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 arachidonic cascade involves three types of metabolic pathways; cyclo-oxygenase, lipoxygenase(LO), and cytochrome P450. The products of LO pathway participate in the pathogenesis of variety of disease such as allergic diseases and hypertension. In particular, 12-hydroxyeicosatetraenoic acid(12-HETE); product of 12-LO pathway, is concerned in the development of hypertension induced by angiotensin-II. In fact, several investigators have reported that 12-HETE has a critical role in hypertension and LO inhibitors have antihypertensive effects in experimental animals. And so, we can expect organ-protective effects of LO inhibitors as well as antihypertensive effects. Besides 12-LO, several investigators mentioned that 5- and 15-LO also have influences to cardiovascular systems. Therefore, we can expect further elucidation of the mechanism of 12-LO's participation in the organ damage and the clinical roles of 12-LO inhibitors to prevent from organ failure in future.
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PMID:[Lipoxygenase inhibition and protection of cardiovascular system]. 1473 52

Two key players in adrenal steroid hormone biosynthesis are the human mitochondrial cytochrome P450 enzymes CYP11B1 and CYP11B2 that catalyze the final steps in the biosynthesis of cortisol and aldosterone, respectively. Overproduction of both hormones contributes to a number of severe diseases, as illustrated by the association of elevated aldosterone levels with hypertension and higher mortality in congestive heart failure, and by Cushing's syndrome as the clinical correlate of chronic hypercortisolism. Thus, CYP11B1 and CYP11B2 comprise new targets for drug treatment and selective inhibitors of both enzymes are of high pharmacological interest. To facilitate the search for such compounds, we have established novel test procedures using recombinant fission yeast strains that stably express these enzymes. The aim of this study was to compare the inhibition profiles displayed by these enzymes in established mammalian cell culture test systems to those obtained with the new fission yeast assays, and to evaluate the usefulness of the Schizosaccharomyces pombe strains as screening systems for the identification of novel lead compounds. Using these test systems, we were able to identify a new and very selective CYP11B2 inhibitor (SIAS-1) that displayed no detectable interference with CYP11B1 activity.
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PMID:Development of test systems for the discovery of selective human aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) inhibitors. Discovery of a new lead compound for the therapy of congestive heart failure, myocardial fibrosis and hypertension. 1513 25

Considerable evidence has accumulated over the last decade implicating a role of cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) in the pathogenesis of hypertension. Indeed, 20-hydroxyeicosatetraenoic acid (20-HETE) is produced by vascular smooth muscle (VSM) cells and is a potent vasoconstrictor that depolarizes VSM by blocking large conductance Ca+-activated K2+ channels. In contrast, epoxyeicosatrienoic acids (EETs) are synthesized by the vascular endothelium and have opposite effects on VSM (hyperpolarization and vasodilatation). Inhibition of the synthesis of 20-HETE attenuates myogenic tone and autoregulation of blood flow and modulates vascular responses to vasodilators (NO and CO) and vasoconstrictors (angiotensin II, endothelin). In the kidney, 20-HETE inhibits sodium transport in the proximal tubule by blocking Na+-K+-ATPase activity. In the thick ascending limb of the loop of Henle, 20-HETE inhibits Na+-K+-2Cl- transport, in part, by blocking a 70 pS apical K+ channel. EETs are produced in the proximal tubule where they inhibit Na+-H+ exchange and in the collecting duct where they inhibit sodium and water transport. Numerous studies have established that the formation of EETs and 20-HETE and the expression of CYP enzymes are altered in the kidney in many genetic and experimental animal models of hypertension and in some forms of human hypertension. However, the functional significance of these changes remains to be determined. Given the importance of this pathway in the control of renal function and vascular tone, it is likely that alterations in the renal formation of CYP-dependent metabolites of AA will be shown to participate in the development of hypertension in many of these models.
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PMID:Role of cytochrome P450 metabolites of arachidonic acid in hypertension. 1518 Apr 94

We examined the influence of interactions between CO and 20-hydroxyeicosatetraenoic acid (20-HETE) on vascular reactivity to phenylephrine and vasopressin. Renal interlobar arteries incubated in Krebs buffer released CO at a rate that is decreased (from 125.0+/-15.2 to 46.3+/-8.8 pmol/mg protein per hour, P<0.05) by the heme oxygenase inhibitor chromium mesoporphyrin (CrMP; 30 micromol/L). The level of 20-HETE in vessels was not affected by CrMP (74.3+/-6.1 versus 72.5+/-16.2 pmol/mg protein), but was decreased (P<0.05) by CO (1 micromol/L; 33.2+/-7.9 pmol/mg protein) or the cytochrome P450-4A inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 micromol/L; 11.4+/-3.3 pmol/mg protein). Phenylephrine elicited development of isometric tension in vascular rings mounted on a wire-myograph (EC(50), 0.29+/-0.02 micromol/L; R(max), 3.78+/-0.19 mN/mm). The sensitivity to phenylephrine was decreased (P<0.05) by CO (1 micromol/L; EC(50), 0.60+/-0.04 micromol/L) or DDMS (EC(50), 0.71+/-0.12 micromol/L) and increased (P<0.05) by 20-HETE (10 micromol/L; EC(50), 0.08+/-0.02 micromol/L) or CrMP (EC(50), 0.11+/-0.02 micromol/L). Notably, neither CO nor CrMP changed the sensitivity to phenylephrine in vessels treated with DDMS. Refractoriness to CO and CrMP in such a setting was eliminated by inclusion of 20-HETE (1 micromol/L) in the bathing buffer. The aforementioned interventions affected the vascular reactivity to vasopressin in a similar manner. These data indicate that the reactivity of renal arteries to phenylephrine and vasopressin is reciprocally influenced by CO and 20-HETE of vascular origin and that CO desensitizes the vascular smooth muscle to constrictor agonists by interfering with the sensitizing influence of 20-HETE.
Hypertension 2004 Aug
PMID:Vascular CO counterbalances the sensitizing influence of 20-HETE on agonist-induced vasoconstriction. 1522 75

This review provides an overview of gender-specific differences in the incidence and development of cardiovascular diseases, including hypertension, atherosclerosis, heart failure and the corresponding myocardial remodeling. The review discusses the possible mechanisms by which estrogen affords a beneficial effect on cardiovascular function via genomic vs non genomic regulation; estrogen receptor-dependent vs estrogen receptor-independent pathways, specific signal transduction cascades, especially those involving protein kinase B (Akt) and mitogen activated protein kinase (MAPK), as well as their downstream targets, such as nitric oxide synthase, cyclooxygenase, cytochrome P450 (CYP), NADPH oxidase and superoxide dismutase. Having considered the essential role of the microcirculation in the control of vascular resistance in vivo, estrogen-related regulation of microvascular function and blood pressure is highlighted. Attention is focused on the effects of estrogen on pressure (myogenic)-dependent and flow/shear stress-dependent mechanisms of arterioles, which contribute significantly to the control of local blood flow and peripheral resistance via alterations in the release of endothelial mediators, such as nitric oxide, prostaglandins and endothelium-derived hyperpolarizing factor.
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PMID:Gender-specific regulation of cardiovascular function: estrogen as key player. 1528 95

Alcoholic cardiomyopathy is characterized by cardiomegaly, disruptions of myofibrillary architecture, reduced myocardial contractility, decreased ejection fraction, and enhanced risk of stroke and hypertension. Although several mechanisms have been postulated for alcoholic cardiomyopathy, including oxidative damage, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament Ca(2+) sensitivity, and impaired protein synthesis, neither the mechanism nor the ultimate toxin has been unveiled. Primary candidates acting as specific toxins of myocardial tissue are ethanol; its first and major metabolic product, acetaldehyde; and fatty acid ethyl esters. Acetaldehyde has been demonstrated to impair directly cardiac contractile function, disrupt cardiac excitation-contractile coupling, and contribute to oxidative damage and lipid peroxidation. Acetaldehyde-elicited cardiac dysfunction may be mediated through cytochrome P450 oxidase, xanthine oxidase, and the stress-signaling cascade. Unfortunately, the most direct approach that can be used to examine toxicity is hampered by the fact that direct intake of acetaldehyde is highly toxic and unsuitable for long-term study. To overcome this obstacle, transgenic mice have been used to alter artificially ethanol/acetaldehyde metabolism, resulting in elevated acetaldehyde concentrations after ethanol ingestion. In this review, we summarize results obtained with the use of transgenic animal models to elucidate the role of acetaldehyde in the mechanism of action in alcoholic cardiomyopathy.
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PMID:Ethanol and acetaldehyde in alcoholic cardiomyopathy: from bad to ugly en route to oxidative stress. 1528 11

Grapefruit juice can alter oral drug pharmacokinetics by different mechanisms. Irreversible inactivation of intestinal cytochrome P450 (CYP) 3A4 is produced by commercial grapefruit juice given as a single normal amount (e.g. 200-300 mL) or by whole fresh fruit segments. As a result, presystemic metabolism is reduced and oral drug bioavailability increased. Enhanced oral drug bioavailability can occur 24 hours after juice consumption. Inhibition of P-glycoprotein (P-gp) is a possible mechanism that increases oral drug bioavailability by reducing intestinal and/or hepatic efflux transport. Recently, inhibition of organic anion transporting polypeptides by grapefruit juice was observed in vitro; intestinal uptake transport appeared decreased as oral drug bioavailability was reduced. Numerous medications used in the prevention or treatment of coronary artery disease and its complications have been observed or are predicted to interact with grapefruit juice. Such interactions may increase the risk of rhabdomyolysis when dyslipidemia is treated with the HMG-CoA reductase inhibitors atorvastatin, lovastatin, or simvastatin. Potential alternative agents are pravastatin, fluvastatin, or rosuvastatin. Such interactions might also cause excessive vasodilatation when hypertension is managed with the dihydropyridines felodipine, nicardipine, nifedipine, nisoldipine, or nitrendipine. An alternative agent could be amlodipine. In contrast, the therapeutic effect of the angiotensin II type 1 receptor antagonist losartan may be reduced by grapefruit juice. Grapefruit juice interacting with the antidiabetic agent repaglinide may cause hypoglycemia, and interaction with the appetite suppressant sibutramine may cause elevated BP and HR. In angina pectoris, administration of grapefruit juice could result in atrioventricular conduction disorders with verapamil or attenuated antiplatelet activity with clopidrogel. Grapefruit juice may enhance drug toxicity for antiarrhythmic agents such as amiodarone, quinidine, disopyramide, or propafenone, and for the congestive heart failure drug, carvediol. Some drugs for the treatment of peripheral or central vascular disease also have the potential to interact with grapefruit juice. Interaction with sildenafil, tadalafil, or vardenafil for erectile dysfunction, may cause serious systemic vasodilatation especially when combined with a nitrate. Interaction between ergotamine for migraine and grapefruit juice may cause gangrene or stroke. In stroke, interaction with nimodipine may cause systemic hypotension. If a drug has low inherent oral bioavailability from presystemic metabolism by CYP3A4 or efflux transport by P-gp and the potential to produce serious overdose toxicity, avoidance of grapefruit juice entirely during pharmacotherapy appears mandatory. Although altered drug response is variable among individuals, the outcome is difficult to predict and avoiding the combination will guarantee toxicity is prevented. The elderly are at particular risk, as they are often prescribed medications and frequently consume grapefruit juice.
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PMID:Interactions between grapefruit juice and cardiovascular drugs. 1544 71

Olmesartan medoxomil is a new angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. Olmesartan medoxomil is a pro-drug that is converted to the active metabolite olmesartan. Olmesartan does not undergo further metabolism and does not interact with cytochrome P450 enzymes. Olmesartan is a potent ARB with high selectivity for the type 1 (AT(1)) receptor subtype and shows insurmountable antagonism against the AT(1) receptor in vascular tissues. This antagonistic mode, which could be attributed to tight binding of this drug to the receptor, would underlie the potent and persistent action of olmesartan medoxomil in vivo. In fact, oral administration of olmesartan medoxomil produces a potent and long-lasting antihypertensive action without inducing tachycardia. The preventive effects of olmesartan medoxomil on end-organ damage in the kidney, heart, and blood vessels have been demonstrated in various animal models. In clinical studies, olmesartan medoxomil is shown to be well tolerated and have an excellent safety profile that is comparable to that of placebo. Head-to-head comparisons with other ARBs (losartan, valsartan, irbesartan, and candesartan cilexetil) conducted in the United States and Europe have revealed that olmesartan medoxomil is superior to these other ARBs in lowering blood pressure. These facts suggest that olmesartan medoxomil would be beneficial for the treatment of hypertension and other end-organ diseases.
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PMID:[Pharmacological profiles and clinical effects of olmesartan medoxomil, a novel angiotensin II receptor blocker]. 1546 59

Overactive bladder is associated with symptoms of urgency, with or without urge incontinence, usually with daytime frequency and nocturia in the absence of local pathological factors. Muscarinic receptor antagonists (antimuscarinics) are the first-line pharmacotherapy. Tolterodine, a competitive, nonselective antimuscarinic specifically developed for the treatment of overactive bladder, demonstrated tissue selectivity for the bladder over the parotid gland in an animal model. As of March 5, 2003, the immediate-release (IR) formulation had been approved in 72 countries and the extended-release (ER) formulation had been approved in 28 countries, and tolterodine had been administered to 5 million patients. This review evaluates the benefit-risk profile of tolterodine in the treatment of adults with overactive bladder, summarising clinical trial and postmarketing surveillance data. Tolterodine has been found to significantly reduce micturition frequency, urgency perception and the number of episodes of urge incontinence and increase the volume voided per micturition. Dry mouth, an antimuscarinic class effect, is the most commonly reported adverse effect but is mostly mild to moderate in severity. Serious adverse effects are reported infrequently. Based on summary and review of postmarketing surveillance and clinical trial safety data received by the market authorization holder and contained in the Periodic Safety Update Reports for tolterodine, several monitored serious events of the gastrointestinal tract (e.g. ileus or haemorrhage), nervous system (e.g. syncope, convulsions and memory disorders) and cardiovascular system (e.g. ventricular arrhythmia, atrial fibrillation, palpitations, bradycardia, transient ischaemic attacks and hypertension) were not considered related to tolterodine. QT or corrected QT (QTc) prolongation was not observed in any of the five cases of verified ventricular arrhythmia in patients administered tolterodine; there is insufficient evidence to indicate that tolterodine causes ventricular arrhythmia or extrasystoles or any specific type of cardiac rhythm abnormality. The safety profile of tolterodine is similar in patients aged > or =65 years and in younger adults. Clinically relevant drug interactions are limited to cytochrome P450 3A4 inhibitors, such as ketoconazole, and co-administration with such agents warrants a tolterodine dosage decrease. In addition, tolterodine IR 2mg twice daily is similar in efficacy to oxybutynin IR 5mg three times daily, and tolterodine ER 4 mg once daily is similar in efficacy to oxybutynin ER 10mg once daily. Dry mouth occurred less frequently with tolterodine than oxybutynin, and moderate to severe dry mouth occurred more than three times less frequently. Based on the low frequency of adverse events, the absence of unexpected adverse events and the very low frequency of serious adverse events, we conclude that tolterodine is a well tolerated treatment for overactive bladder in adults, in whom it should be considered as first-line therapy.
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PMID:Benefit-risk assessment of tolterodine in the treatment of overactive bladder in adults. 1547 9

Members of the cytochrome P450 3A subfamily catalyze the metabolism of endogenous substrates, environmental carcinogens, and clinically important exogenous compounds, such as prescription drugs and therapeutic agents. In particular, the CYP3A4 and CYP3A5 genes play an especially important role in pharmacogenetics, since they metabolize >50% of the drugs on the market. However, known genetic variants at these two loci are not sufficient to account for the observed phenotypic variability in drug response. We used a comparative genomics approach to identify conserved coding and noncoding regions at these genes and resequenced them in three ethnically diverse human populations. We show that remarkable interpopulation differences exist with regard to frequency spectrum and haplotype structure. The non-African samples are characterized by a marked excess of rare variants and the presence of a homogeneous group of long-range haplotypes at high frequency. The CYP3A5*1/*3 polymorphism, which is likely to influence salt and water retention and risk for salt-sensitive hypertension, was genotyped in >1,000 individuals from 52 worldwide population samples. The results reveal an unusual geographic pattern whereby the CYP3A5*3 frequency shows extreme variation across human populations and is significantly correlated with distance from the equator. Furthermore, we show that an unlinked variant, AGT M235T, previously implicated in hypertension and pre-eclampsia, exhibits a similar geographic distribution and is significantly correlated in frequency with CYP3A5*1/*3. Taken together, these results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude.
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PMID:CYP3A variation and the evolution of salt-sensitivity variants. 1549 26


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