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)

11 Beta-hydroxysteroid dehydrogenases type 1 and 2 (11 beta-HSD1 and 11 beta-HSD2) are microsomal enzymes responsible for the interconversion of cortisol into the inactive form cortisone and vice versa. 11 beta-HSD1 is mainly present in the liver, and has predominantly reductase activity although its function has not yet been elucidated. 11 beta-HSD2, present in mineralocorticoid target tissues such as the kidney, converts cortisol into cortisone. Reduced activity due to inhibition or mutations of 11 beta-HSD2 leads to hypertension and hypokalemia resulting in the Apparent Mineralocorticoid Excess Syndrome (AMES). Like humans, cats are highly susceptible for hypertension. As large species differences exist with respect to the kinetic parameters (K(m) and V(max)) and amino acid sequences of both enzymes, we determined these characteristics in the cat. Both enzyme types were found in the kidneys. 11 beta-HSD1 in the feline kidney showed bidirectional activity with predominantly dehydrogenase activity (dehydrogenase: K(m) 1959+/-797 nM, V(max) 766+/-88 pmol/mg*min; reductase: K(m) 778+/-136 nM, V(max) 112+/-4 pmol/mg*min). 11 beta-HSD2 represents a unidirectional dehydrogenase with a higher substrate affinity (K(m) 184+/-24 nM, V(max) 74+/-3 pmol/mg*min). In the liver, only 11 beta-HSD1 is detected exerting reductase activity (K(m) 10462 nM, V(max) 840 pmol/mg*min). Sequence analysis of conserved parts of 11 beta-HSD1 and 11 beta-HSD2 revealed the highest homology of the feline enzymes with the correspondent enzymes found in man. This suggests that the cat may serve as a suitable model species for studies directed to the pathogenesis and treatment of human diseases like AMES and hypertension.
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PMID:Characterisation of 11 beta-hydroxysteroid dehydrogenases in feline kidney and liver. 1473 82

One of the central functions of the kidney is to excrete low molecular weight, water soluble, plasma, waste products into the urine, whereas macromolecules, the size of albumin and larger, are retained. The flow of the glomerular filtrate is thought to follow an extracellular route, passing through the endothelial fenestrae, then across the glomerular basement membrane and finally through the slit diaphragm between the foot processes of podocytes. Recently it has been hypothesized that microalbuminuria leading to proteinuria and to end stage renal disease (ESRD) is mainly due to an altered glomerular fitration barrier at podocyte level. The "conditio sine qua non" for the development of diabetic ESRD is hyperglycemia. However, arterial hypertension and abnormalities of blood lipid concentrations and structure are also an important antecedent of such complication in diabetes mellitus. Interestingly it has been suggested that hyperglycemia, arterial hypertension and dyslipidemia cause disorderes of albumin excretion rate by damaging podocyte and slit diaphragm protein scaffold with over production of and extracellular release of oxygen radical species at glomerular level. The present review will briefly discuss recent reports which describe the relationship between blood glucose and lipid abnormalities and the occurrence and progression of renal damage in diabetes mellitus. More particularly we will give evidence that the risk of a rapid decline of glomerular function abruptly increases when glycated hemoglobin is steadily higher than 7.5% and postprandial blood glucose is above 200 mg/dL. Eventually we will analyze recent reports showing that treatment with statins, the inhibitors of hydroxymethylglutaryl-coenzyme A reductase, ameliorate the course of renal function in type 2 diabetic patients. It is not yet fully understood whether this effect is due to the lowering of the circulating levels of low density lipoproteins (LDL) or to an improved endothelial function or to lower patterns of LDL oxidation.
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PMID:Blood glucose and lipid control as risk factors in the progression of renal damage in type 2 diabetes. 1473

Hydroxymethylglutaryl-coenzyme A reductase inhibitors prevent load-induced left ventricular hypertrophy (LVH). Whether this effect is related to antioxidant properties of this class of drugs is poorly understood. The aim of the present report was to evaluate the regulation of nitrotyrosine production during the development of load-induced LVH and the effect of simvastatin treatment in this process. Rats were subjected to aortic constriction up to 15 days. LVH was evaluated by left/right ventricle mass ratio. Myocardial content of nitrotyrosine, nitric oxide synthase (NOS) isoforms, and phagocyte-type NAD(P)H-oxidase subunits (p67-phox and p22-phox) were analyzed by immunoblotting and immunohistochemistry assays. Another group of rats received treatment with either simvastatin or placebo for 15 days after the onset of pressure overload, and their hearts were also studied. Myocardial nitrotyrosine content was increased from 3 to 15 days of pressure overload in regions of cardiac myocytes in close apposition to myocardial stroma during LVH. Neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) isoforms had their expression increased in coronary vessels (nNOS and iNOS) and in myocardial stroma (eNOS) from day 3 to day 7 of aortic constriction. However, p67-phox and p22-phox expression was increased in cells of myocardial stroma in parallel to augmented myocardial nitrotyrosine content. Simvastatin treatment inhibited the increases in myocardial nitrotyrosine content and in p67-phox and p22-phox expression, and significantly reduced LVH. In conclusion, antioxidant properties of simvastatin might play a role in myocardial remodeling induced by pressure overload.
Hypertension 2004 May
PMID:Simvastatin prevents load-induced protein tyrosine nitration in overloaded hearts. 1502 31

Several intervention studies have shown that some hypolipidemic and hypotensive drugs such as fibrates, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors and calcium (Ca)-antagonists prevent atherosclerosis. The main pathological findings in atherosclerosis include abnormal reactions of neutrophils, lymphocytes and monocytes/ macrophages, vascular smooth muscle cells and vascular endothelial cells, and the accumulation of cholesterol ester in the arterial wall. Therefore, investigating the effects of these drugs on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis. Here, based on recent studies including our own, we describe the relationships between risk factors for atherosclerosis, especially hyperlipidemia and hypertension, and the molecular mechanisms that govern lipid metabolism in the arteries.
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PMID:The possible therapeutic actions of peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists, PPAR gamma agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, angiotensin converting enzyme (ACE) inhibitors and calcium (Ca)-antagonists on vascular endothelial cells. 1503 51

Inflammation occurs in the vasculature as a response to injury, lipid peroxidation, and perhaps infection. Various risk factors, including hypertension, diabetes, and smoking, are amplified by the harmful effects of oxidized low-density-lipoprotein cholesterol, initiating a chronic inflammatory reaction, the result of which is a vulnerable plaque, prone to rupture and thrombosis. Epidemiological and clinical studies have shown strong and consistent relationships between markers of inflammation and risk of future cardiovascular events. Inflammation can potentially be detected locally by imaging techniques as well as emerging techniques, such as identification of temperature or pH heterogeneity. It can be detected systemically by measurement of inflammatory markers. Of these, the most reliable and accessible for clinical use is currently high-sensitivity C-reactive protein. A combination of methods may provide the best identification of persons at risk for cardiovascular events who would benefit from treatment. In randomized, controlled trials, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the form of statins, have been shown to provide effective therapy for lowering CRP, in conjunction with their lipid-lowering effects. Although the magnitude of risk reduction associated with statin use appears to be largest for those with the highest serum levels of CRP, whether CRP reduction per se lowers cardiovascular risk is unknown.
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PMID:Inflammation as a cardiovascular risk factor. 1517 56

An increased incidence of ischemic stroke has been reported in patients with Crohn's disease. Cerebral infarcts are usually considered as a complication of the hypercoagulable state associated with this inflammatory bowel disease (IBD). The association between Crohn's disease, hyperhomocysteinemia and large-artery stroke of the young has rarely been reported. A 39-year-old woman, with prior medical history of Crohn's disease and hypertension, presented with an ischemic stroke of the left internal carotid artery (ICA) territory. Etiological workup disclosed bilateral high-grade ICA stenosis and atheroma of the subclavian and vertebral arteries. Exhaustive search for prothrombotic factors showed inflammation, with an increased level of fibrinogen and factor IX, and a marked hyperhomocysteinemia. Both vitamin B1 and vitamin B6 plasmatic levels were decreased. Heterozygous C677T methylene-tetrahydrofolate reductase gene mutation was present. This observation highlights the combined proatherogenic effect of vitamin B deficiency-induced hyperhomocysteinemia and inflammation leading to large-artery stroke of the young in the setting of Crohn's disease. Our case report stresses the importance of vitamin deficiency screening in patients with IBD in terms of stroke prevention.
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PMID:Large-artery stroke in a young patient with Crohn's disease. Role of vitamin B6 deficiency-induced hyperhomocysteinemia. 1517 25

Pharmacokinetic and pharmacodynamic interactions between simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and diltiazem, a calcium antagonist, were investigated in 7 male and 4 female patients with hypercholesterolemia and hypertension. The patients were given, for one in a three consecutive 4-week periods, oral simvastatin (5 mg/day), oral simvastatin (5 mg/day) combined with diltiazem (90 mg/day), and then oral diltiazem (90 mg/day), respectively. The area under the plasma concentration versus time curve up to 6 hours post-dose (AUC0-6h) and maximum plasma concentrations (Cmax) of the drugs, serum lipid profiles, blood pressures and liver functions were assessed on the last day of each of the three 4-week periods. After the combined treatment period, Cmax of HMG-CoA reductase inhibitor was elevated from 7.8 +/- 2.6 ng/ml to 15.4 +/- 7.9 ng/ml (P < 0.01) and AUC0-6h from 21.7 +/- 4.9 ng x hr/ml to 43.3 +/- 23.4 ng x hr/ml (P < 0.01), while Cmax of diltiazem was decreased from 74.2 +/- 36.4 ng/ml to 58.6 +/- 18.9 ng/ml (P < 0.05) and its AUC0-6h from 365 +/- 153 ng x hr/ml to 287 +/- 113 ng x hr/ml (P < 0.01). Compared to simvastatin monotherapy, combined treatment further reduced LDL-cholesterol levels by 9%, from 129 +/- 16 mg/dl to 119 +/- 17 mg/dl (P < 0.05). No adverse events were observed throughout the study. These apparent pharmacokinetic interactions, namely the increase of HMG-CoA reductase inhibitor concentration by diltiazem and the decrease of diltiazem concentration by simvastatin, enhance the cholesterol-lowering effects of simvastatin during combined treatment.
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PMID:Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension. 1553 80

Aortic valve sclerosis is defined as calcification and thickening of a trileaflet aortic valve in the absence of obstruction of ventricular outflow. Its frequency increases with age, making it a major geriatric problem. Of adults aged > 65 years, 21-29% exhibit aortic valve sclerosis. Incidence of aortic sclerosis increases with age, male gender, smoking, hypertension, high lipoprotein (Lp) (a), high low-density lipoprotein (LDL), and diabetes mellitus. Aortic valves affected by aortic sclerosis contain a higher amount of oxidized LDL cholesterol and show increased expression of metalloproteinases. Clinically, it can be suspected in the presence of soft ejection systolic murmur at the aortic area, normal split of the second heart sound, and normal volume carotid pulse, but it can be best detected by echocardiography. Aortic sclerosis may be accompanied by mitral annulus calcification up to 50% of cases. It is associated with an increase of approximately 50% in the risk of death from cardiovascular causes and the risk of myocardial infarction. The mechanism by which aortic sclerosis contributes to or is associated with increased cardiovascular risk is not known. Aortic sclerosis is associated with systemic endothelial dysfunction, and a small percentage of cases may progress to aortic stenosis. Lowering of LDL cholesterol by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to decrease progression of aortic valve calcification. Aortic sclerosis is not a mere benign finding. Once diagnosis of aortic sclerosis has been made, it should be considered a potential marker of coexisting coronary disease. Aggressive management of modifiable risk factors, especially LDL cholesterol lowering, may slow progression of the disease.
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PMID:Aortic sclerosis--a marker of coronary atherosclerosis. 1562 7

Insufficient efficacy above all, but also the appearance of side effects or the occurrence of complications may motivate a change in the treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (HBP). In terms of efficacy, surgery remains superior to all medical treatments including alphablockers which are the most active. 5-alpha-reductase inhibitors have a slow efficacy which is all the more marked when the prostatic volume is large. Phytotherapy has a slight activity which is higher than that of placebo. Drug combinations are currently being studied and, although a benefit has been shown in certain publications, their clinical efficacy remains to be specified. They may become an alternative in case of failure of single-agent therapy to prevent or delay surgery. The incidence of side effects is low and varies with the treatment used and within a same therapeutic class. With alphablockers for instance, orthostatic hypotension, which is the main side effect, varies from 1% to 8% approximately depending on the study and molecule. The side effects of 5-alpha-reductase inhibitors are mainly sexual disorders, observed in 1 to 4% of cases approximately. Hence, the occurrence of a drug side effect causing treatment discontinuation should incite a change of molecule, even within the same class for alphablockers. On the other hand, if complications of HBP occur, it is then necessary to resort to surgery.
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PMID:[Arguments for deciding to change treatment in benign prostatic hyperplasia]. 1565 92

Recent studies suggest that postnatal neovascularization relies not exclusively on sprouting of preexisting vessels ("angiogenesis"), but also involves the contribution of bone marrow-derived circulating endothelial progenitor cells (EPCs). EPCs can be isolated from peripheral blood or bone marrow mononuclear cells, CD34(+) or CD133(+) hematopoietic progenitors. Infusion of EPCs was shown to promote postnatal neovascularization of ischemic tissue after myocardial infarction in animal models and initial clinical trials. Moreover, circulating endothelial precursor cells can home to denuded arteries after balloon injury and contribute to endothelial regeneration, thereby limiting the development of restenosis. Thus, circulating endothelial cells may exert an important function as endogenous repair mechanism to maintain the integrity of the endothelial monolayer and to promote ischemia-induced neovascularization. However, risk factors for coronary artery disease, such as diabetes, hypercholesterolemia, and hypertension are associated with impaired number and function of EPC in patients with coronary artery disease. Therapeutically, the reduction of EPC number and the decreased functional activity in patients with coronary artery disease was counteracted by 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase inhibitors (statins), vascular endothelial growth factor (VEGF), estrogen, or exercise. At the molecular level, these factors are well established to activate the phosphatidyl-inositol-3-kinase (PI3K)-Akt-dependent activation of the endothelial nitric oxide synthase (eNOS), suggesting that the PI3K-Akt-eNOS signaling pathway may be involved in the transduction of atheroprotective factors. Taken together, the balance of atheroprotective and proatherosclerotic factors may influence EPC levels and their functional capacity to improve neovascularization and endothelial regeneration.
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PMID:Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors. 1584 10


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