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)

Spontaneously hypertensive rats (SH rats) were administered drinking water containing 0, 200 or 1000 ppm ascorbic acid with or without 0.5% NaCl and the usual laboratory stock diet for 130 days. The rats given ascorbic acid with or without 0.5% NaCl had a lower mean systolic blood pressure level than that of the respective control group. The difference in the mean blood pressure level from that of the control group was 18-19 mmHg for 200 ppm ascorbic acid group and 30-40 mmHg for 1000 ppm ascorbic acid group. The SH rats were shown to have some defects of ascorbic acid metabolism by lower tissue ascorbic acid levels in the liver, lung and adrenals, and by lower response of ascorbic acid synthesis to a xenobiotic than the Wistar Kyoto rats, which served as the normotensive control rats for SH rats. The abnormalities of ascorbic acid metabolism in the SH rats may be associated with, in part, their high blood pressure, because exogenous ascorbic acid prevented the blood pressure elevation of SH rats, but some other mechanism may also be involved in the effect of ascorbic acid on blood pressure.
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PMID:Effects of ascorbic acid on blood pressure and ascorbic acid metabolism in spontaneously hypertensive rats (SH rats). 407 2

Over the past several decades emphasis has been given to the elucidation of mechanisms involved in the onset and progression of cardiovascular disorders. Stroke, hypertension, and atherosclerosis continue to rank as primary causes of death in the western world. In the case of atherosclerosis, the preferential localization of atheroma to large- and medium-sized blood vessels and the sequence of events leading to plaque development have been well defined. Damage to luminal endothelial and/or medial smooth muscle cells, migration of inflammatory cells, diffusion or local delivery of mediators within the vessel wall, proliferation of vascular smooth muscle cells, and cellular accumulation of lipids are now recognized as hallmarks of the pathologic process. Although these events have been established with a fair degree of certainty, the mechanisms responsible for initiation of the atherosclerotic process are not yet completely understood. Environmental chemicals have come under increasing scrutiny as evidence continues to accumulate suggesting that toxic insult plays an important role in the initiation and/or progression of atherosclerotic disorders. This review focuses on various aspects of xenobiotic-induced vascular injury with emphasis on the toxic effects of allylamine and benzo[a]pyrene in smooth muscle cells, the primary cellular component of atherosclerotic lesions. Both of these chemicals modulate growth and differentiation programs in aortic smooth muscle cells and have been implicated in the development of atherosclerotic-like lesions in laboratory animals. The major findings from recent studies examining the cellular and molecular basis of toxicant-induced phenotypic modulation of vascular smooth muscle cells to a proliferative state and the role of oxidative metabolism, phospholipid turnover, protein kinase C, ras-related signal transduction, and matrix interactions in the vasculotoxic response to allylamine and benzo[a]pyrene are discussed.
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PMID:Responses of vascular smooth muscle cells to toxic insult: cellular and molecular perspectives for environmental toxicants. 799 Jan 68

During normal pregnancy, serum transaminase levels remain within normal limits. An elevated level observed in a pregnant woman always signals a disease process, most often of hepatic origin, but in certain cases, of muscular origin. During the last three months of pregnancy and in the immediate post partum period a large number of liver diseases can cause elevated transaminase levels, depending upon the clinical presentation. In everyday practice, a complete liver battery together with specialized consultation is required for all pregnant women with raised transaminase levels. Toxaemia gravis may be evident in patients with severely raised blood pressure, especially if seizures occur. Epigastric or subcostal pain should suggest hepatic involvement. Hypertension may however be absent and epigastric or left shoulder pain may be the only clinical signs. Acute liver steatosis is 20 to 50 times more rare than toxaemia and may cause nausea and vomiting. Certain non-specific signs such as asthenia, anorexia, polyalgia, abdominal pain, diarrhoea and fever, together with pruritus should suggest acute hepatitis. A 25-fold increase in transaminase level is commonly encountered. The risk of fulminating hepatitis is less than 1/1000 but should always be entertained. All drugs should be stopped and careful research for recent xenobiotic contamination (drugs, infusions, alphamethyldopa, etc.) should be undertaken. Viral hepatitis requires serovaccination of the newborn at birth. Herpetic hepatitis is rare but requires rapid diagnosis (liver biopsy) and treatment with acyclovir in addition to cesarean section and treatment of the newborn at birth. Rare cases of hepatitis E may occur after a stay in North Africa, the Middle-East, Southeast Asia or Mexico. Chronic cases with or without temporary pruritus suggest infectious hepatitis B or C although, in chronic hepatitis C, serum transaminase levels often return to normal during pregnancy. Rare cases of asymptomatic elevations of serum transaminase levels can reveal subclinical chronic hepatitis.
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PMID:[Significance of elevated transaminase levels at the end of pregnancy]. 802 21

The aim of this manuscript is to review perturbations in bioenergetics that are redundant denominators in the diversity of factors mediating the pathogenesis and progression of coronary heart disease (CHD), congestive heart failure (CHF), hypertension and arrhythmias. This paper likewise assesses the pharmacodynamics of widely prescribed drugs that enhance cellular respiration, maintain positive inotropic, chronotropic, dromotropic cardiac effects, sustain myocardial biosynthesis, reverse the morbidity of heart disease, and assure low levels of toxicity commensurate with the agent's biocompatability. Conversely, it is essential to delineate the modality of xenobiotic drugs that inhibit energy transformations, enhance the pathogenesis of CHD, worsen survival in CHF, provoke arrhythmogenic effects, and induce serious side-effects. Documented evidence, derived from biochemical, physiological and pharmacological data sources, consistently links inhibited mitochondrial decarboxylation to aberrations in cholesterol metabolism, biosynthesis, and calcium balance. Underutilized citrates evolved from inhibited decarboxylation are degraded to acetyl CoA. The acetate is the source of steroid synthesis; its carbon atoms form the molecular basis for all endogenous cholesterol. Myocardial anoxia, a consequence of the atheromatous plaque, inhibits ATP production, impairs biosynthesis, induces negative cardiac inotropic and chronotropic effects, and enhances the pathogenesis of CHF. Inhibited decarboxylation is likewise a factor in the mobilization of in situ cardiac Ca2+, resulting in arrhythmias provoked by the cation's deficiency. The restoration of calcium homeostasis decreases peripheral vasotension, reducing hypertension. Parameters drawn from endocrinopathies and the new physiological dimension of microgravity are developed to illustrate the detrimental effect of inhibited bioenergetics on cardiac pathomorphism and cardiovascular dysfunction. In conclusion, anabolic agents, adjunctive to a productive life-style, can provide the rational basis for the prevention and treatment of cardiac diseases. Failure to understand mechanisms generating cardiovascular morbidity eventuates in ineffective and empirical treatment.
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PMID:Bioenergetics in the pathogenesis, progression and treatment of cardiovascular disorders. 858 65

The XL-I form of xenobiotic-metabolizing medium-chain fatty acid:CoA ligase was purified to apparent homogeneity from bovine liver mitochondria. The procedure gave rise to a 435-fold increase in specific activity, with a yield of 12%. The enzyme eluted from a gel filtration column as a single peak with an apparent molecular weight of ca. 55,000. It ran as a single band on SDS-polyacrylamide gel electrophoresis (SDS-PAGE) which had an apparent molecular weight of 62 kDa. N-Terminal sequence analysis of the enzyme gave no sequence, which indicates a blocked N-terminus. To obtain sequence data, the enzyme was cleaved at methionine residues using CNBr. The resulting peptides were separated by SDS-PAGE. The cleavage pattern revealed two large peptides with molecular weights of ca. 10,000 and 12,000, plus several smaller peptides of lesser intensity. The 10 kDa and 12 kDa peptides were electroblotted onto Trans-Blot, and then sequenced directly from the blot. The N-terminal sequences of these two peptides are presented. When compared with known sequences it was discovered that these two peptides both have high homology with regions of the SA essential hypertension protein. This suggests a role for a carboxylic acid:CoA ligase in the control of high blood pressure.
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PMID:Purification and partial sequencing of the XL-I form of xenobiotic-metabolizing medium chain fatty acid:CoA ligase from bovine liver mitochondria, and its homology with the essential hypertension protein. 921 7

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

Many of the estimated 50 million Americans with high blood pressure receive medications for hypertension and for other conditions, placing them at risk for adverse drug interactions. The risk for hypertension and for adverse drug reactions is highest in the elderly, who have the greatest need for pharmacologic therapy. The most important class of drug interactions involves the cytochrome P450 microsomal enzyme system, which handles a variety of xenobiotic substances. A potential for interactions with these enzymes exists with calcium channel blockers, beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers but not with diuretic antihypertensives, which are renally eliminated and more vulnerable to drug interactions that occur in the kidney. This article reviews the cytochrome P450 enzyme system, identifies drugs and foods that have been implicated in metabolic interactions with antihypertensive agents, and suggests measures for reducing the risk of adverse events when drugs are coadministered.
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PMID:Implications of cytochrome P450 interactions when prescribing medication for hypertension. 1243 17

Transplantation has transformed the treatment of patients with organ failure in a number of clinical settings, and immunosuppressive drug therapy is fundamental to its success. However, all the drugs in current use have a narrow therapeutic index. Under-dosing can lead to rejection, while over-dosing increases the risks of infection, malignant disease, and serious drug-specific adverse effects, including diabetes mellitus, nephrotoxicity, hypertension, and hyperlipidemia. Heterogeneity in the pharmacokinetics of these drugs makes initial dose determination difficult, as there is a poor correlation between dose and blood concentration. This results in difficulties in achieving target blood concentrations early after transplantation, which are important for reducing the rate of immunological rejection. This problem is compounded by the observation that neither drug dose nor drug blood concentration accurately predict clinical efficacy or toxicity. The main determinant of heterogeneity in dose requirements is intestinal absorption of the active drug. The oxidative enzymes, cytochrome P450 (CYP) 3A4 and CYP3A5, and the drug efflux pump P-glycoprotein (P-gp) in enterocytes regulate this process. Most substrates for the P-gp pump are also substrates for the CYP3A enzymes. An efficient barrier to xenobiotic absorption is formed by the CYP enzymes and P-gp, and by the two systems working synergistically. Genetic polymorphisms have been reported for the genes associated with the expression of the CYP3A enzymes and P-gp. Genotyping patients for CYP3A genes has the potential to aid the establishment of optimal dosage regimens for transplant patients. Genetic polymorphism of the multiple drug resistance gene-1 (MDR1, also known as ABCB1) [3435C/T] and the CYP3A5 genes (CYP3A5*1, CYP3AP1*1) have the greatest potential to influence the pharmacokinetics of immunosuppressants. Homozygosity of the T allele of the MDR1 3435C/T polymorphism has been associated with reduced enterocyte expression of P-gp resulting in increased drug absorption. The presence of the CYP3A5*1 allele is necessary for the production of a fully catalytic CYP3A5 protein, and also influences the ratio of CYP3A4 : CYP3A5 as well as the overall CYP3A catalytic activity. The CYP3A4 : CYP3A5 ratio may, in turn, influence the pattern of drug metabolites formed. Heterogeneity in the production of active and inactive metabolites has implications for both the pharmacokinetics and pharmacodynamics of these drugs.Gene frequencies and drug dose requirements differ between ethnic groups. Ethnic differences in dose requirements for immunosuppressants have been discussed widely. However, ethnicity is a rather crude marker for genotype. Pharmacogenetic typing offers the possibility of significant improvement in the individualization of immunosuppressive drug prescribing with reduced rates of rejection and toxicity.
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PMID:The pharmacogenetics of immunosuppression for organ transplantation: a route to individualization of drug administration. 1457 18

The pioneering work of Gerry Brooks on cyclodiene insecticides led to the discovery of a class of enzymes known as epoxide hydrolases. The results from four decades of work confirm Brooks' first observations that the microsomal epoxide hydrolase is important in foreign compound metabolism. Brooks and associates went on to be the first to carry out a systematic study of the inhibition of this enzyme. A second role for this enzyme family was in the degradation of insect juvenile hormone (JH). JH epoxide hydrolases have now been cloned and expressed from several species, and there is interest in developing inhibitors for them. Interestingly, the distantly related mammalian soluble epoxide hydrolase has emerged as a promising pharmacological target for treating hypertension, inflammatory disease and pain. Tight-binding transition-state inhibitors were developed with good ADME (absorption, distribution, metabolism and excretion). These compounds stabilize endogenous epoxides of fatty acids, including arachidonic acid, which have profound therapeutic effects. Now EHs from microorganisms and plants are used in green chemistry. From his seminal work, Dr Brooks opened the field of epoxide hydrolase research in many directions including xenobiotic metabolism, insect physiology and human health, as well as asymmetric organic synthesis.
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PMID:Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical. 1838 2

The CYP3A locus encodes hepatic enzymes that metabolize many clinically used drugs. However, there is marked interindividual variability in enzyme expression and clearance of drugs metabolized by these enzymes. We utilized comparative genomics and computational prediction of transcriptional factor binding sites to evaluate regions within CYP3A that were most likely to contribute to this variation. We then used a haplotype tagging single-nucleotide polymorphisms (htSNPs) approach to evaluate the entire locus with the fewest number of maximally informative SNPs. We investigated the association between these htSNPs and in vivo CYP3A enzyme activity using a single-point IV midazolam clearance assay. We found associations between the midazolam phenotype and age, diagnosis of hypertension and one htSNP (141689) located upstream of CYP3A4. 141689 lies near the xenobiotic responsive enhancer module (XREM) regulatory region of CYP3A4. Cell-based studies show increased transcriptional activation with the minor allele at 141689, in agreement with the in vivo association study findings. This study marks the first systematic evaluation of coding and noncoding variation that may contribute to CYP3A phenotypic variability.
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PMID:Prediction of CYP3A4 enzyme activity using haplotype tag SNPs in African Americans. 1882 62

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