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)

Cytochrome P45011B1 (11 beta-hydroxylase) was detected in the brain of male rats by in situ hybridization methods. Normal Sprague-Dawley rats were compared to the transgenic strain TGR(mRen2)27, characterized by the expression of the murine Ren-2d renin gene and the development of severe hypertension. Specific riboprobes were generated by in the vitro transcription of a 152 base-pair long cDNA template 35S-labeled riboprobes were hybridized to cryostat sections from adrenal glands and from two different levels of the brain using standard protocols and varying washing conditions. After exposure of the radiolabeled sections to X-ray film, the signals were quantified and compared. Following autoradiography and counterstaining, cytochrome P45011B1 mRNA was clearly localized in the zona fasciculata/reticularis of the adrenal cortex and in distinct layers of the cerebral cortex. High signal densities were obtained in the layers II-IV of the neocortex and in the layer II of the piriform cortex, although the concentrations of cytochrome P45011B1 mRNA were remarkably lower in the central nervous system as compared to adrenal glands. As revealed by the semi-quantitative analysis, there was a slight increase in adrenal 11 beta-hydroxylase mRNA in the transgenic rats, whereas the brain seems to express nearly the same amount of this enzyme in both strains. The cytochrome P45011B1 mRNA expression in distinct cells, probably nerve cells, and especially in regions with high densities of glucocorticoid receptors points to a possible function of brain derived corticosterone in receptor activation.
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PMID:Expression of cytochrome P45011B1 mRNA in the brain of normal and hypertensive transgenic rats. 889 Dec 50

Recent studies suggest that superoxide production by the NADPH/NADH oxidase may be involved in smooth muscle cell growth and the pathogenesis of hypertension. We previously showed that angiotensin II (Ang II) activates a p22phoxbased NADPH/NADH oxidase in cultured rat vascular smooth muscle cells and in animals made hypertensive by infusion of Ang II. To investigate the mechanism responsible for this increased oxidase activity, we examined p22phox mRNA expression in rats made hypertensive by implanting an osmotic minipump that delivered Ang II (0.7 mg/kg per day). Blood pressure began to increase 3 days after the start of Ang II infusion and remained elevated for up to 14 days. Expression of p22phox mRNA in aorta was also increased after 3 days and reached a maximum increase of 338 +/- 41% by 5 days after pump implantation compared with the value after sham operation. This increase in mRNA expression was accompanied by an increase in the content of the corresponding cytochrome (twofold) and NADPH oxidase activity (179 +/- 11% of that in sham-operated rats 5 days after pump implantation). Treatment with the antihypertensive agents losartan (25 mg/kg per day) or hydralazine (15 mg/kg per day) inhibited this upregulation of mRNA levels and activity. Furthermore, infusion of recombinant heparin-binding superoxide dismutase decreased both blood pressure and p22phox mRNA expression. In situ hybridization of aortic tissue showed that p22phox mRNA was expressed in medial smooth muscle as well as in the adventitia. These findings suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several components of this oxidase system, including the p22phox, and that the NADPH/NADH oxidase system is associated with the pathology of hypertension in vivo.
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PMID:p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. 897 21

Nitric oxide (NO) inhibits a variety of heme-containing enzymes, including NO synthase and cytochrome P4501A1 and 2B1. The present study examined whether NO inhibits the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504A enzymes and whether blockade of the production of this substance contributes to the vascular effects of NO. Sodium nitroprusside (SNP; 10(-5), 10(-4), and 10(-3) mol/L) reduced the production of 20-HETE by renal microsomes incubated with arachidonic acid to 71 +/- 5%, 29 +/- 4%, and 4 +/- 2% of control, respectively (n = 5). Similar results were obtained with the use of 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (n = 3). To determine whether inhibition of 20-HETE contributes to the vasodilatory effects of NO, the effects of dibromo-dodecenyl-methylsulfimide (DDMS), a selective inhibitor of the formation of 20-HETE, on the response to SNP (10(-7) to 10(-3) mol/L) were examined in rat renal arterioles preconstricted with phenylephrine (n = 5). SNP increased vascular diameter in a concentration-dependent manner to 82 +/- 4% of control. After DDMS (25 mumol/L), SNP (10(-3) mol/L) increased vascular diameter by only 17 +/- 3%. The effects of DDMS on the mean arterial pressure (MAP) and renal blood flow (RBF) responses to infusion of an NO donor and a synthase inhibitor were also examined in thiobutabarbital-anesthetized, Sprague-Dawley rats. Infusion of MAHMA NONOate at 1, 3, 5, and 10 nmol/min reduced MAP by 16 +/- 2, 30 +/- 3, 40 +/- 5, and 48 +/- 5 mm Hg and lowered renal vascular resistance (RVR) by 15 +/- 3%, 26 +/- 2%, 30 +/- 3%, and 34 +/- 4% of control. After DDMS (10 mg/kg, n = 7 rats), the MAP and RVR responses to 1-hexamine, 6-(2-hydroxy-1-methyl-2-nitrohydrazino)N-methyl (MAHMA NONOate) averaged only 20% of those seen during control. In other experiments, MAP increased by 32 +/- 4% and RBF fell to 56 +/- 5% of control after administration of N-nitro-L-arginine (L-NArg) (10 mg/kg IV). After DDMS (10 mg/kg, n = 7 rats), MAP increased by only 19 +/- 4% and RBF fell by only 7 +/- 4% after L-NArg. These results indicate that NO inhibits cytochrome P4504A enzymes and that inhibition of the production of 20-HETE contributes to the vasodilatory effects of NO.
Hypertension 1997 Jan
PMID:Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide. 903 22

A genetic disorder in cytochrome P450c17 results in 17 alpha-hydroxylase/17,20-lyase deficiency. In the present study, a Japanese patient with 17 alpha-hydroxylase/17,20-lyase deficiency underwent molecular analysis. The patient presented with complete female genitalia with a 46,XY karyotype, absent pubertal development, and hypertension. the exons and exon-intron boundaries of P450c17 genetic region were amplified and sequenced. DNA sequencing revealed a compound heterozygous mutation. One allele showed a G to A transition corresponding to a premature termination codon at tryptophane in codon 17 (W17X). The other allele showed a G to T substitution at the fifth nucleotide from the splice donor site in intron 2 (436 + 5G --> T). W17X was found in one allele of the father, and 436 + 5G --> T was found in one allele of the mother. A previous report presented a patient with 17 alpha-hydroxylase/17,20-lyase deficiency who was homozygous for W17X. However, the present case is a novel 436 + 5G --> T mutation. Reverse transcription-PCR analysis using total ribonucleic acid isolated from the testes of the patient revealed that an intron 2 donor site mutation caused abnormal splicing, such that exon 2 was spliced with intron 2. Skipping the exon alters the translational reading frame of exon 3 and introduces a premature termination codon. In semiquantitative analysis, the majority of the transcript for 436 + 5G --> T skips exon 2. The present findings indicate that in this patient, 17 alpha-hydroxylase/17,20-lyase deficiency was caused by the compound heterozygous mutation of exon and splice site mutation in cytochrome P450c17 gene.
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PMID:A new compound heterozygous mutation (W17X, 436 + 5G --> T) in the cytochrome P450c17 gene causes 17 alpha-hydroxylase/17,20-lyase deficiency. 943 41

Inducing renal cytochrome P4504A (P4504A) activity with clofibrate prevents the development of hypertension in Dahl salt-sensitive (Dahl S) rats. To determine if this also occurs with other antilipidemic agents, we compared the effects of a related drug, fenofibrate, with those of an unrelated agent, pravastatin, on blood pressure, renal histology, and P4504A activity. Dahl S rats were pretreated with fenofibrate (95 mg/kg per day), pravastatin (70 mg/kg per day), or vehicle for 7 days before and after being switched from a low-salt (0.1% NaCl) to a high-salt (8.0% NaCl) diet. After 3 weeks on the high-salt diet, mean arterial pressures averaged 183+/-13 (n=9), 126+/-10 (n=9), and 148+/-11 mm Hg (n=8), respectively, in vehicle-, fenofibrate-, and pravastatin-treated animals. Both drugs reduced the degree of proteinuria and glomerular injury. P4504A protein levels and the synthesis of 20-hydroxyeicosa-5,8,11,14-tetraenoic acid (20-HETE) were increased in the liver and kidney of fenofibrate-treated, but not pravastatin-treated rats. We also administered these agents to Dahl S rats in which hypertension had previously been induced by a high-salt diet. Mean arterial pressures averaged 164+/-10, 113+/-23, and 160+/-15 mm Hg in rats treated with vehicle, fenofibrate, or pravastatin for 3 weeks. Fenofibrate-treated rats exhibited a natriuresis. Proteinuria and glomerular injury were reduced by pravastatin but not by fenofibrate. These results indicate that fenofibrate prevented the development of hypertension and reduced subsequent glomerular injury in Dahl S rats, probably secondary to increased renal production of 20-HETE. Although pravastatin did not induce renal P4504A activity in these animals, it reduced the severity of hypertension and renal damage through some other mechanism.
Hypertension 1998 Jan
PMID:Effects of lipid-lowering agents in the Dahl salt-sensitive rat. 945 7

19-Nor-corticosteroids are substances which have high mineralocorticoid activity and have been implicated in the development of essential hypertension. 19-Nor-deoxycorticosterone (19-nor-DOC) has been found in the urine of certain hypertensive patients suffering. However, very little is known regarding the origin and metabolism of 19-nor-DOC. Expression of the hamster adrenal cytochrome P450C11 cDNA in COS-1 cells has shown that this cytochrome has strong 19-hydroxylase activity, this activity being equivalent to that of 11beta-hydroxylase. Since one potential precursor of 19-nor-DOC is 19-hydroxy-deoxycorticosterone (19-OH-DOC), we have incubated this substrate in the presence of the hamster P450C11 expressed in COS-1 cells. We have found that the hamster P450C11 can transform 19-OH-DOC to 19-nor-DOC in high yield. These studies target, for the first time, the potential role of cytochrome P450C11 in the formation of 19-nor-DOC, a mineralocorticoid of adrenal origin that is possibly involved in the development of some types of hypertension.
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PMID:Characterization of the enzyme involved in the production of 19-Nor-deoxycorticosterone in hamster. 988 55

Pharmacological interaction is identified among other aspects when the effects of a drug are significantly altered clinically by the presence of food. The most important clinical significance in the history of drug-food interactions occurred in the fifties, the vitamin B6 deficiency when administering the tuberculostatic isoniazide, but there is no doubt that the interaction in the sixties between drugs that were inhibitors of the enzyme mono-amine oxidase and the biogenic amines tyramine and histamine had an important clinical significance due to the increase in hypertension and deaths due to cerebro-vascular accidents. In the seventies the types of interactions were due to the chelation between tetracyclines and the calcium of milk products, influencing the bioavailability of the antibiotic, and from this point on, studies explore in depth the interaction of foods with the different steps in the pharmacokinetics of the drugs (absorption, distribution, metabolization, and excretion), and these have helped to explain the metabolization interactions of drugs like the clinical significance between grapefruit juice whose naringenine flavonoid is a powerful inhibitor of cytochrome 450, particularly the CYP3A4 family, and terfenadine (antihistamine), with an increase in the plasma levels of the drug and patient death due to ventricular arrhythmia. In the USA the Joint Commission on Accreditation of Health Care Organization (JCAHO) has recommended monitoring of the possible drug and food interactions since 1985, and recommends that patients be informed of this. Despite the recommendations of the JCAHO, few American hospitals have protocolized these interactions and even fewer comply with these, and according to some authors, this is due to the lack of motivation caused by the lack of clinical significance. In this chapter we will study the effect of foods on drugs in two aspects: at the pharamcokinetic level with the possible alterations in absorption, distribution, metabolization, and excretion, and at the pharamcodynamic level, by alterations in the action of the drug. Also, based on a study by Delgado, which we have changed somewhat, we will report how the drugs should be taken to avoid interactions with foods. As a conclusion, it is difficult to establish which are the relevant drug-food interactions, unless they have given clinical problems. The following are important: a) drugs with a narrow therapeutic margin in which an absorption problem or a metabolization problem may disrupt the plasma levels and the patient needs (digoxin, teophylline, cyclosporin, etc). And b) the drugs like some antibiotics that, because of their action mechanisms, need to maintain adequate plasma concentrations.
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PMID:[Drug-food interactions]. 1054 35

Seventeen alpha-hydroxylase/17,20-lyase deficiency is a rare, autosomal recessive form of congenital adrenal hyperplasia not linked to human leukocyte antigen and characterized by the coexistence of hypertension caused by the hyperproduction of mineralocorticoid precursors and sexual abnormalities, such as male pseudohermaphroditism and sexual infantilism in female, due to impaired production of sex hormones. Both 17alpha-hydroxylase and 17,20-lyase reactions are catalyzed by a single polypeptide, cytochrome P450c17 (CYP17), which is encoded by the CYP17 gene located on chromosome 10q24-q25. Mutations in the CYP17 gene have been recognized to cause the 17alpha-hydroxylase/17,20-lyase deficiency syndrome. Here, we describe two phenotypically and hormonally affected Italian patients with 17alpha-hydroxylase/17,20-lyase deficiency. The family history revealed consanguinity of the parents. Linkage and haplotype analyses using microsatellites on chromosome 10q24-q25 demonstrated that the two affected individuals were homozygous at these loci. The mutation screening of the CYP17 gene identified a new Phe93Cys missense mutation in exon 1. The amino acid substitution is located in a highly conserved region of the protein and is not a polymorphism because it is not present in one hundred normal alleles. In vitro functional studies showed that the Phe93Cys mutated CYP17 retains only 10% of both 17alphahydroxylase and 17,20-lyase activities, according to the severe phenotype. Our results shed more light on the structure-function relationship of the CYP17 protein indicating that Phe 93 is crucial for both enzymatic activities.
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PMID:Combined 17alpha-Hydroxylase/17,20-lyase deficiency caused by Phe93Cys mutation in the CYP17 gene. 1183 39

Estradiol inhibits cardiac fibroblast growth and may protect against cardiac remodeling associated with heart disease. However, the mechanisms by which estradiol attenuates cardiac fibroblast growth remain unclear. Because cardiac fibroblasts express cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT) capable of converting estradiol to hydroxyestradiols and methoxyestradiols, respectively, and because hydroxyestradiols and methoxyestradiols (estradiol metabolites with little affinity for estrogen receptors) are potent inhibitors of cardiac fibroblast growth, we hypothesized that the antimitogenic effects of estradiol are mediated via hydroxyestradiols and/or methoxyestradiols. The inhibitory effects of estradiol (1 to 100 nmol/L) on serum-stimulated (3)H-thymidine incorporation (DNA synthesis), (3)H-proline incorporation (collagen synthesis), and cell number (proliferation) were enhanced (P<0.005) by CYP450 inducers 3-methylcholanthrene (10 micromol/L) and phenobarbital (10 micromol/L). Moreover, the inhibitory effects of estradiol were blocked by the CYP450 inhibitor 1-aminobenzotriazole (10 micromol/L) and the COMT inhibitors quercetin (10 micromol/L) and OR486 (10 micromol/L). In contrast to estradiol, the modulators of CYP450 and COMT were poor ligands for estrogen receptors (binding affinity less-than-or-equal 0.0001% versus estradiol). In cardiac fibroblasts, both quercetin and OR486 inhibited the metabolism of hydroxyestradiol to methoxyestradiol and blocked the inhibitory effects of hydroxyestradiol on cardiac fibroblast proliferation and DNA and collagen synthesis. The abrogating effects of quercetin and OR486 on the metabolism and antimitogenic effects of 2-hydroxyestradiol were mimicked by 20 micromol/L norepinephrine and isoproterenol, substrates for COMT. Our findings provide evidence that estradiol can inhibit cardiac fibroblast growth via an estrogen receptor--independent pathway that involves the local metabolism of estradiol to methoxyestradiols.
Hypertension 2002 Feb
PMID:Methoxyestradiols mediate the antimitogenic effects of locally applied estradiol on cardiac fibroblast growth. 1188 82

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.
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PMID:Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179. 1196 66

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