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

Cells were isolated from the outer medulla of the rabbit kidney, primarily from the thick ascending limb of Henle's loop (mTALH). These mTALH cells are heavily invested with a cytochrome P450-linked monooxygenase that represents the third pathway by which arachidonic acid is metabolized. After cell separation, approximately 80% of the cells proved to be mTALH in origin, based on electron microscopic criteria and immunofluorescent localization of Tamm-Horsfall protein, a specific marker for mTALH cells. The specific activity of alkaline phosphatase, a marker for proximal tubular cells, decreased threefold after separation of mTALH cells from outer medullary cells, associated with a fourfold increase in the capacity of the separated mTALH cells to metabolize arachidonic acid. Incubation of mTALH cells with 14C-arachidonic acid resulted in formation of oxygenated metabolites, identified as two peaks (P1 and P2), which accounted for 30 to 40% of the recovered radioactivity. Formation of prostaglandin E2 and F2 alpha accounted for only 3 to 5%. The chromatographic retention times of P1 and P2 were different from products of lipoxygenases. An inhibitor of cytochrome P450-dependent enzymes, SKF-525A (50 microM), reduced product formation by mTALH cells by more than 70%, while induction of cytochrome P450 increased product formation. Formation of P1 and P2 by cell-free homogenates of mTALH was totally dependent on the presence of nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), which suggests a NADPH-dependent cytochrome P450-linked monooxygenase pathway. Vasopressin and calcitonin (10(-10) M to 10(-7) M) stimulated release of arachidonic acid metabolites from mTALH cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension
PMID:Renal arachidonic acid metabolism. The third pathway. 298 23

Adrenal function was assessed in control rats and in rats treated for 2 and 4 weeks with 17 alpha-methylandrostenediol (MAD; 17 alpha-methyl-5-androstene-3 beta-diol), a synthetic androgen known to produce hypertensive cardiovascular disease. In both groups and at both time periods, a circadian rhythm of blood corticosteroid concentrations was observed. The high point for serum corticosterone (B), 18-hydroxy-11-deoxycorticosterone (18-hydroxy-DOC), and 11-deoxycorticosterone (DOC) concentrations occurred at the beginning of the dark period (1800 hours), and the low point occurred at the onset of the light period (0600 hours). Serum concentrations of DOC were always found to be higher in MAD-treated rats as compared with controls. The serum concentrations of B and 18-hydroxy-DOC were lower than control values at 1800 hours but higher than control concentrations at 0600 hours. The in vitro 11 beta- and 18-hydroxylation of DOC was markedly reduced with MAD treatment. In contrast, cholesterol side-chain cleavage activity was higher in animals treated with MAD. These in vitro findings correlated with spectral studies that showed a decreased binding of DOC to cytochrome P450(11) beta and increased binding of cholesterol to cytochrome P450scc. These studies suggest that MAD treatment selectively decreases 11 beta- and 18-hydroxylation in adrenal mitochondria, and this results in an increased serum concentration of DOC, a hypertensinogenic steroid. This effect of MAD on peripheral serum DOC concentration is most readily observed in quiescent animals at the high point of the circadian rhythm.
Hypertension
PMID:Peripheral serum corticosteroid concentrations in relation to the rat adrenal cortical circadian rhythm in androgen-induced hypertension. 741 67

Excess dietary salt induces a cytochrome P450 arachidonic acid epoxygenase isoform in rat kidneys (Capdevila, J. H., S. Wei, J. Yang, A. Karara, H. R. Jacobson, J. R. Falck, F. P. Guengerich, and R. N. Dubois. 1992. J. Biol. Chem. 267:21720-21726). Treatment of rats on a high salt diet with the epoxygenase inhibitor, clotrimazole, produces significant increases in mean arterial blood pressure (122 +/- 2 and 145 +/- 4 mmHg for salt and salt- and clotrimazole-treated rats, respectively). The salt- and clotrimazole-dependent hypertension is accompanied by reductions in the urinary excretion of epoxygenase metabolites and by a selective inhibition of the renal microsomal epoxygenase reaction. The prohypertensive effects of clotrimazole are readily reversed when either the salt or clotrimazole treatment is discontinued. The indication that a salt-inducible renal epoxygenase protects against hypertension, are supported by studies with the Dahl rat model of genetic salt-sensitive hypertension. Dahl resistant animals responded to excess dietary salt by inducing the activity of their kidney microsomal epoxygenase(s) (0.102 +/- 0.01 and 0.240 +/- 0.04 nmol of products formed/min per mg of microsomal protein for control and salt-treated rats, respectively). Despite severe hypertension during excess dietary salt intake (200 +/- 20 mmHg), Dahl salt-sensitive rats demonstrated no increase in renal epoxygenase activity. These studies indicate that acquired or inherited abnormalities in renal epoxygenase activities and/or regulation can be related to salt-sensitive hypertension in rodents. Studies on the human renal epoxygenase and its relationship to salt hypertension may prove useful.
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PMID:Experimental and/or genetically controlled alterations of the renal microsomal cytochrome P450 epoxygenase induce hypertension in rats fed a high salt diet. 798 98

Steroid 11 beta-hydroxylase deficiency is the second most frequent cause of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol. About two thirds of patients with this disorder have hypertension, presumably due to elevated levels of deoxycorticosterone or other metabolites. Signs of androgen excess also often are prominent. This disease is caused by mutations in the CYP11B1 gene, which encodes a mitochondrial cytochrome P450 enzyme. The main treatment is glucocorticoid replacement, which suppresses excessive secretion of mineralocorticoids and androgens by the adrenal cortex.
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PMID:Steroid 11 beta-hydroxylase deficiency and related disorders. 807 Apr 25

We previously reported a significant derangement of intracellular free calcium ion concentration in the isolated perfused kidney of adult spontaneously hypertensive rat (SHR) (J. Biol. Chem. 267, 3637-3643, 1992). In order to investigate whether an abnormality in intracellular free calcium or another ion precedes the development of elevated blood pressure in SHR, we have now compared intracellular free Ca2+, Na+ and pH, using 31P, 19F, and triple quantum-filtered (TQ) 23Na NMR, in perfused kidneys from prehypertensive young SHR and normotensive young Wistar-Kyoto (WKY) rats (5-6 weeks old) which showed no significant difference in blood pressure (B.P. = 120 +/- 5 mmHg and 115 +/- 3 mmHg, for SHR and WKY rats, respectively). Like the adult kidney, no significant differences in intracellular ATP concentration or intracellular pH were found between young prehypertensive SHR and normotensive WKY rat kidneys. The TQ 23Na NMR signal was 47% higher in the SHR kidney, but, due to biological variability and measurement errors, this difference could not be shown to be statistically significant. However, a significant (40%; P < 0.05) increase was found in O2 consumption rate, a measure of the Na+/K(+)-ATPase activity, of the young prehypertensive SHR kidney in comparison to the age-matched WKY rat kidney (7.25 +/- 0.75 for SHR vs. 5.17 +/- 0.18 mumol O2/min g for WKY rat, n = 6). Furthermore, a highly significant (92%; P < 0.02) increase in intracellular free Ca2+ concentration was observed in kidneys from young SHR that had not yet developed high blood pressure in comparison to the kidneys from young normotensive WKY rats (648 +/- 76 nM vs. 339 +/- 39 nM, n = 4), despite the fact that there was no significant difference in blood pressure. Increased intracellular free Ca2+ thus appears to be part of a primary defect, in the prehypertensive young SHR kidney, which may, by way of increased release of arachidonic acid, and subsequent increased production of vasoconstricting arachidonic acid metabolites via the cytochrome P450 pathway, induce elevated blood pressure in the adult SHR.
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PMID:Multinuclear NMR studies of intracellular cations in the prehypertensive rat kidney. 815 43

We investigated the age-related changes of renal cytochrome P450-dependent arachidonic acid metabolism in 3-, 5-, 7-, 9-, 11-, 13- and 20-week-old male Dahl salt-sensitive (DS) and -resistant (DR) rats on a low sodium diet (0.3% NaCl). NADPH-dependent arachidonic acid metabolism was separated and measured by a radio-HPLC system. The formation of 19-hydroxyeicosatetraenoic acid (HETE), 20 HETE, 1,20-dioic acid, epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acid (DHET) was age dependent in both DS and DR rats. omega-Hydroxylase (20-HETE and 1,20-dioic acid formation) and (omega-1)-hydroxylase (19-HETE formation) were increased from 3 to 5 weeks age, then decreased with aging in DR rats. Whilst omega/(omega-1)-hydroxylase activities were increased from 3- to 9-week-old rats, they decreased with aging in DS rats. omega/(omega-1)-Hydroxylase activities were higher in 3-5-week-old DR than DS rats. Epoxygenase activities (EETs and DHET formations) were highest in 3-week-old DS and DR rats, and showed no significant differences between two strains of rats at any ages tested. Renal cytochrome P450-dependent arachidonic acid metabolites have a wide and contrasting spectrum of biological and renal effects, and their relative rates of production may influence not only renal hemodynamics but also pro- and antihypertensive mechanisms of hypertension in Dahl rats.
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PMID:Effect of aging on renal cytochrome P450-dependent arachidonic acid metabolism in Dahl rats. 835 95

The endothelium regulates vascular tone by releasing factors involved in relaxation and contraction, in coagulation and thrombus formation, and in growth inhibition and stimulation. Endothelium-dependent relaxations are elicited by transmitters, hormones, platelet substances, and the coagulation system, and by physical stimuli such as the shear stress from circulating blood. They are mediated by the endothelium-derived relaxing factor, recently identified as nitric oxide, which causes vasodilation and platelet deactivation. Other proposed endothelium-derived relaxing factors include a hyperpolarizing factor, lipooxygenase products, and the cytochrome P450 pathway. Endothelium-derived contracting factors are produced by the cyclooxygenase pathway and by endothelial cells, which produce the peptide endothelin-1, a potent vasoconstrictor that under normal conditions circulates at low levels. The endothelium produces both growth inhibitors--normally dominant--and growth stimuli. Denuded or dysfunctional endothelium leads to a proliferative response and intimal hyperplasia in the vessel wall; moreover, platelets adhere to the site and release potent growth factors. Endothelial dysfunction has numerous causes: Aging is associated with increased formation of contracting factor and decreased relaxing factor; denudation, such as by coronary angioplasty, impairs the capacities of regenerated endothelial cells; oxidized low-density lipoproteins and hypercholesterolemia interfere with nitric oxide production; hypertension morphologically and functionally alters the endothelium; and atherosclerosis markedly attenuates some endothelium-dependent relaxations. For patients with coronary bypass grafts, differences in endothelium-derived vasoactive factors between the internal mammary artery and the saphenous vein may be important determinants of graft function, with the mammary artery having more pronounced relaxations than the saphenous vein and thus a higher patency rate.
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PMID:Endothelial regulation of vascular tone and growth. 839 13

Ten years ago, the term "oxidative stress" (sigma -O2) was created to define oxidative damage inflicted to the organism. This definition brings together processes involving reactive oxygen species production and action such as free radical production during univalent reduction of oxygen within mitochondria, activation of NADPH-dependent oxidase system on the membrane surface of neutrophils, flavoprotein-catalyzed redox cycling of xenobiotics and exposure to chemical and physical agents in the environment. Since the discovery of the nitric oxide biosynthetic pathway, the deleterious effects of uncontrolled nitric oxide generation are generally classified as oxidative stress. Indeed, products of the reaction of NO and superoxide lead to oxidants such as peroxinitrite, nitrogen dioxide and hydroxyl radical, which are involved in mechanisms of cell-mediated immune reactions and defence of the intracellular environment against microbiol invasion. However NO can also regulate many biological reactions and signal transduction pathways that lead to a variety of physiological responses such as blood pressure, neurotransmission, platelet aggregation, endothelin generation or smooth muscle cell proliferation. Then the uncontrolled NO production can lead to a variety of physiological and pathophysiological responses similar to a Nitric Oxide Stress: activation of guanylate cyclase and production of cGMP: overstimulation of the inducible L-arginine to L-citrulline and NO pathway by bactericidal endotoxins and cytokines has been shown to promote undesired increases in vasodilatation, which may account for hypotension in septic shock and cytokine therapy. stimulation of auto-ADP-ribosylation and modification of SH-groups of glyceraldehyde-3-phosphate dehydrogenase in a cGMP-independent mechanism: by this way, NO in excess can strongly inhibits this important glycolytic enzyme and reduce the cellular energy production. inhibition of ribonucleotide reductase: extensive inhibition of this key enzyme in DNA synthesis in the presence of large amounts of NO could lead to important antiproliferative effects; inhibition of cytochrome P450-dependent metabolism: in Kupffer cells and hepatocytes, LPS-induced overproduction of NO has been shown to inhibit cytochrome P450-dependent metabolism and to mediate the suppression of hepatic metabolism. Moreover, NO synthetized in the peripheral nervous system is known to mediate nonadrenergic noncholinergic (NANC) neurotransmission. Overstimulation of NO synthases might therefore contribute to pathophysiological states such as: gastrointestinal motility, reflux oesophagitis, asthma, adult respiratory distress syndrome (ARDS) and chronic pulmonary artery hypertension. To these NO-mediated biological functions, one could add the biological effects of NO-derivatives such as N-nitrosocompounds, which act as carcinogenic agents, or C-nitrosocompound which were recently used as "zinc-ejecting" agents to inhibit HIV-1 infectivity of human T-lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Does nitric oxide stress exist?]. 852 Oct 87

Differences in the renal metabolism of arachidonic acid by cytochrome P450 have been reported in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rats, but the contribution of this system to the development of hypertension is unclear. The present study compared renal P450 activity and blood pressure in SHR and Brown-Norway rats (BN) under control conditions and in response to an elevation in sodium intake; genetic linkage analysis was performed in an F2 population (n=219) derived from these strains. Basal renal P4504A enzyme activity measured by conversion of [C(14)]arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) was significantly greater in the kidneys of adult SHR (n=7) than of BN (n=8) (82 +/- 7 versus 60 +/- 5 pmol/min per milligram protein). Renal 20-HETE production fell 45 percent in SHR and 22 percent in BN in which salt intake was elevated by drinking of saline instead of water for 2 weeks. Mean arterial pressure averaged 157 +/- 3mm Hg in SHR (n = 9) and 100 +/- 2 mm Hg in BN fed a normal salt diet, and it rose to 170 +/- 7 mm Hg (P<.05) in SHR and fell to 90 +/- 3 mm Hg (P<.05) in BN (n=8) after sodium intake was elevated. A polymorphic marker, D5Rjr1, that spanned a repeated element in the P4504A gene on chromosome 5, where all three P4504A isoforms are located, was used for genotyping of the F2 population. The P4504A genotype did not cosegregate with baseline mean arterial pressure in the F2 population; however, significant linkage was observed with the change in mean arterial pressure after sodium intake of the rats was elevated. The degree of linkage differed in male and female rats, and the highest LOD score (3.6) was observed in male F2 rats with a BN grandfather. These findings suggest that the difference in renal P450 activity in SHR and BN does not contribute to the development of hypertension in this F2 population, but it may play some role in determining the blood pressure response to an elevation in salt intake.
Hypertension 1996 Jun
PMID:Renal cytochrome P4504A activity and salt sensitivity in spontaneously hypertensive rats. 864 44

Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life. To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects received a single 100 mg oral dose of losartan before and during phenobarbital administration (100 mg/day for 16 days), and five subjects received losartan before and during placebo. Urinary excretion of 6-beta-hydroxycortisol (relative to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome P450 induction. The geometric mean area under the plasma concentration-time curve ratios (with/without phenobarbital and 90% confidence intervals) for losartan and its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820), respectively, indicating that phenobarbital treatment significantly but to a clinically minor extent reduced plasma concentrations of losartan and E-3174 (p<0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6-beta-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital group (p < 0.001) and did not change appreciably in the placebo group.
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PMID:Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. 865 89


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