Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen receptors (ERs) are considered to mediate the ability of 17beta-estradiol (estradiol) to reduce injury-induced proliferation of vascular smooth muscle cells (VSMCs), leading to vascular lesions. However, the finding that estradiol attenuates formation of vascular lesions in response to vascular injury in knockout mice that lack either ER-alpha or ER-beta challenges this concept. Our hypothesis is that the local metabolism of estradiol to methoxyestradiols, metabolites of estradiol with little affinity for ERs, mediates the ER-independent antimitogenic effects of estradiol on VSMCs. In human VSMCs, 2-methoxyestradiol and 2-hydroxyestradiol were more potent than was estradiol in inhibiting DNA synthesis (3[H]-thymidine incorporation), collagen synthesis (3[H]-proline incorporation), cell proliferation (cell number), and cell migration (movement of cells across a polycarbonate membrane). The inhibitory effects of estradiol on VSMCs were enhanced by cytochrome-P450 (CYP450) inducers 3-methylcholanthrene and phenobarbital. Moreover, the inhibitory effects of estradiol were blocked in the presence of the CYP450 inhibitor 1-aminobenzotriazole and the catechol-O-methyltransferase inhibitors quercetin and OR486. Both OR486 and quercetin blocked the conversion of 2-hydroxyestradiol to 2-methoxyestradiol; moreover, they blocked the antimitogenic effects of 2-hydroxyestradiol but not of 2-methoxyestradiol. The ER antagonist ICI182780 blocked the inhibitor effects of estradiol on VSMCs, but only at concentrations (>50 micromol/L) that also inhibit the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). In conclusion, the inhibitory effects of locally applied estradiol on human VSMCs are mediated via a novel ER-independent mechanism involving estradiol metabolism. These findings imply that vascular estradiol metabolism may be an important determinant of the cardiovascular protective effects of estradiol and that nonfeminizing estradiol metabolites may confer cardiovascular protection regardless of gender.
Hypertension 2002 Apr
PMID:Methoxyestradiols mediate estradiol-induced antimitogenesis in human aortic SMCs. 1196 42

The demonstration of a role for microsomal P450 in the metabolism of endogenous pools of arachidonic acid established this enzyme system as a member of the arachidonic acid cascade and characterized a new an important metabolic function for this enzyme system. Studies from several laboratories documenting the powerful biological activities of the P450-derived eicosanoids have suggested important roles for the P450 arachidonic acid monooxygenase in renal and vascular physiology, and in the pathophysiology of experimental hypertension. These studies provide significant evidence to indicate that in addition to its recognized traditional toxicological and pharmacological roles, microsomal P450s also play important physiological roles in the control of tissue and body homeostasis.
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PMID:Microsomal cytochrome P450 and eicosanoid metabolism. 1208 78

Transgenic rats overexpressing both human renin and angiotensinogen genes (dTGR) develop hypertension, inflammation, and renal failure. We tested the hypothesis that these pathological features are associated with changes in renal P450-dependent arachidonic acid (AA) metabolism. Samples were prepared from 5- and 7-week-old dTGR and from normotensive Sprague-Dawley (SD) rats, ie, before and after the dTGR developed severe hypertension and albuminuria. At both stages, dTGR showed significantly lower renal microsomal AA epoxygenase and hydroxylase activities that reached 63% and 76% of the control values at week 7. Furthermore, the protein levels of several potential AA epoxygenases (CYP2C11, CYP2C23, and CYP2J) were significantly reduced. Immunoinhibition studies identified CYP2C23 as the major AA epoxygenase, both in dTGR and SD rats. Immunohistochemistry showed that CYP2C23 was localized in cortical and outer medullary tubules that progressively lost this enzyme from week 5 to week 7 in dTGR. CYP2C11 expression occurred only in the outer medullary tubules and was markedly reduced in dTGR compared with age-matched SD rats. These findings indicate site-specific decreases in the availability of AA epoxygenase products in the kidney of dTGR. In contrast to renal microsomes, liver microsomes of dTGR and SD rats showed no change in the expression and activity of AA epoxygenases and hydroxylases. We conclude that hypertension and end-organ damage in dTGR is associated with kidney-specific downregulation of P450-dependent AA metabolism. Because the products of AA epoxygenation have anti-inflammatory properties, this alteration may contribute to uncontrolled renal inflammation, which is a major cause of renal damage in dTGR.
Hypertension 2002 Sep
PMID:P450-dependent arachidonic acid metabolism and angiotensin II-induced renal damage. 1221 66

A 43-year-old Japanese woman presented hypertension, hypokalemia and typical Cushingoid signs. Autonomous secretion of both aldosterone and cortisol was shown. Abdominal computed tomography demonstrated a single tumor in the right adrenal gland, which established the diagnosis of combined primary aldosteronism and Cushing's syndrome. The resected tumor was a golden yellow-colored adenoma (diameter 4.3 cm) which expressed P450(aldo) and P450(11beta), causing oversecretion of both hormones from this adenoma. After tumor resection, overproduction of both hormones disappeared and she developed adrenal insufficiency, suggesting the strong suppression of normal adrenal function. This case was complicated by Hashimoto's thyroiditis.
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PMID:Combined primary aldosteronism and Cushing's syndrome due to a single adrenocortical adenoma complicated by Hashimoto's thyroiditis. 1248 54

Excess dietary salt intake differentially modulates the activity of cytochrome (CYP) P450 enzymes in kidney cortex. Exactly how increased angiotensin (Ang) II levels and hypertension change the regulatory effect of high salt on CYP450 enzymes remains unclear. The present study investigated the effects of combined administration of Ang II and a high-salt diet on P450 epoxygenase and hydroxylase protein levels in kidney, as well as afferent arteriolar responses to acetylcholine and sodium nitroprusside. High dietary salt administration for 14 days resulted in increased renal cortical CYP2C11 protein levels, and a significant increase of CYP2C11 and CYP2C23 protein levels in renal microvessels. Administration of Ang II in combination with a high-salt diet prevented the upregulation of renal cortical CYP2C11 protein expression observed with high dietary salt alone, and significantly downregulated expression of CYP2C11, CYP2C23, and CYP2J protein in renal microvessels. A high-salt diet alone decreased CYP4A protein in kidney cortex, and renal cortical CYP4A protein level remained at a low level in Ang II-infused rats treated with a high-salt diet. Increases in blood pressure during Ang II infusion were greater in rats fed a high-salt diet. In addition, afferent arteriolar responsiveness to acetylcholine and sodium nitroprusside was significantly attenuated in Ang II-treated rats versus controls. This decrease was significantly enhanced in Ang II-treated rats given a high-salt diet. These results support the hypothesis that an inability to upregulate CYP2C and maintain CYP2J in the rat kidney and impaired afferent arteriolar vasodilation with chronic Ang II infusion contribute to salt-induced elevation of arterial pressure.
Hypertension 2003 Mar
PMID:Decreased renal cytochrome P450 2C enzymes and impaired vasodilation are associated with angiotensin salt-sensitive hypertension. 1262 84

Although the rifampin-cyclosporine interaction is well described, information on the extent, duration, and potency of the rifampin-tacrolimus interaction is limited. We describe a renal transplant recipient who demonstrated an increase in tacrolimus metabolism as a result of rifampin administration. A 40-year-old Asian woman received a cadaveric renal transplant for end-stage renal disease due to IgA nephropathy and was administered tacrolimus, thymoglobulin, mycophenolate mofetil, and prednisone, along with diltiazem for hypertension. On postoperative day (POD) 5, donor bronchioalveolar lavage revealed active tuberculosis. The recipient received rifampin 600 mg/d, and the diltiazem dose was increased. Over the next 12 days, the tacrolimus dose was increased to 32 mg/d to achieve a target trough level of 10 to 15 ng/mL, finally reached on POD34, when the serum creatinine was 145 micromol/L. The patient also received a course of fluconazole 100 mg/d and clarithromycin 1000 mg/d starting on POD38 and POD41, respectively. Despite this, there was no increase in tacrolimus levels. Rifampin was discontinued on POD76, after which therapeutic tacrolimus levels were finally attained with usual doses by POD132. Rifampin had potent and prolonged effects on tacrolimus metabolism. Induction of the hepatic cytochrome P4503A4 system by rifampin was sufficient to overcome the inhibitory effects of diltiazem; fluconazole, and clarithromycin, necessitating the use of large doses of tacrolimus. Close monitoring of tacrolimus levels and frequent dose adjustments are required whenever rifampin is administered posttransplant, regardless of P450 inhibitors used, to optimize allograft function.
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PMID:Severe reduction in tacrolimus levels with rifampin despite multiple cytochrome P450 inhibitors: a case report. 1461 83

Although the angiotensin-converting enzyme (ACE) inhibitor-induced bradykinin enhances nitric oxide (NO) release, bradykinin may also stimulate the production of an additional vasodilator, endothelium-derived hyperpolarizing factor (EDHF). This study examined the role of EDHF in mediating the NO-independent action of ACE inhibitors in canine renal microcirculation in vivo. We used intravital CCD camera videomicroscopy that allowed direct visualization of renal microcirculation in superficial and juxtamedullary nephrons in an in vivo, in situ, and relatively intact setting. In the presence of E4177 (an angiotensin receptor blocker), cilazaprilat (30 microg/kg) had no effect on diameter of superficial afferent arterioles (Aff), but it increased renal contents of bradykinin and nitrate plus nitrite, and it elicited dilation of juxtamedullary Aff (from 24.0+/-0.2 to 28.2+/-0.8 microm), juxtamedullary efferent arterioles (Eff) (from 24.2+/-0.2 to 28.0+/-0.8 microm), and superficial Eff (from 18.2+/-0.2 to 19.7+/-0.2 microm). These changes in diameters were prevented by N(alpha)-adamantaneacetyl-d-Arg-[Hyp(3),Thi(5,8),D-Phe(7)]bradykinin, a bradykinin receptor antagonist. The pretreatment with nitro-l-arginine methylester (l-NAME) plus E4177 eliminated the dilator response of juxtamedullary/superficial Eff and the increase in renal nitrate plus nitrite levels induced by cilazaprilat. In contrast, in the presence of E4177+l-NAME, cilazaprilat still caused 8%+/-3% dilation of juxtamedullary Aff, which was completely eliminated by proadifen, a cytochrome-P450 and K(Ca) channel blocker. Collectively, the ACE inhibitor exerts multiple vasodilator mechanisms, including the inhibition of angiotensin II formation; blockade of angiotensin II activity appears to be a dominant mechanism in superficial Aff, whereas the bradykinin-induced NO acts on superficial Eff and juxtamedullary Aff/Eff. Furthermore, a putative EDHF is an additional mechanism for the ACE inhibitor-induced vasodilation of juxtamedullary Aff in vivo.
Hypertension 2004 Mar
PMID:Role of endothelium-derived hyperpolarizing factor in ACE inhibitor-induced renal vasodilation in vivo. 1475 81

The terminal stages in the synthesis of aldosterone and cortisol are catalysed by the enzymes aldosterone synthase and 11beta-hydroxylase respectively. We have previously reported that polymorphic variation in the 5' promoter region (-344C/T) of the gene encoding aldosterone synthase (CYP11B2) is associated with increased aldosterone metabolite excretion and with hypertension associated with a raised aldosterone to renin ratio (ARR). Additionally, basal and ACTH-stimulated plasma levels of 11-deoxycortisol, the precursor of cortisol, are higher in subjects carrying the T-allelic variant. We have now identified in a family study (573 individuals from 105 extended families ascertained through a hypertensive proband) that excretion of the main metabolite of this steroid (tetrahydro-11-deoxycortisol, THS) is heritable (19.4%) and that the T-allele of CYP11B2 is more strongly associated with higher THS levels than the C-allele. Raised plasma and urinary levels of 11-deoxycortisol suggest that there is relative inefficiency of 11beta-hydroxylation in the zona fasciculata; the P450 enzyme responsible for this step is encoded by the gene CYP11B1, which is highly homologous with and adjacent to CYP11B2. The association of genetic variation in the promoter of CYP11B2 which, in the adrenal cortex, is only expressed in zona glomerulosa, and zona fasciculata 11beta-hydroxylation function is paradoxical. There may be linkage dys-equilibrium between this polymorphism and a quantitative trait locus (QTL) in CYP11B1. Chronic alteration of 11beta-hydroxylase activity may increase ACTH drive to the adrenal cortex, altering the regulation of aldosterone synthesis. This may explain, at least partly, the association between CYP11B2 polymorphisms and hypertension.
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PMID:The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation. 1513 24

The traditional concept of adipose tissue as a passive reservoir for energy storage is no longer valid because it has been demonstrated that adipose tissue is a complex, essential, and highly active metabolic and endocrine organ that not only responds to afferent signals from traditional hormone systems and the central nervous system (CNS), but also expresses and secretes factors with important endocrine functions. These factors include leptin and other cytokines. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by adverse metabolic consequences of both adipose tissue excess and deficiency. Adipose tissue excess, particularly in visceral compartment, is associated with insulin resistance, hyperglycemia, dyslipidemia, hypertension, and prothrombotic and proinflammatory states. Liver is one of the principal targets of lipid-associated damage by mechanisms that involve apoptosis activation by source of tumoral necrosis factor-alpha and caspase activation and liberation of oxygen-reactive species by oxidative stress and enzymatic chains such as P450, CYP2E1, and CYP3A4, resulting in a continuum involving non alcohol-related fatty liver, non-alcoholic steatohepatitis with or without fibrosis, and liver cirrhosis. This work presents an overview of endocrine functions of adipose tissue and its influence on mechanisms of liver damage.
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PMID:[Obesity and steatohepatitis. Histologic aspects]. 1564 70

Androgens and estrogens are primarily made from dehydroepiandrosterone (DHEA), which is made from cholesterol via four steps. First, cholesterol enters the mitochondria with the assistance of the steroidogenic acute regulatory protein (StAR). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia (lipoid CAH), a potentially lethal disease in which virtually no steroids are made. Lipoid CAH is common among Palestinian Arabs and people from eastern Arabia, and among Korean and Japanese people. Second, within the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc; disorder of this enzyme is very rare, probably due to embryonic lethality. Third, pregnenolone undergoes 17alpha-hydroxylation by microsomal P450c17. 17alpha-Hydroxylase deficiency, manifesting as female sexual infantilism and hypertension, is rare except in Brazil. Finally, 17-OH pregnenolone is converted to DHEA by the 17,20 lyase activity of P450c17. The ratio of the 17,20 lyase to 17alpha-hydroxylase activity of P450c17 determines the ratio of C21 to C19 steroids produced. This ratio is regulated posttranslationally by at least three factors: the abundance of the electron-donating protein P450 oxidoreductase (POR), the presence of cytochrome b5 and the serine phosphorylation of P450c17. Mutations of POR are a new, recently described disorder manifesting as the Antley-Bixler skeletal dysplasia syndrome, and a form of polycystic ovary syndrome.
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PMID:Disorders of androgen synthesis--from cholesterol to dehydroepiandrosterone. 1610 14


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