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

Cytochrome P450-dependent metabolites of arachidonic acid (AA) are increased in the kidneys of spontaneously hypertensive rats (SHR) as compared to control rats (WKY) in the period of rapid elevation of blood pressure (BP) from 5 to 13 weeks. We treated rats with stannous chloride (SnCl2) (10 mg/100 g body weight/day for 4 days) to decrease selectively renal cytochrome P450 content through increasing renal heme oxygenase activity. A decrease in renal cytochrome P450-dependent AA metabolites was associated with decreased BP and increased urinary Na+ excretion in 7- but not in 20-week-old SHR rats. Chronic treatment with SnCl2 (10 mg/100 g body weight twice a week) from 5 to 20 weeks prevented the elevation of BP in SHR rats. Further, the antihypertensive effects of tin persisted for 7 weeks beyond its discontinuation. BP in WKY rats was unaffected by tin. Both the acute and chronic treatment with tin are the first studies to demonstrate amelioration of hypertension in SHR by an intervention which is targeted at a single enzyme system.
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PMID:Effect of acute and chronic treatment of tin on blood pressure in spontaneously hypertensive rats. 141 49

Cytochrome P450 represents the third metabolic pathway of arachidonic acid giving rise to several biologically active compounds, such as 19-HETE, 20-HETE and EETs and their corresponding DHETs. The kidney is the rich source of these metabolites which have some important biologic actions within the kidney. These metabolites have a wide and contrasting spectrum of biological and renal effects, from vasodilation to vasoconstriction and from inhibition to stimulation of Na-K-ATPase, their relative production rates may influence not only renal hemodynamics but also pro- and anti-hypertensive mechanisms of hypertension. There is increasing evidence that the abnormality of these metabolites in animal models of hypertension. However, sufficient evidence of the physiological and pathophysiological roles of hypertension in man is still lacking.
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PMID:Roles of renal cytochrome P450-dependent arachidonic acid metabolites in hypertension. 141 50

Cytochrome P450 content and activities are increased in the kidneys of spontaneously hypertensive rats (SHR) as compared with those of normotensive, Wistar-Kyoto (WKY), control rats during the period of rapid elevation of blood pressure. We studied the effect of heme arginate, a potent inducer of heme oxygenase (EC 1.14.99.3), on microsomal cytochrome P450 levels and activities and blood pressure in SHR at 7 wk of age. Administration of heme arginate (15 mg/kg body weight for 4 d) resulted in a marked decrease in blood pressure from 156.3 +/- 4.7 to 129.8 +/- 4.5 mm Hg (P less than 0.001), whereas blood pressure in SHR receiving the vehicle control was not affected. The blood pressure of age-matched WKY was not affected by heme arginate. Heme oxygenase activity increased in both hepatic and renal microsomes of SHR and WKY by two- to four-fold after treatment with heme arginate. Maximal increase of heme oxygenase mRNA occurred 5-7 h after the last injection of heme arginate and returned to control levels after 24 h. The increase in heme oxygenase activity was associated with a parallel decrease in cytochrome P450 content and in the activity of cytochrome P450 omega/omega-1 arachidonate hydroxylases in kidneys of SHR. It is postulated that heme arginate treatment resulted in induction of heme oxygenase which consequently led to a diminution of cytochrome P450, especially the arachidonate omega/omega-1 hydroxylases leading to a marked decrease in 19-hydroxyeicosatetraenoic acid (HETE) and 20-HETE. The effect of heme arginate on blood pressure may be mediated via these biochemical events inasmuch as both 19-HETE and 20-HETE produced by the kidney may promote hypertension by causing vasoconstriction and sodium retention.
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PMID:Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats. 211 25

Cytochrome P450(11 beta) is deeply involved in the final steps of biosynthesis of mineralocorticoids. This paper deals with following issues about this enzyme. (1) The structure and function of the enzymes of various animal species are discussed. By making alignment of amino acid sequences of the enzymes, we identified peptide domains essential for the enzyme actions such as a putative steroid binding domain and a heme binding region. Estimates of molecular similarity among the P450(11 beta) family enzymes suggested that the enzymes having both 11 beta-hydroxylation activity and aldosterone (ALDO) synthetic activity of certain animals such as frog, cattle and pig are more similar to the ALDO synthases of the other animals, such as rat, mouse and human, than the 11 beta-hydroxylases of these animals. (2) The molecular nature of the P450(11 beta) family enzymes of genetically hypertensive rats as well as adrenal regeneration hypertension (ARH) rats is examined. (i) Mutation was found in the P450(11 beta) gene of Dahl's salt-resistant normotensive rat. Steroidogenic activity expressed by the mutated gene accounted well for abnormal plasma levels of steroid hormones in this rat. (ii) 11 beta-, 18- and 19-Hydroxylation activities of adrenal mitochondrial prepared from spontaneously hypertensive rat (SHR), Wistar-Kyoto rat (WKY), and stroke-prone (SP)-SHR were not significantly different from each other. Levels of mRNA of ALDO synthase in adrenal glands of 50-week-old SHR was significantly lower than those of 10-week-old SHR, WKY and SHR-SP. (iii) No significant difference in 19-hydroxylation activity was found between adrenal mitochondria prepared from ARH rat and those from control rat. The level of message of ALDO synthase was lower in adrenal glands of ARH rat.
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PMID:Cytochrome P450(11 beta): structure-function relationship of the enzyme and its involvement in blood pressure regulation. 762 22

Cytochrome P450 (P450)-dependent arachidonic acid metabolites may act as mediators in the regulation of vascular tone and renal function. We studied arachidonic acid hydroxylase activities in renal microsomes from normotensive NMRI mice, desoxycorticosterone acetate (DOCA)-salt hypertensive mice, and DOCA-salt mice treated with either lovastatin or bezafibrate, both of which improve hemodynamics in this model. Control renal microsomes had arachidonic acid hydroxylase activities of 175+/-12 pmol. min(-1). mg(-1). The metabolites formed were 20- and 19-hydroxyarachidonic acid, representing approximately 80% and approximately 20% of the total hydroxylation. Treatment with DOCA-salt resulted in significantly decreased hydroxylase activities (to 84+/-4 pmol. min(-1). mg(-1)) of the total microsomal P450 content and a decrease in immunodetectable Cyp4a proteins. Lovastatin had no effect on these variables, whereas bezafibrate increased arachidonic acid hydroxylase activities to 163+/-12 pmol. min(-1). mg(-1). In situ hybridization with probes for Cyp4a-10, 12, and 14 revealed that Cyp4a-14 was the P450 isoform most strongly induced by bezafibrate. The expression was concentrated in the cortical medullary junction and was localized predominantly in the proximal tubules. In conclusion, these results suggest that the capacity to produce 20-hydroxyarachidonic acid is impaired in the kidneys of DOCA-salt hypertensive mice. Furthermore, bezafibrate may ameliorate hemodynamics in this model by restoring P450-dependent arachidonic acid hydroxylase activities. Lovastatin, on the other hand, exerts its effects via P450-independent mechanisms.
Hypertension 2000 Oct
PMID:Cytochrome P450-dependent renal arachidonic acid metabolism in desoxycorticosterone acetate-salt hypertensive mice. 1104 Feb 44

1. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP)-dependent pathways to epoxyeicosatrienoic acids (EET) and 20-hydroxyeicosatetraenoic acid (20-HETE) in the kidney and the peripheral vasculature. 2. The present short review summarizes the renal and cardiovascular actions of these important mediators. 3. Epoxyeicosatrienoic acids are vasodilators produced by the endothelium that hyperpolarize vascular smooth muscle (VSM) cells by opening Ca2+-activated K+ (KCa) channels. 20-Hydroxyeicosatetraenoic acid is a vasoconstrictor that inhibits the opening of KCa channels in VSM cells. Cytochrome P450 4A inhibitors block the myogenic response of small arterioles to elevations in transmural pressure and autoregulation of renal and cerebral blood flow in vivo. Cytochrome P450 4A blockers also attenuate the vasoconstrictor response to elevations in tissue PO2, suggesting that this system may serve as a vascular oxygen sensor. Nitric oxide and carbon monoxide inhibit the formation of 20-HETE and a fall in 20-HETE levels contributes to the activation of KCa channels in VSM cells and the vasodilator response to these gaseous mediators. 20-Hydroxyeicosatetraenoic acid also mediates the inhibitory actions of peptide hormones on sodium transport in the kidney and the mitogenic effects of growth factors in VSM and mesangial cells. A deficiency in the renal production of 20-HETE is associated with the development of hypertension in Dahl salt-sensitive rats. 4. In summary, the available evidence indicates that CYP metabolites of AA play a central role in the regulation of renal, pulmonary and vascular function and that abnormalities in this system may contribute to the pathogenesis of cardiovascular diseases.
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PMID:Renal and cardiovascular actions of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids. 1107 Dec 99

Cytochrome P450 (CYP) enzymes participate in the metabolism of a variety of naturally occurring and foreign compounds by reactions requiring NADPH and O2. The diversity of reactions catalyzed and its extensive substrate specificity render CYP enzymes as one of the most versatile known catalysts. Individual members of the CYP superfamily are expressed in almost every cell type in the body. As compared to hepatic enzymes, the regulation of human extrahepatic CYPs has not been so well studied. In general, the levels of some hepatic CYP enzymes are depressed by diseases, causing potential and documented impairment of drug clearence and clinical drug toxicity. However, modulation of CYPs is enzyme selective and this selectivity differs in different diseases. This article reviews some basic concepts about CYP and its regulation in some disease states such as hypertension, diabetes, obesity and hepatic, infectious and inflammatory diseases.
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PMID:[Cytochrome P450 activity and its alteration in different diseases]. 1537 59

Cytochrome P450-catalyzed metabolism of arachidonic acid is an important pathway for the formation of paracrine and autocrine mediators of numerous biological effects. The omega-hydroxylation of arachidonic acid generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in numerous tissues, particularly the vasculature and kidney tubules. Members of the cytochrome P450 4A and 4F families are the major omega-hydroxylases, and the substrate selectivity and regulation of these enzymes has been the subject of numerous studies. Altered expression and function of arachidonic acid omega-hydroxylases in models of hypertension, diabetes, inflammation, and pregnancy suggest that 20-HETE may be involved in the pathogenesis of these diseases. Our understanding of the biological significance of 20-HETE has been greatly aided by the development and characterization of selective and potent inhibitors of the arachidonic acid omega-hydroxylases. This review discusses the substrate selectivity and expression of arachidonic acid omega-hydroxylases, regulation of these enzymes during disease, and the application of enzyme inhibitors to study 20-HETE function.
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PMID:Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation. 1582 83

Angiotensin II and the arachidonic acid metabolite derived via cytochrome P450 20-hydroxyeicostetraenoic acid promote vasoconstriction and vascular smooth muscle cell (VSMC) proliferation. This study was conducted to determine if 20-hydroxyeicostetraenoic acid contributes to angiotensin II-induced neointimal formation in balloon-injured rat carotid artery. In anesthetized rats, the drugs were infused into the clamped segment of the injured right common carotid artery for 60 minutes. The drug solution and catheter were withdrawn, the common carotid artery was ligated, and blood flow was restored. Exposure of the injured artery to angiotensin II (200 nmol/L) or arachidonic acid (10 micromol/L) increased neointimal thickening at day 14 (intima/media ratio 0.71+/-0.14 with vehicle versus 1.65+/-0.10 with angiotensin II or 1.31+/-0.13 with arachidonic acid; P<0.05). Cytochrome P450 4A1 antisense, but not scrambled, oligodeoxynucleotide (100 nmol/L) reduced angiotensin II-induced or arachidonic acid-induced neointimal thickening (intima/media ratio 0.90+/-0.07 for angiotensin II and 0.95+/-0.06 for arachidonic acid). 20-hydroxyeicostetraenoic acid (0.5 micromol/L) also increased neointimal thickening of injured artery (intima/media ratio 1.15+/-0.03); this was not altered by cytochrome P450 4A1 antisense oligodeoxynucleotide. Angiotensin II, arachidonic acid, and 20-hydroxyeicostetraenoic acid also induced the expression of cytochrome P450 4A and increased the number of CD45-positive cells; the latter effect of angiotensin II and arachidonic acid, but not 20-hydroxyeicostetraenoic acid, was diminished by cytochrome P450 4A1 antisense oligodeoxynucleotide. These data suggest that arachidonic acid metabolites derived via cytochrome P450 4A, most likely 20-hydroxyeicostetraenoic acid, mediate angiotensin II-induced neointimal thickening in injured rat carotid artery.
Hypertension 2005 Jun
PMID:Contribution of arachidonic acid metabolites derived via cytochrome P4504A to angiotensin II-induced neointimal growth. 1589 59

During pregnancy, maternal vascular function is altered through mechanisms that remain unclear. Progesterone synthesis and metabolism are also increased. Progesterone metabolites are potent endogenous ligands for the pregnane X receptor (PXR), a nuclear receptor that induces the expression of hepatic cytochrome P450 enzymes. Cytochrome P450 enzymes located in the vasculature can metabolize arachidonic acid to produce epoxyeicosatrienoic acids, known vasodilators. We hypothesized that PXR is present in vascular tissue and contributes to vascular adaptations to pregnancy. PXR mRNA was detected in mouse mesenteric arteries by quantitative RT-PCR. Constrictor and relaxation responses in wildtype (PXR(+/+)) and PXR-deficient (PXR(-/-)) mice were compared by wire myography. Relative to nonpregnant controls, arteries from pregnant PXR(+/+) mice had reduced sensitivity to phenylephrine-induced constriction (EC(50): 2.77+/-0.32 mumol/L versus 5.13+/-0.36 mumol/L; P=0.009) and enhanced maximal vasorelaxation to bradykinin (26+/-3% versus 44+/-16%; P=0.013). However, these pregnancy adaptations were absent in PXR(-/-) mice. We also hypothesized that PXR is activated by progesterone metabolites. Treatment of PXR(+/+) and PXR(-/-) nonpregnant mice with 5beta-dihydroprogesterone for 7 days enhanced endothelium-dependent relaxation in only the PXR(+/+) mice, similarly to that seen in pregnancy. In treated mice, inhibition of cytochrome P450 epoxygenase activity with N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide attenuated vasorelaxation in arteries from PXR(+/+) but not PXR(-/-) mice. We conclude that PXR contributes to the development of vascular adaptations to pregnancy, likely in response to activation by progesterone metabolites, and that PXR-dependent increases in vasorelaxation may be because of activation of cytochrome P450 epoxygenases.
Hypertension 2007 Feb
PMID:Regulation of vascular tone during pregnancy: a novel role for the pregnane X receptor. 1715 84


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