HS) group, and high-salt with doenjang (HSD) group. The salinity of doenjang and saltwater was adjusted to 8% using Mohr’s method. Blood pressure was significantly reduced in the HSD group compared with the HS group. Water intake and urine excretion volume has significantly increased in the HS group compared with the HSD group. The excreted concentrations of urine sodium, urine potassium, and feces potassium significantly increased in the HSD group compared with the HS and NS groups. Renin level was significantly decreased in the HSD group compared to the other groups. These results indicate that eating traditional salty fermented food is not a direct cause of hypertension, and the intake of doenjang in normal healthy animals improved blood pressure.

scholarly journals Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
Author(s):  
Yanling Yan ◽  
Jiayan Wang ◽  
Muhammad A. Chaudhry ◽  
Ying Nie ◽  
Shuyan Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Significant Rise ◽  
Protein Carbonylation ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

Endothelin B receptors impair baroreflex function and increase blood pressure variability during high salt diet

2021 ◽  
pp. 102796
Author(s):  
Bryan K. Becker ◽  
Jermaine G. Johnston ◽  
Carolyn Young ◽  
Alfredo A. Torres Rodriguez ◽  
Chunhua Jin ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Variability ◽  
High Salt ◽  
Increase Blood Pressure ◽  
High Salt Diet ◽  
Salt Diet ◽  
Baroreflex Function ◽  
Endothelin B

Abstract 16835: Targeted Disruption of Paraoxonase 3 in a Dahl Salt-Sensitive Rat Model of Chronic Kidney Disease Increases Renal Cortical Pro-Inflammatory Eicosanoids

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Chrysan J Mohammed ◽  
Fatimah K Khalaf ◽  
Prabhatchandra Dube ◽  
Tyler J Reid ◽  
Jacob A Connolly ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Renal Cortex ◽  
High Salt ◽  
High Density Lipoproteins ◽  
Wild Type ◽  
Targeted Disruption ◽  
High Salt Diet ◽  
Salt Diet ◽  
Mediators Of Inflammation

Background: Paraoxonase 3 (Pon3), is one of the three isoforms of the paraoxonase gene family. While Pon1 and Pon2 are widely studied, there is a paucity of knowledge regarding Pon3. Pon3 is synthesized in the liver and can circulate bound to high-density lipoproteins. There is significant expression in the kidney also. Pon3 has the ability to metabolize eicosanoids, which can act as signaling molecules and have known roles in the pathophysiology of some renal diseases. Decreased Pon activity is associated with elevated levels of eicosanoid metabolites and adverse clinical outcomes. We tested the hypothesis that targeted disruption of Pon3 results in elevated levels of pro-inflammatory eicosanoids and progression of renal injury. Methods/ Results: Ten week old male Dahl salt-sensitive (SS rats) and Pon3 mutant rats (SS Pon3 KO) were maintained on 8% high salt diet for eight weeks, to initiate salt-sensitive hypertensive renal disease. Previously we observed that SS Pon3 KO rats on eight weeks high salt diet demonstrated significantly increased phenotypic renal injury and mortality. In the current study, we noted that SS Pon3 KO had significantly decreased (p<0.05) glomerular filtration rate compared to SS wild type. Blood pressure (radiotelemetry) as well as plasma angiotensin and aldosterone (LC-MS/MS) were not different between the two groups after high salt diet. We used targeted lipidomic profiling to determine eicosanoid content in renal cortex from SS Pon3 KO and SS wild type rats at the end of eight weeks of high salt diet. We found that hydroxyl fatty acids 5-HEPE and 5-HETE (5-lipoxygenase dependent arachidonic acid metabolites) were significantly (p<0.05) elevated in the renal cortex of SS Pon3 KO compared to SS wild type rats. In addition to being mediators of inflammation, these metabolites are associated with renal cell injury and death. Furthermore, prostaglandin 6-keto-PGF 1α , which has known links to renal inflammation, was significantly (p<0.05) increased in renal cortex of SS- Pon3 KO compared to SS wild type rats. Conclusion: These findings suggest that targeted deletion of Pon3 increases pro-inflammatory eicosanoids (5-HETE and 5-HEPE) and prostaglandins (6-keto-PGF 1α ), as well as increases renal damage independent of blood pressure.

Abstract 096: Leptin and High Salt Diet Induce Greater Increases in Blood Pressure in Female than Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Eric J Belin de Chantemele
Keyword(s):  
Blood Pressure ◽  
Recovery Period ◽  
Pressure Rise ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Male And Female ◽  
Female Mice ◽  
Males And Females ◽  
Blood Pressure Responses

Recent studies by our group demonstrated that leptin is a direct regulator of aldosterone secretion and increases blood pressure via sex-specific mechanisms involving leptin-mediated activation of the aldosterone-mineralocorticoid receptor signaling pathway in females and sympatho-activation in males. Although it is well accepted that females secrete more leptin and aldosterone than males, it is unknown whether leptin infusion raises blood pressure similarly in male and female mice and whether higher aldosterone levels sensitize females to salt-induced hypertension. We hypothesized that female mice would be more sensitive to leptin than males and also have a potentiated blood pressure rise in response to high salt diet compared to males. Male and female Balb/C mice were implanted with radiotelemeters for continuous measurement of mean arterial pressure (MAP) at 10 weeks of age. MAP was measured for seven days prior to feeding with a high-salt diet (HS, 4%NaCl) for seven days. Following a recovery period, animals were then implanted with osmotic minipumps containing leptin (0.9mg/kg/day) recorded for seven days. Baseline MAP was similar between males and females (101.3±2.9 vs 99.3±3.7 mmHg, n=4 and 5, respectively), however, HS diet resulted in a greater MAP increase in females (15.0±2.6 mmHg) compared to males (3.1±4.5 mmHg, P<0.05). MAP with leptin treatment was increased with leptin in females moreso than in males, however, this did not reach significance (6.8±5.8 vs 1.8±5.9 mmHg, respectively). This potential sex difference in blood pressure responses to leptin was not associated with changes in body weight (0.07±0.44 vs -0.22±0.2 g, respectively) nor changes in blood glucose (-19.67±15.06 vs -15.4±11.4 mg/dl, respectively) in males and females in response to leptin. In summary, female mice are more sensitive to HS diet-induced blood pressure increases than males. Females may be more sensitive to leptin-mediated blood pressure increases than males. Further investigation is needed to determine whether these sex differences in blood pressure responses to HS diet and leptin are mediated by aldosterone or other mechanisms.

Abstract 376: The Expression of (pro)renin Receptor is Upregulated in the Kidney by High Salt Diet and No Inhibition

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Rong Rong ◽  
Osamu Ito ◽  
Nobuyoshi Mori ◽  
Yuma Tamura ◽  
Akihiro Sakuyama ◽  
...  
Keyword(s):  
Collecting Duct ◽  
High Salt ◽  
Kidney Cortex ◽  
Control Group ◽  
Thick Ascending Limb ◽  
High Salt Diet ◽  
Salt Diet ◽  
Protein Levels ◽  
Nephron Segments ◽  
Sd Rats

The (pro)renin receptor ((P)RR)-bound (pro)renin not only causes the generation of angiotensin II via the increased enzymatic activity, it also activates the receptor’s own intracellular signaling pathways up-regulating the expression of the profibrotic proteins. To clarify the regulation of (P)RR expression, the present study examined the effects of high salt diet and nitric oxide synthase (NOS) inhibition on the (P)RR expression in the kidney. The nephron segments were isolated from male Sprague-Dawley (SD) rats by microdissection and bulk isolation technique, and the (P)RR mRNA and protein expressions were examined by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. In adiition, 5 week-old, male SD rats were randomly divided into 3 groups: a control group, a high salt diet (HS) group and a Nω-Nitro-L-arginine (L-NAME) group, and each group was treated with vehicle, high salt diet (8%, NaCl), or L-NAME (600mg/ml in drinking water), respectively. After 4 weeks, the (P)RR expression in the kidney was compared among these groups. The (P)RR mRNA was expressed in the glomerulus (Glm), the proximal convoluted and straight tubule, the cortical and medullary thick ascending limb (TAL) and collecting duct. The (P)RR protein as well as mRNA was expressed widely in the nephron segments; the preglomerular arteriole, the Glm, the proximal tubules (PT), the medullary TAL (mTAL) and inner medullary collecting duct (IMCD). Compared with the control group, the (P)RR protein levels significantly increased in the kidney cortex of both HS group and L-NAME group by 96% (p<0.01) and 506% (p<0.01) and in the inner medulla of L-NAME group by 148% (p<0.05), but did not significantly change in the outer medulla of HS group or L-NAME group. HS increased the (P)RR protein levels in the Glm and PT by 48% (p<0.05) and 39% (p<0.01), but did not affect them in other nephron segments. These results indicated that (P)RR is expressed widely in the nephron segments and that HS and NOS inhibition upregulate the (P)RR expression in the kidney, suggesting roles of (P)RR in hypertensive kidney disorder.

Abstract 370: Upregulation of Renal D5 Dopamine Receptor Ameliorates Hypertension in D3 Deficient Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Xiaoyan Wang ◽  
Crisanto S Escano ◽  
Laureano Asico ◽  
John E Jones ◽  
Alan Barte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Nadph Oxidase ◽  
Protein Expression ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Deficient Mice

D 3 dopamine receptor (D 3 R) deficient mice have renin-dependent hypertension but the hypertension is mild and is not associated with oxidative stress. In order to determine if any compensatory mechanism in the kidney is involved in the regulation of blood pressure with disruption of D 3 R, we measured the renal protein expression of dopamine receptors in D 3 R homozygous (D 3 -/-) and heterozygous (D 3 +/-) knockout mice and their wild type (D 3 +/+) littermates. D 5 dopamine receptor (D 5 R) (169±23%, reported as % of D 3 +/+, n=5/group) expression was increased but D 4 dopamine receptors protein expression (59±8%) was decreased, while no significant changes were found with D 1 and D 2 dopamine receptors. Immunocytochemistry showed a stronger renal staining of D 5 R but without a change in renal tubule cell distribution in D 3 -/- relative to D 3 +/+ mice. D 5 R abundance was also increased in D 3 +/- (205±30%, n=5/group) relative to D 3 +/+ mice, while D 1 R abundance was similar between D 3 +/- and D 3 +/+ mice. The increase in D 5 R expression was abolished while blood pressure was increased further in D 3 -/- mice fed a high salt diet. Treatment of the D 1 -like (including D 1 and D 5 receptors) antagonist, SCH23390 , increased the blood pressure to a greater extent in anesthetized D 3 -/- mice than in D 3 +/+ mice (n=4/group), suggesting that the upregulation of D 5 R may modulate the hypertension in mice caused by the disruption of D 3 R. Since dopamine inhibits the NADPH oxidase-induced production of reactive oxygen species (ROS) via the D 5 R, we also measured the protein expression of NOXs in the kidney and isoprostane in the urine. No NADPH oxidase subunit was increased in D 3 -/- and D 3 +/- mice relative to D 3 +/+ mice fed a normal or salt high salt diet, and urinary isoprostane excretion was also similar in D 3 -/- and D 3 +/+ mice. Our findings suggest that the upregulation of D 5 R may minimize the hypertension and prevent oxidative stress in D 3 -/- mice.

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