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)

The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14, 15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22+/-4 mm Hg (P:<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N:, N:'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.
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PMID:Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. 1109 May 43

Geriatric patients with major depression present clinical challenges not encountered in younger individuals, including a greater incidence of medical comorbidity, higher rates of multiple medication use, changes in drug metabolism due to age or physical illness, and increased sensitivity to antidepressant side effects. Nevertheless, successful treatment of depressive disorders in the elderly improves mental and physical functioning, decreases morbidity and perhaps mortality, and enhances quality of life. Recent research indicates that newer antidepressants are effective for late life depression and safer for older individuals. Among newer antidepressants, venlafaxine has a pharmacological profile that makes it an attractive choice for geriatric patients. It has limited potential to interact with other medications because it only weakly inhibits the cytochrome P450 system and binds to plasma proteins at a low level. Dosing may have to be adjusted for patients with renal failure, but typically not for those with liver disease or other medical conditions. Data from three double-blind and four open clinical trials support the safety and efficacy of venlafaxine for geriatric depression. Patients may experience transient, generally tolerable side effects such as insomnia, nausea, agitation, or dry mouth early in treatment, but more serious problems such as falls or cardiac rhythm disturbances seem to be rare. Treatment emergent hypertension occurs in a small percentage of older patients, generally at doses above 150 mg/day. Finally, emerging data suggest that venlafaxine may be effective for conditions such as stroke, anxiety, and neuropathic pain that frequently accompany depressive disorders in the elderly.
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PMID:Efficacy of venlafaxine in geriatric depression. 1109 16

A 60-year-old woman presented with a history of palpitations, headaches and severe hypertension, which was resistant to hypotensive agents. She had a 2-year history of obesity and a moon face. Her plasma adrenocorticotropic hormone level was below the limits of detection and did not respond to corticotropin-releasing hormone. Urinary-free cortisol was elevated and the circadian rhythm of serum cortisol level had completely disappeared. Imaging analysis demonstrated a unilaterally functioning mass in the left adrenal gland. Serum cortisol level in the left adrenal vein was elevated. The resected adrenal mass measured 4 x 3.5 x 2.5 cm, and ranged from yellow to tan in color. The adrenal cortex adjacent to the nodule did not demonstrate cortical atrophy. The mass was well circumscribed but not encapsulated, and consisted of multiple cortical nodules. These nodules were composed predominantly of clear cortical cells, and partly of compact cortical cells. Immunoreactivity of steroidogenic enzymes including cholesterol side-chain-cleavage P450, 3beta-hydroxysteroid dehydrogenase, 21-hydroxylase cytochrome P450, 11beta-hydroxylase cytochrome P450 and 17alpha-hydroxylase cytochrome P450 was marked in cortical nodules, but minimal in non-nodular cortex. Ultrastructural examination of nodular cortical cells also demonstrated well-developed mitochondria and smooth endoplasmic reticulum, consistent with elevated steroidogenesis in these cells.
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PMID:Adrenocorticotropin-independent unilateral adrenocortical hyperplasia with Cushing's syndrome: Immunohistochemical studies of steroidogenic enzymes, ultrastructural examination and a review of the literature. 1116 51

Recent studies indicate that arachidonic acid is primarily metabolized by cytochrome P450 enzymes of the 4A and 2C families in the kidney to 20-hydroxyeicosatetraenoic acid (HETE), epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids. These compounds play central roles in the regulation of renal tubular and vascular function. 20-HETE is produced by renal vascular smooth muscle (VSM) cells and is a potent constrictor that depolarizes VSM cells by blocking the calcium-activated potassium channel. Inhibition of the formation of 20-HETE blocks the myogenic response of isolated renal arterioles in vitro, and autoregulation of renal blood flow and tubuloglomerular feedback responses in vivo. EETs are products formed in the endothelium and are potent dilators that activate the calcium-activated potassium channel in renal VSM. Endothelial-dependent vasodilators stimulate the release of EETs, and these compounds appear to serve as an endothelial-derived hyperpolarizing factor. EETs and 20-HETE are produced in the proximal tubule. There, they regulate sodium/potassium-ATPase activity and serve as second messengers for the natriuretic effects of dopamine, parathyroid hormone and angiotensin II. 20-HETE is also produced in the thick ascending loop of Henle. It regulates sodium-potassium-chloride transport in this nephron segment. The renal production of cytochrome P450 metabolites of arachidonic acid is altered in hypertension, diabetes, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of cytochrome P450 metabolites of arachidonic acid in the control of renal function, 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:Cytochrome P450 metabolites of arachidonic acid in the control of renal function. 1119 57

Angiotensin II (Ang II) activates cytosolic phospholipase A(2) (cPLA(2)) and phospholipase D (PLD) in rabbit vascular smooth muscle cells (VSMCs). Ang II also activates ras/mitogen-activated protein (MAP) kinase in VSMCs; this activation is mediated by 20-hydroxyeicosatetraenoic acid (HETE) and 12(S)-HETE, which are metabolites of arachidonic acid generated by cytochrome P450 4A and lipoxygenase, respectively, produced on activation of cPLA(2). The purpose of this study was to determine if Ang II-induced PLD activation in VSMCs is mediated through the ras/extracellular signal-regulating kinase (ERK) pathway by arachidonic acid metabolites that are generated consequent to cPLA(2) stimulation. Inhibitors of PLD (C(2) ceramide), phosphatidate phosphohydrolase (propranolol), and diacylglycerol lipase (RHC 80267) attenuated Ang II-induced arachidonic acid release. Ang II-induced PLD activation, as measured by [(3)H]phosphatidylethanol production, was inhibited by C(2) ceramide but not by propranolol or RHC 80267. Ang II-induced PLD activation was decreased by the inhibitor methyl arachidonylfluorophosphate (MAFP) and the antisense oligonucleotide of cPLA(2). Inhibitors of lipoxygenases (baicalein) and cytochrome P450 4A (ODYA) attenuated Ang II-induced PLD activation. 20-HETE and 12(S)-HETE increased PLD activity. Inhibitors of ras farnesyltransferase (FPT III and BMS-191563) and MAP kinase kinase (UO126) attenuated the increase in PLD activity elicited by 20-HETE and Ang II. PLD2 was the main isoform activated by Ang II in VSMCs. These data suggest that the CYP4A metabolite 20-HETE, which is generated from arachidonic acid after cPLA(2) activation by Ang II, stimulates the ras/MAP kinase pathway, which in turn activates PLD2 and releases further arachidonic acid for prostaglandin synthesis through the phosphatidate phosphohydrolase/diacylglycerol lipase pathway.
Hypertension 2001 Feb
PMID:20-Hydroxyeicosatetraenoic acid mediates angiotensin ii-induced phospholipase d activation in vascular smooth muscle cells. 1123 Mar 46

We tested the hypothesis that cyclooxygenase-independent vasodilation produced by arachidonic acid (AA) is mediated by epoxyeicosatrienoic acids (EETs) and is blunted in the spontaneously hypertensive rat (SHR). At normal perfusion pressure (PP; 70 to 90 mm Hg), AA constricted the renal vasculature in both SHR and normotensive Wistar-Kyoto rats, an effect abolished by cyclooxygenase inhibition, and converted to vasodilation when PP was raised to approximately 200 mm Hg. Unexpectedly, renal vasodilation elicited by AA was greater in the SHR at high PP; for example, 2.5, 5, and 10 microg of AA produced PP declines of 54+/-9, 92+/-10, and 112+/-5 mm Hg, respectively, in SHR compared with 26+/-3, 45+/-5, and 77+/-6 mm Hg in Wistar-Kyoto rats (P:<0.01). However, the renal vasodilator responses to acetylcholine (0.1 microg) and sodium nitroprusside (1 microg) did not differ between strains, indicating that vascular responsiveness to AA was independent of intrinsic changes in vascular smooth muscle. Hyperresponsiveness of the renal vasculature to AA may be unique for the SHR, because it did not occur in Sprague-Dawley rats with angiotensin II-induced hypertension. 5,8,11,14-Eicosatetraynoic acid (ETYA; 4 micromol/L), an inhibitor of all AA pathways, attenuated the vasodilator responses to AA, as did treatment with stannous chloride, which depletes cytochrome P450 enzymes, suggesting that a cytochrome P450 AA metabolite mediated the renal vasodilation. N:-Methylsulfonyl-12,12-dibromododec-11-en-amide (DDMS; 2 micromol/L), a selective omega-hydroxylase inhibitor, did not affect AA-induced vasodilation, whereas selective inhibition of epoxygenases with either miconazole (0.3 micromol/L) or N:-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH; 12 micromol/L) did, indicating that one or more EETs were involved in the renal vasodilator action of AA at high PP. This conclusion was supported by the demonstration that AA greatly enhanced the renal efflux of EETs at high PP but not at basal PP.
Hypertension 2001 Mar
PMID:Epoxyeicosatrienoic acid-mediated renal vasodilation to arachidonic acid is enhanced in SHR. 1124 13

The pressure-natriuresis relationship is shifted to higher pressures in genetic and experimental models of hypertension; however, the factors responsible for altering kidney function remain to be determined. In spontaneously hypertensive (SHR) and Lyon hypertensive rats, the resetting of pressure-natriuresis results from increased preglomerular renal vascular tone, whereas sodium reabsorption is elevated in the thick ascending loop of Henle (TALH) of Dahl S rats. Recently, a new route for the renal metabolism of arachidonic acid (AA) has been described, and there is evidence that this pathway contributes to the resetting of renal function in hypertension. In the kidney, cytochrome P450 (CYP) enzymes metabolize AA primarily to 20-HETE and EETs. 20-HETE is a potent constrictor of renal arterioles that has an important role in autoregulation of renal blood flow and tubuloglomerular feedback. 20-HETE and EETS also inhibit sodium reabsorption in the proximal tubule and TALH. In the SHR, the renal production of 20-HETE is elevated and inhibitors of the formation of 20-HETE decrease arterial pressure. Blockade of 20-HETE formation also reduces blood pressure or improves renal function in deoxycorticosterone acetate (DOCA)-salt, angiotensin II--infused, and Lyon hypertensive rats. In contrast, 20-HETE formation is reduced in the TALH of Dahl S rats and this contributes to elevated sodium reabsorption. Induction of 20-HETE synthesis improves pressure-natriuresis and lowers blood pressure in Dahl S rats, whereas inhibitors of the synthesis of 20-HETE promote the development of hypertension in Lewis rats. These findings indicate that the renal production of CYP metabolites of AA is altered in genetic and experimental models of hypertension and that this system contributes to the resetting of pressure-natriuresis and the development of hypertension in some models.
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PMID:Abnormal pressure-natriuresis in hypertension: role of cytochrome P450 metabolites of arachidonic acid. 1141 71

A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.
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PMID:Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. 1144 60

The studies of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase, now established as a major pathway for the bioactivation of AA, have uncovered new and important functional roles for this enzyme system in cell and organ physiology, and in the metabolism of endogenous substrate. Past and present advances in P450 biochemistry and molecular biology are beginning to provide a description of the P450 isoform specificity of AA bioactivation, and the mechanisms of action and physiological relevance of the P450 metabolites. Associations between genetically controlled alterations in P450 function, expression, or regulation and functionally meaningful phenotypes point to the critical roles played by the AA monooxygenase in the control of systemic blood pressure and the pathophysiology of hypertension.
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PMID:The CYP P450 arachidonic acid monooxygenases: from cell signaling to blood pressure regulation. 1145 30

Irbesartan is an angiotensin II receptor antagonist indicated for the treatment of patients with hypertension. Although irbesartan does not require biotransformation for its pharmacological activity, it does undergo metabolism via the cytochrome P450 (CYP) 2C9 isoenzyme and negligible metabolism by the CYP3A4 isoenzyme. The long term treatment of patients with hypertension is generally required for effective management of the disease, and the use of concurrent medications is usually inevitable. This paper reviews the drug and food interaction trials involving irbesartan that have been conducted to date. Based on the available literature, no significant interactions have been identified between irbesartan and hydrochlorothiazide, nifedipine, simvastatin, tolbutamide, warfarin, magnesium and aluminum hydroxides, digoxin or food. Fluconazole did increase the steady-state peak plasma concentration (by 19%) and area under the concentration-time curve (by 63%) of irbesartan, but these increases are not likely to be clinically significant. In summary, irbesartan has demonstrated minimal potential for drug or food interactions in trials conducted to date.
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PMID:Drug interactions with irbesartan. 1152 26


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