UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to being metabolized by cyclooxygenase and lipooxygenase to prostaglandins and leukotrienes, arachidonic acid can be metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P450 enzymes omega-hydroxylases. As 20-HETE has both pro-hypertensive and antihypertensive actions, inhibitors of 20-HETE synthase may not be useful as antihypertensives in all forms of hypertension. However, 20-HETE synthase inhibitors can have cardioprotective and cerebroprotective effects in animal models, and can inhibit angiogenesis; therefore they may have clinical potential in these areas.
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PMID:Taking the 20-HETE out of the cardiovascular system: the potential of 20-HETE synthesis inhibitors. 1618 90

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 adeno-associated 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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PMID:Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase. 1621 78

This study compared renal hemodynamics, the expression of CYP4A isoforms [the enzymes for 20-hydroxyeicosatetraenoic acid (20-HETE) production], and tubular sodium transporters in male rats fed a high-fat (HF) or control diet for 10 weeks. We also studied the effect of treatment with clofibrate, a CYP4A inducer, on sodium retention and renal function and on CYP4A expression in HF rats. HF rats had higher blood pressure (BP), renal plasma flow, and glomerular filtration rate (GFR), but no significant change in renal vascular resistance. Reverse transcription-polymerase chain reaction analysis showed that CYP4A1 and CYP4A8 expression was significantly decreased in the renal cortex of HF rats. Western blot analysis showed up-regulation of expression of the alpha-subunit of the epithelial sodium channel (alpha-ENaC), the beta-subunit of the epithelial sodium channel (beta-ENaC), sodium/hydrogen exchanger (NHE)-3, and the renal outer medulla K(+) channel (ROMK) in HF rats, whereas expression of the gamma-subunit of the epithelial sodium channel and the alpha1-subunit of Na(+)-K(+)-ATPase remained unchanged. Thus, HF treatment caused the reduction of renal CYP4A1 and CYP4A8 expression, whereas the increases in alpha-ENaC, beta-ENaC, NHE-3, and ROMK expression in renal tubules may have contributed sodium retention and hypertension in HF rats. Furthermore, clofibrate treatment (240 mg/kg/day) caused the decrease of BP and GFR and the attenuation of cumulative sodium balance in HF rats. The attenuation of sodium retention by clofibrate treatment is linked to decreased expression of NHE-3 in renal cortex. Clofibrate induction of CYP4A expression occurred in proximal tubules and in the thick ascending limb of the loop of Henle but not in renal microvessels. This induction correlated with the expression of peroxisome proliferator-activated receptor (PPARalpha) in renal tubules. Therefore, these results suggest that the effects of clofibrate on sodium retention and blood pressure regulation in HF rats may be due to the induction of renal tubular 20-HETE production through the PPARalpha pathway.
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PMID:Induction of renal 20-hydroxyeicosatetraenoic acid by clofibrate attenuates high-fat diet-induced hypertension in rats. 1633 92

The present study examined whether transfer of overlapping regions of chromosome 5 that include (4A+) or exclude the cytochrome P-450 (CYP) 4A genes from the Lewis rat alters the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and/or the development of hypertension in congenic strains of Dahl salt-sensitive (S) rats. The expression of CYP4A protein and the production of 20-HETE in the renal outer medulla was greater in the 4A+ congenic strain than the levels seen in S rats or in overlapping control congenic strains that exclude the CYP4A region. Mean arterial pressure (MAP) rose from 122 +/- 2 to 190 +/- 7 mmHg in S rats and from 119 +/- 2 and 123 +/- 2 to 189 +/- 7 and 187 +/- 3 mmHg in the two control congenic strains fed an 8.0% NaCl diet for 3 wk. In contrast, MAP only increased from 112 +/- 2 to 150 +/- 5 mmHg in the 4A+ congenic strain. Chronic blockade of the formation of 20-HETE with N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide (TS-011; 1 mg/kg bid) restored the salt-sensitive phenotype in the 4A+ congenic strain and MAP rose to 181 +/- 6 mmHg after an 8.0% NaCl dietary challenge. TS-011 had no effect on the development of hypertension in S rats or the two control congenic strains. The pressure-natriuretic and diuretic responses were fivefold greater in the 4A+ congenic strain than in S rats. These results indicate that transfer of the region of chromosome 5 between markers D5Rat108 to D5Rat31 from the Lewis rat into the Dahl S genetic background increases the renal production of 20-HETE, improves pressure-natriuresis and opposes the development of salt-induced hypertension.
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PMID:Characterization of blood pressure and renal function in chromosome 5 congenic strains of Dahl S rats. 1639 43

Alcohol-induced hypertension is well recognized with clear evidence for a direct pressor effect of chronic alcohol consumption provided by a number of intervention studies in humans. In experimental animals, the effect of alcohol on blood pressure is less consistent; however, in Sprague-Dawley rats, alcohol feeding consistently induces a hypertensive response. The mechanism of alcohol-induced hypertension is not clearly understood. Ethanol is known to induce certain cytochrome P450 (CYP) enzymes, particularly the 2E1 isoform, which has been shown to metabolise arachidonic acid (AA) to the 19-hydroxy metabolite (19-HETE), which could have pro-hypertensive activity; CYP4A, by comparison, is the principal AA omega-hydroxylase in the liver. Polyphenolic compounds, such as flavonoids, have been shown to inhibit some CYPs. 2. In this study, we determined the effect of alcohol administration on blood pressure and CYP-dependent AA metabolism in the rat and its possible modulation by red wine polyphenols. 3. Thirty male Sprague-Dawley rats were randomly allocated to three groups, which received water, low-dose ethanol (5% v/v) or red wine (diluted to contain 5% ethanol) for a period of 9 weeks. Bodyweight and blood pressure were measured weekly and 24h urine collected at baseline and every 2 weeks. Animals were killed at 9 weeks and blood and tissue samples were collected. The blood pressure of rats fed with alcohol increased significantly over the period of the study compared with controls (P<0.001). The blood pressure of animals fed 5% alcohol in the form of red wine was not significantly different from controls over the study period. The urinary excretion of 20-HETE did not differ significantly among the treatment groups over the study period and there was no effect of any treatment on the metabolism of AA by renal microsomes. Red wine, but not administration of the relatively low dose of alcohol alone, increased the expression of CYP2E1 protein in the liver and kidney and CYP4A in the kidney. Both red wine and alcohol decreased CYP4A protein levels in the liver compared with controls. 4. Our results suggest that constituents of red wine, possibly polyphenols, can attenuate the alcohol-induced rise in blood pressure in the Sprague-Dawley rat, although this effect does not appear to be mediated by the inhibition of CYP-derived AA metabolism.
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PMID:Effect of alcohol on cytochrome p450 arachidonic acid metabolism and blood pressure in rats and its modulation by red wine polyphenolics. 1648 60

Vascular cytochrome P450 (CYP) 4A enzymes catalyze the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid which participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor and myogenic stimuli. This study was undertaken to investigate the consequences of CYP4A overexpression on blood pressure and endothelial function in rats treated with adenoviral vectors carrying the CYP4A2 construct. Intravenous injection of Adv-CYP4A2 increased blood pressure (from 114+/-1 to 133+/-1 mm Hg, P<0.001), and interlobar renal arteries from these rats displayed decreased relaxing responsiveness to acetylcholine, which was offset by treatment with an inhibitor of CYP4A. Relative to data in control rats, arteries from Adv-CYP4A2-transduced rats produced more 20-HETE (129+/-10 versus 97+/-7 pmol/mg protein, P<0.01) and less nitric oxide (NO; 4.2+/-1.6 versus 8.4+/-1 nmol nitrite+nitrate/mg; P<0.05). They also displayed higher levels of oxidative stress as measured by increased generation of superoxide anion and increased expression of nitrotyrosine and gp91phox. Collectively, these findings demonstrate that augmentation in vascular 20-HETE promotes the development of hypertension and causes endothelial dysfunction, a condition characterized by decreased NO synthesis and/or bioavailability, imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, and enhanced endothelial activation.
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PMID:Endothelial dysfunction and hypertension in rats transduced with CYP4A2 adenovirus. 1661 11

AA (arachidonic acid) hydroxylation to 20-HETE (20-hydroxyeicosatetraenoic acid) influences renal vascular and tubular function. To identify the CYP (cytochrome P450) isoforms catalysing this reaction in the mouse kidney, we analysed the substrate specificity of Cyp4a10, 4a12a, 4a12b and 4a14 and determined sex- and strain-specific expressions. All recombinant enzymes showed high lauric acid hydroxylase activities. Cyp4a12a and Cyp4a12b efficiently hydroxylated AA to 20-HETE with V(max) values of approx. 10 nmol x nmol(-1) x min(-1) and K(m) values of 20-40 microM. 20-Carboxyeicosatetraenoic acid occurred as a secondary metabolite. AA hydroxylase activities were approx. 25-75-fold lower with Cyp4a10 and not detectable with Cyp4a14. Cyp4a12a and Cyp4a12b also efficiently converted EPA (eicosapentaenoic acid) into 19/20-OH- and 17,18-epoxy-EPA. In male mice, renal microsomal AA hydroxylase activities ranged between approx. 100 (NMRI), 45-55 (FVB/N, 129 Sv/J and Balb/c) and 25 pmol x min(-1) x mg(-1) (C57BL/6). The activities correlated with differences in Cyp4a12a protein and mRNA levels. Treatment with 5alpha-dihydrotestosterone induced both 20-HETE production and Cyp4a12a expression more than 4-fold in male C57BL/6 mice. All female mice showed low AA hydroxylase activities (15-25 pmol x min(-1) x mg(-1)) and very low Cyp4a12a mRNA and protein levels, but high Cyp4a10 and Cyp4a14 expression. Renal Cyp4a12b mRNA expression was almost undetectable in both sexes of all strains. Thus Cyp4a12a is the predominant 20-HETE synthase in the mouse kidney. Cyp4a12a expression determines the sex- and strain-specific differences in 20-HETE generation and may explain sex and strain differences in the susceptibility to hypertension and target organ damage.
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PMID:Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation. 1711 42

Chronic arsenic exposure is a known risk factor for cardiovascular disease and has a strong correlation with hypertension. Oxidative stress may be one of the major contributors to arsenic-induced hypertension. To investigate the antioxidative and CYP systems through which inorganic arsenic compounds may contribute to blood pressure elevation in rats, we administered 50ppm arsenic (as arsenite and arsenate) in drinking water to Wistar rats for 200 successive days. Systolic blood pressure was determined every 20 days, and blood samples and tissues were collected at each time point for biological analysis. Compared to the control group, weight gain in the arsenic-exposed animals was slightly but significantly lower, whereas the relative weights of the various tissues was higher. Blood pressure was elevated until day 80 in both arsenic groups followed by a time-dependent change in the antioxidative enzyme system. The hypertensive effect remained until day 200 for arsenite when the change by arsenate was minimized. Patterns of antioxidative enzyme change differed between arsenite and arsenate. However, the most common marker of hypertension, the angiotensin-converting enzyme, showed no significant change in either arsenic group. CYP4A was highly expressed in both arsenic groups, particularly in the arsenite group. These results indicate that low but chronic arsenic exposure might cause elevated blood pressure and antioxidative interference. Furthermore, CYP4A might be more important than ACE in contributing to arsenic-induced hypertension.
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PMID:Lifelong inorganic arsenic compounds consumption affected blood pressure in rats. 1768 91

Nitric oxide (NO), generated from L-arginine by endothelial nitric oxide synthase (eNOS), is a key endothelial-derived factor whose bioavailability is essential to the normal function of the endothelium. Endothelium dysfunction is characterized by loss of NO bioavailability because of either reduced formation or accelerated degradation of NO. We have recently reported that overexpression of vascular cytochrome P-450 (CYP) 4A in rats caused hypertension and endothelial dysfunction driven by increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a major vasoconstrictor eicosanoid in the microcirculation. To further explore cellular mechanisms underlying CYP4A-20-HETE-driven endothelial dysfunction, the interactions between 20-HETE and the eNOS-NO system were examined in vitro. Addition of 20-HETE to endothelial cells at concentrations as low as 1 nM reduced calcium ionophore-stimulated NO release by 50%. This reduction was associated with a significant increase in superoxide production. The increase in superoxide in response to 20-HETE was prevented by N(G)-nitro-L-arginine methyl ester, suggesting that uncoupled eNOS is a source of this superoxide. The response to 20-HETE was specific in that 19-HETE did not affect NO or superoxide production, and, in fact, the response to 20-HETE could be competitively antagonized by 19(R)-HETE. 20-HETE had no effect on phosphorylation of eNOS protein at serine-1179 or threonine-497 following addition of calcium ionophore; however, 20-HETE inhibited association of eNOS with 90-kDa heat shock protein (HSP90). In vivo, impaired acetylcholine-induced relaxation in arteries overexpressing CYP4A was associated with a marked reduction in the levels of phosphorylated vasodilator-stimulated phosphoprotein, an indicator of bioactive NO, that was reversed by inhibition of 20-HETE synthesis or action. Because association of HSP90 with eNOS is critical for eNOS activation and coupled enzyme activity, inhibition of this association by 20-HETE may underlie the mechanism, at least in part, by which increased CYP4A expression and activity cause endothelial dysfunction.
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PMID:20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling. 1815 92

Pepsin-digested soy protein hydrolysate (SPH) has been reported to be responsible for many of the physiological benefits associated with soy protein consumption. In the present study, we investigated the effects of SPH with angiotensin-converting enzyme (ACE) inhibitory potential on blood pressure and renal injuries in rats with N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertension. Rats were fed a diet containing L-NAME (50 mg/kg body weight) with or without SPH (at 1%, 3%, or 5%) for 6 weeks. We found that ingestion of SPH ameliorated the development of hypertension during the 6-week experimental period. SPH was also found to ameliorate renal function by decreasing urinary protein excretion and elevating the creatinine clearance rate. The levels of kidney ACE activity, malonaldehyde, tumor necrosis factor-a and plasminogen activator inhibitor-1, and the expression of CYP4A decreased in the 5% SPH group. Consumption of 5% SPH also ameliorated renal damage according to the histopathological analysis. These findings suggest that SPH might ameliorate the elevation of blood pressure and show renoprotective effects in nitric oxide (NO)-deficient rats, and one possible mechanism might be mediation via its ACE inhibitory activity.
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PMID:Renoprotective effects of soy protein hydrolysates in N(omega)-nitro-L-arginine methyl ester hydrochloride-induced hypertensive rats. 1895 19

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