Fenofibrate lowers blood pressure in two genetic models of hypertension

Shatara, Raied Khaled; Quest, Dale; Wilson, Thomas W.

doi:10.1139/cjpp-78-5-367

Cited by 29 publications

(32 citation statements)

References 18 publications

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“…Indeed, there is evidence that nitric oxide (24) and carbon monoxide (1,3) that is present in the outer medulla binds to the heme of CYP4A proteins and inhibits the formation of 20-HETE. Nonetheless, our finding that increasing the renal formation of 20-HETE in this case by transfer of chromosome 5 reduces salt sensitivity of blood pressure in SS.5 BN rats is consistent with previous data, indicating that induction of the synthesis of 20-HETE in the kidney with fibrates opposes the development of hypertension in SS rats and other models of hypertension (30,33,43). In contrast, the increase in 20-HETE formation in renal microvessels in the SS.5 BN strain would be expected to increase vascular tone and promote the development of hypertension.…”

Section: Discussionsupporting

confidence: 82%

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Williams

Fan

Murphy

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5 BN (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5 BN rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 Ϯ 1 to 183 Ϯ 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 Ϯ 5 mmHg in SS.5 BN rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5 BN rats compared with SS rats. Protein excretion rose to 354 Ϯ 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 Ϯ 13 mg/day in the SS.5 BN rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5 BN rats (43 Ϯ 1 mmHg) and Dahl S (44 Ϯ 2 mmHg) rats. However, Pgc increased to 59 Ϯ 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5 BN rats (43 Ϯ 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg Ϫ1 ·day Ϫ1 iv) reversed the antihypertensive phenotype seen in the SS.5 BN rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5 BN consomic strain.hypertension; glomerulosclerosis; chromosome 5; Dahl S rats; pressure natriuresis; renal hemodynamics; kidney THE DAHL SALT-SENSITIVE (SS) rat is an inbred genetic model that rapidly develops severe hypertension, proteinuria, glomerulosclerosis, and renal interstitial fibrosis when fed a high salt (HS) diet (4, 7-8, 23, 25, 27, 30, 38, 43). However, the genes and pathways that contribute to the development of hypertension and renal disease have yet to be identified. Previous studies from our laboratory have demonstrated that the pressure natriuretic relationship is impaired in SS rats and that this is associated with increased Cl Ϫ transport in the thick ascending limb of Henle (TALH) (13, 15-16, 29, 44). They also exhibit a deficiency in the renal production of 20-HETE that contributes to the increase in loop Cl Ϫ transport (13,35,44).More recently, Mattson et al. (20) demonstrated that substitution of chromosome 5 from the Brown Norway (BN) rat onto the SS genetic background (SS.5 BN strain) attenuates the development of hypertension and proteinuria in SS.5 BN rats fed a high-salt (HS) diet for 21 days, but the mechanism is unknown. Because the CYP4A genes that produce 20-HETE are located on chromosome 5 and this region has been found to cosegre...

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Section: Discussionsupporting

confidence: 82%

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Williams

Fan

Murphy

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Further studies have indicated that induction of renal P4504A activity with clofibrate improves the pressure natriuresis relationship in Dahl S rats by primarily increasing GFR [29,30]. These contradictory results remain to be explained, and may, in fact, reflect the differences among various animal models [31].…”

Section: Discussionmentioning

confidence: 99%

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

et al. 2005

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Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adenoassociated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV·4A1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV·anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxylases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hypertension by blocking expression of CYP 4A in kidneys.

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“…Furthermore, the effect of fenofibrate to reverse the elevated blood pressure response to angiotensin II infusion is accompanied by decreased oxidative stress and inflammation in the vascular wall (11). PPAR␣ expression is increased in blood vessels of spontaneously hypertensive rats (22), and fenofibrate lowers blood pressure in these rats (11,23). Fenofibrate also prevents cardiac fibrosis in mineralocorticoid-dependent hypertensive rats (24).…”

Section: Effects Of Therapies On Adiponectin and Insulin Resistancementioning

confidence: 99%

Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients

et al. 2006

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OBJECTIVE -Mechanisms underlying fibric acid and angiotensin II type 1 receptor blocker therapies differ. Signaling from peroxisome proliferator-activated receptor ␣ may cross-talk with the angiotensin II system. We investigated vascular and metabolic responses to these therapies either alone or in combination in hypertriglyceridemic hypertensive patients.RESEARCH DESIGN AND METHODS -This was a randomized, double-blind, placebo-controlled, cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty-four patients were given 200 mg fenofibrate and placebo, 200 mg fenofibrate and 16 mg candesartan, or 16 mg candesartan and placebo daily during each treatment period.RESULTS -Fenofibrate, combined therapy, or candesartan therapy significantly reduced blood pressure. However, combined therapy significantly reduced blood pressure more than fenofibrate or candesartan alone (P Ͻ 0.001 by ANOVA). When compared with candesartan, fenofibrate or combined therapy significantly improved the lipoprotein profile. All three treatment arms significantly improved flow-mediated dilator response to hyperemia. Combined therapy significantly decreased plasma malondialdehyde, high-sensitivity C-reactive protein, and soluble CD40L levels relative to baseline measurements. Importantly, these parameters were changed to a greater extent with combined therapy when compared with monotherapy (P Ͻ 0.001, P ϭ 0.002, P ϭ 0.050, and P ϭ 0.032 by ANOVA, respectively). Fenofibrate, combined therapy, and candesartan significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. However, the magnitude of these increases were not significantly different among the three therapies (P ϭ 0.246 and P ϭ 0.153 by ANOVA, respectively).CONCLUSIONS -Fenofibrate combined with candesartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy in hypertriglyceridemic hypertensive patients. Diabetes Care 29:195-201, 2006H ypertriglyceridemia and hypertension are major public health problems that are frequently treated with fenofibrate and angiotensin II type 1 receptor (AT 1 R) blockers (ARBs), respectively. Although the mechanisms of action for these two classes of drugs differ, both classes have beneficial effects on the vasculature. Large-scale clinical studies have demonstrated that micronized fenofibrate, fibric acid, and losartan, an ARB, prevent and retard the progression of coronary heart disease (1,2). Hypertension and coronary heart disease are frequently associated with insulin resistance and disorders of metabolic homeostasis such as obesity and type 2 diabetes. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance and the pathophysiology of diabetes and its vascular complications (3). Indeed, large-scale clinical studies have demonstrated that candesartan reduces the onset of type 2 diabetes (4). The mechanisms of this benefit may relate to the ability of these therapies t...

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Fenofibrate lowers blood pressure in two genetic models of hypertension

Cited by 29 publications

References 18 publications

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients

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