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

Erectile dysfunction (ED) in men is amenable to correction with Viagra in a majority of patients. The accumulated experience of prescribing Viagra across the broad continuum of men suffering from ED is sufficient for a meaningful assessment of the safety of Viagra in clinical practice. The use of Viagra necessitates caution in cardiac failure and when used within six months of acute myocardial infarction and stroke. It is inadvisable in patients with unstable angina pectoris. The co-administration of Viagra with organic nitrates, for example, glyceryl trinitrate or isosorbide dinitrate, is unsafe. The relative contraindications to Viagra in cardiovascular disease are uncontrolled hypertension and impaired cardiac reserve. With respect to interactions with other drugs, the potential influence on the metabolism of Viagra by medications that affect the cytochrome-P-450 system does not translate into clinical effects. The vasodilatory properties of sildenafil citrate are largely responsible for unwanted effects. The most common side effects are headache, flushing (due to vasodilation), and dyspepsia (due to relaxation of the smooth muscle of the gastroesophageal sphincter with reflux). In the recommended single-dose range (25-100 mg), the use of Viagra for erectile dysfunction, in the absence of contraindications, is extremely safe provided the drug is taken under proper conditions.
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PMID:The clinical safety of viagra. 1207 89

Arachidonic acid can be metabolized by cytochrome p450 (CYP450) enzymes to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs), their corresponding dihydroxyeicosa-trienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE). These arachidonic acid metabolites are involved in the regulation of renal epithelial transport and vascular function. 20-HETE and EETs are produced in the renal microvascular smooth muscle cells and endothelial cells, respectively. 20-HETE constricts the preglomerular arterioles by inhibiting K(+) channels, and contributes importantly to renal blood flow autoregulatory responsiveness of the afferent arterioles. EETs dilate the preglomerular arterioles by activating the renal smooth muscle cell Ca(2+)-activated K(+) channels and hyperpolarizing smooth muscle cells. These EET actions are consistent with their identification as endothelium-derived hyperpolarizing factors (EDHFs). In the kidney, EETs and 20-HETE are also produced in the proximal tubule and the thick ascending loop of Henle, and these metabolites modulate ion transport in the proximal tubules and the thick ascending limb by inhibiting Na(+)-K(+)-ATPase and the Na(+)-K(+)-2Cl(-) cotransporter. CYP450 metabolites also act as second messengers for many paracrine and hormonal agents, including endothelin, nitric oxide, and angiotensin II. The production of kidney CYP450 arachidonic acid metabolites is altered in diabetes, pregnancy, hepatorenal syndrome, and in various models of hypertension, and it is likely that changes in this system contribute to the abnormalities in renal function that are associated with many of these conditions.
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PMID:Kidney CYP450 enzymes: biological actions beyond drug metabolism. 1257 Jul 47

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

The purpose of this study is to test the hypothesis that the inhibitory effects of estradiol in human coronary vascular smooth muscle cells are mediated via local conversion to methoxyestradiols via specific cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT). The inhibitory effects of estradiol on serum-induced cell activity (DNA synthesis, cell number, collagen synthesis, and cell migration) were enhanced by 3-methylcholantherene, phenobarbital (broad-spectrum CYP450 inducers), and beta-naphthoflavone (CYP1A1/1A2 inducer) and were blocked by 1-aminobenzotriazole (broad-spectrum CYP450 inhibitor). Ellipticine, alpha-naphthoflavone (selective CYP1A1 inhibitors), and pyrene (selective CYP1B1 inhibitor), but not ketoconazole (selective CYP3A4 inhibitor) or furafylline (selective CYP1A2 inhibitor), abrogated the inhibitor effects of estradiol on cell activity, a profile consistent with a CYP1A1/CYP1B1-mediated mechanism. The inhibitory effects of estradiol were blocked by the COMT inhibitors OR486 and quercetin. The estrogen receptor antagonist ICI 182,780 blocked the inhibitory effects of estradiol, but only at concentrations that also blocked the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). Western blot analysis revealed that coronary smooth muscle cells expressed CYP1A1 and CYP1B1. Moreover, these cells metabolized estradiol to hydroxyestradiols and methoxyestradiols, and the conversion of 2-hydroxyestradiol to 2-methoxyestradiol was blocked by OR486 and quercetin. These findings provide evidence that the inhibitory effects of estradiol on coronary smooth muscle cells are largely mediated via CYP1A1- and CYP1B1-derived hydroxyestradiols that are converted to methoxyestradiols by COMT.
Hypertension 2003 Mar
PMID:CYP450- and COMT-derived estradiol metabolites inhibit activity of human coronary artery SMCs. 1262

A single-nucleotide polymorphism (A6986G) in the cytochrome p-450 3A5 (CYP3A5) gene distinguishes an expressor (*1) and a reduced-expressor (*3) allele and largely predicts CYP3A5 content in liver and intestine. CYP3A5 is the prevailing CYP3A isoform in kidney. We report that, among renal microsomes from 21 organ donors, those from *1/*3 individuals had at least eightfold higher mean kidney microsomal CYP3A5 content and 18-fold higher mean CYP3A catalytic activity than did those from *3/*3 individuals (P = 0.0001 and P = 0.0137, respectively). We also report significant associations between the A6986G polymorphism and systolic blood pressure (P = 0.0007), mean arterial pressure (P = 0.0075), and creatinine clearance (P = 0.0035) among 25 healthy African-American adults. These associations remained significant when sex, age, and body mass index were taken into account. The mean systolic blood pressure of homozygous CYP3A5 expressors (*1/*1) exceeded that of homozygous nonexpressors (*3/*3) by 19.3 mmHg. We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population.
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PMID:CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. 1275 75

The ever-increasing introduction of new therapeutic agents means that the potential for drug interactions is likely to escalate. Numerous different classes of drugs are currently used to treat hypertension. The angiotensin receptor blockers offer one of the newest approaches to the management of patients with high blood pressure. Compared with other classes of antihypertensive agents, the angiotensin receptor blockers appear overall to have a low potential for drug interactions, but variations within the class have been detected. Losartan and irbesartan have a greater affinity for cytochrome p450 (CYP) isoenzymes and, thus, are more likely to be implicated in drug interactions. There is pharmacokinetic evidence to suggest that such interactions could have a clinical impact. Candesartan cilexetil, valsartan and eprosartan have variable but generally modest affinity and telmisartan has no affinity for any of the CYP isoenzymes. In vitro studies and pharmacokinetic/pharmacodynamic evaluation can provide evidence for some interactions, but only a relatively small number of drug combinations are usually studied in this way. The absence of any pharmacokinetic evidence of drug interaction, however, should not lead to complacency. Patients should be made aware of possible interactions, especially involving the concurrent use of over-the-counter products, and it may be prudent for all patients receiving antihypertensive treatment to be monitored for possible drug interactions at their regular check-ups. The physician can help by prescribing agents with a low potential for interaction, such as angiotensin receptor blockers.
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PMID:Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives. 1286 5

Angiotensin (Ang) peptides play a critical role in regulating vascular reactivity and structure. We showed that Ang-(1-7) reduced smooth muscle growth after vascular injury and attenuated the proliferation of vascular smooth muscle cells (VSMCs). This study investigated the molecular mechanisms of the antiproliferative effects of Ang-(1-7) in cultured rat aortic VSMCs. Ang-(1-7) caused a dose-dependent release of prostacyclin from VSMCs, with a maximal release of 277.9+/-25.2% of basal values (P<0.05) by 100 nmol/L Ang-(1-7). The cyclooxygenase inhibitor indomethacin significantly attenuated growth inhibition by Ang-(1-7). In contrast, neither a lipoxygenase inhibitor nor a cytochrome p450 epoxygenase inhibitor prevented the antiproliferative effects of Ang-(1-7). These results suggest that Ang-(1-7) inhibits vascular growth by releasing prostacyclin. Ang-(1-7) caused a dose-dependent release of cAMP, which might result from prostacyclin-mediated activation of adenylate cyclase. The cAMP-dependent protein kinase inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate attenuated the Ang-(1-7)-mediated inhibition of serum-stimulated thymidine incorporation. Finally, Ang-(1-7) inhibited Ang II stimulation of mitogen-activated protein kinase activities (ERK1/2). Incubation of VSMCs with concentrations of Ang-(1-7) up to 1 micromol/L had no effect on ERK1/2 activation. However, preincubation with increasing concentrations of Ang-(1-7) caused a dose-dependent reduction in Ang II-stimulated ERK1/2 activities. Ang-(1-7) (1 micromol/L) reduced 100 nmol/L Ang II-stimulated ERK1 and ERK2 activation by 42.3+/-6.2% and 41.2+/-4.2%, respectively (P<0.01). These results suggest that Ang-(1-7) inhibits vascular growth through the release of prostacyclin, through the prostacyclin-mediated production of cAMP and activation of cAMP-dependent protein kinase, and by attenuation of mitogen-activated protein kinase activation.
Hypertension 2003 Oct
PMID:Molecular mechanisms of inhibition of vascular growth by angiotensin-(1-7). 1295 14

An 89-year-old man with severe hypertension (190/82 mm Hg) and chronic heart failure (New York Heart Association class II) despite treatment with benidipine, doxazosin mesylate (INN, doxazosin), and furosemide was given oral candesartan cilexetil (4 mg/d), an angiotensin II type 1 receptor blocker metabolized via cytochrome p450 (CYP) 2C9. Two days later, he started to have severe dizziness and returned to the hospital on the fourth day without taking any of his medications. The blood pressure 30 hours after the last dose of candesartan was 126/64 mm Hg. Polymorphism analysis revealed the heterozygous poor metabolizer genotype CYP2C9*1/*3. The area under the concentration-time curve and the mean residence time of candesartan were both increased 2.5-fold, and the oral clearance of candesartan was 48% lower than that of the average elderly Japanese patient with hypertension. These results suggest that the CYP2C9*1/*3 genotype could be associated with decreased clearance and increased plasma concentration of candesartan, potentially enhancing its hypotensive effect.
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PMID:Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C91/3 genotype. 1458 91

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


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