Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Recent pharmacological studies confirmed the role of hypercholesterolemia in the pathogenesis of coronary atherosclerosis. A 10% reduction in cholesterol levels can reduce the risk of coronary heart disease by 15%. However many hypercholesterolemic patients often suffer from arterial hypertension and drugs such as thiazide diuretics cause an imbalance in lipid metabolism. The efficacy and the tolerability of simvastatin (a inhibitor of HGM-CoA reductase) with that of gemfibrozil (a fibric acid derivative, which can reduce the VLDL level) were compared in a placebo-controlled study in 2 groups of patients with primary hypercholesterolemia and mild-to-moderate essential hypertension treated with hydrochlorothiazide. After 10 weeks standard hypolipidemic diet and hydrochlorothiazide (25 mg od) therapy, 30 patients whose cholesterol levels were still greater than or equal to 250 mg/100 ml and whose diastolic blood pressure was less than 95 mmHg were randomized to one of the following treatments: simvastatin, 20 mg od, gemfibrozil, 600 mg bid or placebo, while continuing dietetic and diuretic treatment. After 24 weeks treatment, simvastatin induced a 37% reduction in cholesterol plasma levels, a 9% increase of HDL and a 16% reduction of LDL. APO-A1 showed a 4% increase, while APO-B showed a 3% reduction. Gemfibrozil induced a 20% reduction in plasma triglycerides and a 13% decrease in plasma cholesterol, with a significant 19% increase in HDL and a 11% reduction in LDL. No significant variations in any of the lipid parameters monitored were observed in the placebo group. Treatment with simvastatin or gemfibrozil in hypertensive patients in hydrochlorothiazide monotherapy can reduce total cholesterol and LDL-cholesterol plasma levels, while significantly increasing HDL plasma levels compared to placebo. Simvastatin, however, resulted more efficient than gemfibrozil on total cholesterol or cholesterol fractions.
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PMID:[Simvastatin versus gemfibrozil in the treatment of primary hypercholesterolemia in hypertensive patients treated with hydrochlorothiazide]. 224 35

Ingestion of licorice or treatment with chemical derivatives of glycyrrhetinic acid (GA), an active principle of licorice, can cause hypertension, sodium retention, and hypokalemia. Although GA has been shown to inhibit 11 beta-hydroxysteroid dehydrogenase, it may not be the only hepatic enzyme affected by this licorice derivative. Therefore, we studied the effects of GA on other major hepatic steroid-metabolizing enzymes from adrenalectomized male rats using aldosterone as the substrate; namely, delta 4-5 alpha- and delta 4-5 beta-reductases and 3 alpha- and 3 beta-hydroxysteroid dehydrogenases (3 alpha- and 3 beta-HSD). From these in vitro studies, we demonstrated that GA does not affect either microsomal 5 alpha-reductase or cytosolic 3 alpha-HSD activity. However, GA is a potent inhibitor of cytosolic 5 beta-reductase; the K(is) and K(ii) were calculated from enzyme kinetic analysis to be 6.79 and 5.41 microM, respectively, using the Cleland equation, indicating that GA is a noncompetitive inhibitor of aldosterone. In addition, GA specifically inhibited microsomal 3 beta-HSD enzyme activity by what appears to be a competitive inhibition mechanism, causing a build-up of the intermediate, 5 alpha-dihydroaldosterone (DHAldo). Thus, this study has indicated that GA has a profound effect on hepatic ring A-reduction of aldosterone. Inhibition of 5 beta-reductase and 3 beta-HSD results in decreased synthesis of both 3 alpha, 5 beta-tetrahydroaldosterone (THAldo) and 3 beta, 5 alpha-THAldo and, hence, accumulation of aldosterone and 5 alpha-DHAldo, both potent mineralocorticoids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of the licorice derivative, glycyrrhetinic acid, on hepatic 3 alpha- and 3 beta-hydroxysteroid dehydrogenases and 5 alpha- and 5 beta-reductase pathways of metabolism of aldosterone in male rats. 232 27

The role of lipids in the pathogenesis of focal glomerulosclerosis (FGS) was evaluated using two chemically different lipid lowering agents, clofibric acid and mevinolin. Pharmacologically, these two agents have different mechanisms of action. Clofibric acid affects both cholesterol and triglyceride metabolism, while mevinolin inhibits 3-hydroxy-3 methyl-glutaryl coenzyme A reductase, the rate limiting enzyme in cellular cholesterol synthesis. In two different models of FGS in which hyperlipidemia occurs, the obese Zucker rat and the 5/6 nephrectomy model, both agents significantly reduced FGS and albuminuria. Since glomerular hemodynamic function is normal in obese Zucker rats, these results suggested that lipids are an independent factor in the pathogenesis of FGS. Moreover, in the 5/6 nephrectomy model, the beneficial effects on glomerular structure of reducing serum lipids occurred despite persistent systemic and glomerular hypertension. Thus, we postulated that a synergistic interaction between lipids and hypertension might exist in the pathogenesis of FGS.
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PMID:The role of lipids in progressive glomerular disease. 344 53

We documented 17-hydroxylase deficiency in a newborn male infant with micropenis, perineoscrotal hypospadias, and a bifid scrotum containing two histologically normal testes. Mild hypertension developed at 20 months of age. The diagnosis was made on the basis of elevated serum levels of progesterone (180-475 ng/dl), corticosterone (1.8-20.2 micrograms/dl), and desoxycorticosterone (56-330 ng/dl). There was an exaggerated response of these steroids to ACTH-(1-24) and suppression by dexamethasone. Mass spectrometric analysis of urinary steroids showed an abnormally high ratio of C21 to C19 3 beta-hydroxy-5-ene steroids due to reduced C19 steroid formation. We suggest that this infant has a form of 17-hydroxylase deficiency which is less severe than previously reported cases in view of his partial prenatal virilization, the minimal testosterone response to CG the absence of hypokalemia, and the presence of normal cortisol levels after prolonged ACTH stimulation. Family studies suggest reduced 17-hydroxylase activity in the father. A surprising coincident finding of no apparent clinical significance was in vitro evidence of 5 alpha-reductase deficiency in genital skin fibroblasts.
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PMID:Diagnosis and natural history of 17-hydroxylase deficiency in a newborn male. 608 2

11 beta-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone. This activity may be required to confer normal ligand specificity upon the mineralocorticoid receptor. Although an isozyme of 11-HSD was previously isolated from rat liver, a different isozyme is apparently expressed in mineralocorticoid target tissues. We isolated a sheep kidney cDNA clone encoding this isozyme by expression screening using Xenopus oocytes. The cDNA is 1.8 kb in length and encodes a protein of 427 amino acid residues with a predicted M(r) of 46,700. When expressed in oocytes, this enzyme functions as an NAD(+)-dependent 11 beta-hydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD(+)-dependent isozyme of 17 beta-hydroxysteroid dehydrogenase, but only 20% identical to the NADP(+)-dependent liver isozyme of 11-HSD. It is expressed at high levels in the kidney and adrenal and at lower levels in the colon. The corresponding gene is present in a single copy in the sheep genome. In humans, this gene is a candidate locus for the syndrome of apparent mineralocorticoid excess, a form of hypertension postulated to result from 11-HSD deficiency in mineralocorticoid target tissues.
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PMID:Cloning of cDNA encoding an NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase in sheep kidney. 758 2

A case of acute inflammatory myopathy associated with the use of pravastatin, a new hydrophilic 3-hydroxy-3 methylglutaril coenzyme A reductase inhibitor, is reported. The patient, a 69-year-old man was affected by non-insulin-dependent diabetes mellitus and hypertension. He assumed pravastatin (20 mg/day) because of hypercholesterolemia. He was admitted with acute myopathy of the lower limbs which resolved in a few days after pravastatin discontinuation. A previously unknown hypothyroidism, probably due to chronic autoimmune thyroiditis, was evidenced. Muscle biopsy (left gastrocnemius) revealed a perimysial and endomysial inflammatory infiltrate with a prevalence of CD4+ lymphocytes. While lovastatin and simvastatin have been associated with toxic myopathy, pravastatin-associated myopathy could represent a distinct, inflammatory entity.
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PMID:Pravastatin-associated myopathy. Report of a case. 760 76

Previous data in rat conductance vessels indicated that cellular mevalonate contributes to vascular tone and systemic blood pressure control. Using exogenous mevalonate (M) or lovastatin, a 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor (L), we characterized the role of mevalonate availability in resistance artery function, both in experimental animals and humans. Rat mesenteric artery resistance vessels (MARV, n = 9) were incubated for 48 h with either L, M, L + M, or vehicle (V) and tested for reactivity to NE, serotonin, acetylcholine, atrial natriuretic peptide, and sodium nitroprusside (SNP). Lovastatin increased sensitivity to NE (P < 0.03) and serotonin (P < 0.003), and significantly impaired the response to all three vasodilators. These effects were reversed by co-incubation with mevalonate. Mevalonate alone had no effect. In separate experiments, intravascular free Ca2+ concentration (ivfCa2+) was determined in fura-2AM loaded MARV. Basal ivfCa2+ was increased after a 48-h exposure to L (52.7 +/- 4.6 nM, L, vs. 29.7 +/- 2.4 nM, V, n = 12, P < 0.003), as were ivfCa2+ levels following stimulation with low (100 nM) NE concentrations. Similar ivfCa2+ concentrations were achieved during maximum contraction with NE (10 mM) in both groups. Human resistance arteries of human adipose tissue were also studied. Lovastatin increased the sensitivity to NE (ED50 = 372 +/- 56 nM, V, and 99 +/- 33 nM, L, P < 0.001) and significantly decreased the relaxation to acetylcholine and SNP of human vessels. We conclude that mevalonate availability directly contribute to resistance vessel function and vascular signal transduction systems in both experimental animals and humans. The study calls for the identification of non-sterol, mevalonate-derived vasoactive metabolites, and suggests that disorders of the mevalonate pathway can alter vascular tone and cause hypertension.
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PMID:Mevalonate availability affects human and rat resistance vessel function. 761 93

Homocyst(e)ine [H(e)], the sum of homocysteine, homocystine, and the homocysteine-cysteine mixed disulfide, free and protein-bound, has been shown to be associated in retrospective case control studies, and in one prospective study, with vascular disease, including coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease. Elevated levels of homocyst(e)ine severe enough to cause homocystinuria are seen in severe nutritional deficiencies of vitamin B12, folic acid and vitamin B6. Rare genetic disorders of vitamin B12 synthesis of 5'-10'-methylene tetrahydrofolate reductase, or the pyridoxal phosphate-dependent enzyme cystathionine beta-synthase may cause severe hyperhomocyst(e)inemia and homocystinuria. The clinical manifestation of these disorders are mental retardation, neurological disorders, and widespread thromboembolic phenomena. The measurement of H(e) is currently performed using high-pressure liquid chromatography with fluorescence detection. Other methods, especially mass spectroscopy, are also used. Internal standards using increasing concentrations of homocystine and acetylcysteine and several external standards are used to ensure accuracy of the assay. Milder elevations of H(e) have recently been associated with vascular disease, in both men and women. The strength of this association appears to be stronger for peripheral and cerebrovascular disease than for CAD. Nevertheless, several case control studies in Europe, Canada, and the United States have shown that H(e) levels are elevated in CAD patients compared with controls, and H(e) levels are independent of the conventional cardiovascular risk factors (age, gender, lipid and lipoprotein cholesterol levels, hypertension, or cigarette smoking). One prospective study, the Physicians' Health Study, has shown that H(e) levels are slightly but significantly higher in CAD cases vs controls in a population of US physicians.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Measurement of homocyst(e)ine in the prediction of arteriosclerosis. 762 74

This study estimated the cost-effectiveness of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors available in Canada for the primary prevention of coronary heart disease (CHD). A model of the cost-effectiveness of therapy used to modify low-density lipoprotein (LDL) cholesterol and high-density lipoprotein cholesterol levels was developed in the primary prevention of CHD based on risk functions from the Framingham Heart Study and Canadian data on coronary risk factors and the cost of treating the leading manifestations of CHD. Relative to no treatment, discounted gains in life expectancy range from 0.174 year for fluvastatin 40 mg to 0.215 year for simvastatin 10 mg. Costs per year-of-life-saved range from $38,800 for fluvastatin 40 mg to $56,200 for pravastatin 20 mg. In the incremental analysis relative to fluvastatin 40 mg, additional gains in life expectancy range from 0.011 year for pravastatin 20 mg to 0.041 year for simvastatin 10 mg, and incremental cost-effectiveness ratios range from $88,200 for simvastatin, 10 mg to $330,300 for pravastatin 20 mg. Our analysis showed that the cost-effectiveness of cholesterol-lowering therapy is sensitive to pretreatment risk of CHD, as expressed by pretreatment cholesterol levels and the presence of additional risk factors such as hypertension, diabetes, and smoking. The results of the analysis suggest that it is more cost-effective to initiate treatment with fluvastatin than with pravastatin, simvastatin, or lovastatin. Sensitivity analysis showed the results to be stable even if the lipid-lowering effect of fluvastatin is varied by 23% from the original assumption of 25% LDL reduction (ie, from 19.3% to 30.8%). Limitations of the study are recognized and discussed. A head-to-head comparison of these HMG-CoA reductase inhibitors could provide further evidence that therapy initiated with fluvastatin may be the most cost-effective way to treat patients with hypercholesterolemia who are eligible for treatment with HMG-CoA reductase inhibitors.
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PMID:Cost-effectiveness analysis of lipid-modifying therapy in Canada: comparison of HMG-CoA reductase inhibitors in the primary prevention of coronary heart disease. 758 61

The activities of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) and 5 beta-reductase were analyzed in 39 normotensive controls and 128 patients with essential hypertension. The activity of 11 beta-HSD was obtained by dividing the 24-hour urinary tetrahydrocortisone by the sum of tetrahydrocortisol (THF) and allotetrahydrocortisol (aTHF), whereas the activity of 5 beta-reductase was obtained by dividing the 24-hour urinary THF by aTHF. The activity of 5 beta-reductase was significantly lower in essential hypertensives compared with normotensive controls (P < 0.05). However, the activity of 11 beta-HSD did not differ between normotensive controls and essential hypertensives. A positive correlation between the activities of 11 beta-HSD and 5 beta-reductase was observed in essential hypertensives (r = 0.60, P < 0.01). Neither 11 beta-HSD nor 5 beta-reductase activity correlated with indices of renal mineralocorticoid receptor activation, which were assessed by determination of plasma potassium and urinary excretion of sodium as well as potassium. Taken together, these results suggest that disturbances of one of the inactivation pathways of cortisol may contribute to the pathogenesis of hypertension.
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PMID:The activities of 5 beta-reductase and 11 beta-hydroxysteroid dehydrogenase in essential hypertension. 770 42


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