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)

To elucidate the role of oxygen free radicals and lipid peroxidation in the pathogenesis of early hypertension and atherosclerosis, we studied the native distribution of three primary arterial antioxidant enzymes (AEs). Specific immunohistochemical localization of superoxide dismutase (Cu-Zn SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) was examined in the arterial wall of New Zealand White rabbits: six sham-operated normotensive/normolipidemics (NT/NL), seven coarctation-induced hypertensive/normolipidemics (HT/NL), eight normotensive diet-induced hyperlipidemics (NT/HL), and six hypertensive/hyperlipidemics (HT/HL). All three AEs were confined primarily to the endothelium in NT/NL rabbit aortas. However, in HT and HL rabbits a greater proportion of the arterial wall, including the endothelium, inner media, and middle media, displayed immunolocalization of three AEs. Multiple linear-regression analysis revealed that more than 70% of the total variability in the depth of immunolocalization of arterial AEs could be explained by changes in blood pressure and/or total cholesterol. Also, levels of plasma and arterial cholesterol oxides were significantly different (p less than 0.05) in HT and HL rabbits compared with controls, with twofold increases in NT/HLs, threefold increases in HT/NLs, and fourfold increases in HT/HLs. We conclude that intense free-radical activity in the arterial wall of HT and HL animals is one possibility and that this occurs despite the presence of abundant AEs.
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PMID:Immunolocalization of native antioxidant scavenger enzymes in early hypertensive and atherosclerotic arteries. Role of oxygen free radicals. 155 32

1. The activities of glutathione (GSH) transferases in male, spontaneously hypertensive rats (SHR) and stroke-prone rats (SHR-SP) were different from those of normotensive male Wistar Kyoto rats (WKY). 2. These alterations of the enzyme activities were partly due to the changes in the levels of subunits 2 and 4. 3. Subunit selective alterations were observed in pathophysiological conditions, namely spontaneous hypertension. 4. The sex-related difference of GSH transferases in these animals was also discussed.
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PMID:Subunit selective alteration of hepatic glutathione transferases in spontaneously hypertensive rats. 195 32

The role of glutathione in the central nervous system in regulating blood pressure (BP) and sympathetic nerve activity (SNA) was investigated in rats. Intracerebroventricular (ICV) injection of glutathione disulfide (GSSG: 1.7-33 nmol) resulted in a dose-dependent increase in BP [delta mean BP: 17 +/- 1 mm Hg (n = 7) for 33-nmol dose] together with a marked increase in SNA [163 +/- 13 to 672 +/- 70 spikes/10 s (n = 7), p less than 0.001]. Intracerebroventricular administration of its reduced form (GSH, 33 nmol) produced a vasodepressor response (delta mean BP: -9 +/- 2 mm Hg) accompanied by a corresponding decrease in SNA [192 +/- 15 to 54 +/- 22 spikes/10 s (n = 6), p less than 0.01]. These responses were not due to a leakage into the systemic circulation, since intravenous injection of GSSG or GSH (33 nmol) did not show any cardiovascular effects. Electrical stimulation of the posterior hypothalamus induced hypertension with a significant decrease of GSSG in the brain stem. The results indicate that GSSG has a stimulatory control over the sympathetic nervous system while GSH has an inhibitory effect on SNA. Glutathione disulfide and GSH may act within the central nervous system to modulate the tone of the sympathetic nervous system.
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PMID:Brain glutathione and blood pressure control. 245 61

The role of brain glutathione metabolism in hypertensive animals was studied. In spontaneously hypertensive rats (SHR) from prehypertension to established hypertension, the content of oxidized glutathione (GSSG) and the ratio of GSSG to GSH in the hypothalamus were significantly (p less than 0.05) higher than those in age-matched normotensive Wistar Kyoto rats (WKY). Hypothalamic glutathione reductase (GR) activities in prehypertensive and established hypertensive SHR were significantly (p less than 0.05) lower than those in WKY. DOCA-salt hypertensive rats (DSR) also had a significantly (p less than 0.05) higher content of GSSG and GSSG/GSH ratio and a significantly (p less than 0.05) lower GR activity in the hypothalamus than the normotensive control. There were no significant differences in these values in the brain stem between hypertensive and normotensive rats. These results suggest that the increased GSSG/GSH ratio due to reduced activity of GR in the hypothalamus may have an important role in the development of hypertension in SHR and DSR.
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PMID:The role of hypothalamic glutathione in hypertensive animals. 324 1

The incipient timing of cerebral strokes in the stroke-prone spontaneously hypertensive rats (SHRSP) was biochemically determined by investigating the relationship between the glutathione peroxidase (GSH-Px) activity in erythrocytes and the extent of stroke lesions. When the blood pressure of SHRSPs was maintained at over 240 mmHg, the GSH-Px activity fell, and the body weight also decreased. In SHRSP whose GSH-Px activity in erythrocytes had dropped below 23 units/ml of blood, the incidence of cerebral strokes was 98% (n = 88/90). The hematocrit level did not change even after the GSH-Px activity had dropped to 23 units/ml of blood. The reduced GSH-Px activity in erythrocytes observed during continued hypertension was found to be due to a decrease in GSH-Px protein, and not to any inactivation of the enzyme, as evident from immunochemical titration. At the moment when the GSH-Px activity had dropped to 23 units/ml of blood, and the control diet was changed to one based on fish or a hydralazine treatment given, the activity recovered, and an increase in body weight and prolongation of the life-span were observed. It was deduced from these findings that tracing the GSH-Px activity in erythrocytes in SHRSP would serve as an indicator for predicting and prognosing stroke lesions.
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PMID:Prediction of stroke lesions in stroke-prone spontaneously hypertensive rats by glutathione peroxidase in erythrocytes. 754 98

Accelerated atherosclerotic vascular disease is the leading cause of mortality in patients with diabetes mellitus. Endothelium-derived nitric oxide (NO) is a potent endogenous nitrovasodilator and plays a major role in modulation of vascular tone. Selective impairment of endothelium-dependent relaxation has been demonstrated in aortas of both nondiabetic animals exposed to elevated concentrations of glucose in vitro and insulin-dependent diabetic animals. The impaired NO release in experimentally induced diabetes may be prevented by a number of antioxidants. It has been hypothesized that oxygen-derived free radicals (OFR) generated during both glucose autoxidation and formation of advanced glycosylation end products may interfere with NO action and attenuate its vasodilatory activity. The oxidative injury may also be increased in diabetes mellitus because of a weakened defense due to reduced endogenous antioxidants (vitamin E, reduced glutathione [GSH]). A defective endothelium-dependent vascular relaxation has been found in animal models of hypertension and in hypertensive patients. An imbalance due to reduced production of NO or increased production of free radicals, mainly superoxide anion, may facilitate the development of an arterial functional spasm. Treatment with different antioxidants increases blood flow in the forearm and decreases blood pressure and viscosity in normal humans; vitamin E inhibits nonenzymatic glycosylation, oxidative stress, and red blood cell microviscosity in diabetic patients. Long-term randomized clinical trials of adequate size in secondary and primary prevention could support the free-radical hypothesis for diabetic diabetic vascular complications and the use of antioxidants to reduce the risk of coronary heart disease.
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PMID:Diabetes mellitus, hypertension, and cardiovascular disease: which role for oxidative stress? 788 82

The effects of age and hypertension on the antioxidant defence systems and the lipid peroxidation in rat isolated hepatocytes were studied. Four different age groups (1, 3, 6 and 12 months) were considered in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Age-associated changes were observed on vitamin E status, glutathione (GSH) level, MDA formation and glutathione peroxidase (GSH-Px) activity in both strains. Maximal levels or activities of these parameters were found at 3 and 6 months, except for MDA which was low at 3 months. Then, a fall was observed at 12-month-old compared to 6-month values. In addition, GSH-Px activity was significantly lower in SHR than in WKY rats, except at the age of one month. The decrease of this enzyme activity could induce an increased cellular generation of radical species and lipid peroxidation, which might be link to hypertension.
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PMID:Age-related changes in antioxidant defence mechanisms and peroxidation in isolated hepatocytes from spontaneously hypertensive and normotensive rats. 807 5

Steroid 11 beta-hydroxylase is encoded by two homologous genes, CYP11B1 and CYP11B2, located on chromosome 8q21-22. CYP11B1 encodes a specific cytochrome P-450 (P-450c11) necessary for cortisol biosynthesis, with predominantly 11 beta-hydroxylase and moderate 18-hydroxylase activity, whereas CYP11B2 encodes another isozyme (P-450cmo) necessary for aldosterone biosynthesis, with 11 beta-hydroxylase, 18-hydroxylase and 18-oxidase activities (the latter two termed corticosterone methyl-oxidase I and II; CMO-I and II, respectively). Two steroid biosynthetic defects, both relatively frequent in Israel, are caused by specific mutations in each of these genes. 11 beta-Hydroxylase deficiency is frequent among Jews from Morocco (1 in 5000 to 7000 births), and is characterized by virilization, hypertension, impaired cortisol biosynthesis, and increased deoxycorticosterone and androgens. Affected individuals have a single base substitution in exon 8 of CYP11B1, codon 448, from CGC (arginine) to CAC (histidine). This sequence, normally absent in CYP11B2, constitutes a true point mutation within the heme binding domain of CYP11B1 that results in marked impairment of enzymatic activity. The clinical expression is characterized by a wide range of variability in the signs of both androgen and mineralocorticoid excess, even though an identical mutation was found in all but one of the affected alleles examined. CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births), and is characterized by a typical salt-wasting syndrome, increased 18-hydroxycorticosterone, impaired aldosterone biosynthesis, and a high ratio of these steroids. No mutation was found in CYP11B1, but all individuals affected were homozygous for two missense mutations in CYP11B2. The first, in exon 3, codon 181, from CGG (arginine) to TGG (tryptophane) is a mutation that completely abolishes both CMO-I and II activities, whereas the second, in exon 7, codon 386, from GTG (valine) to GCG (alanine) is a more conservative substitution that produces only a minimal reduction in CMO-I activity. Individuals homozygous for either one of these mutations are asymptomatic.
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PMID:Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. 848 57

Monocrotaline (MONO), a pyrrolizidine alkaloid, causes pulmonary arterial hypertension and right ventricular hypertrophy due to hepatic metabolism to the alkylating pyrrole dehydromonocrotaline. Taurine a sulfonic amino acid, is hepato- and cardioprotective in a variety of conditions. We have examined the effects of taurine and its amidino analog, guanidinoethane sulfonate (GES), in rats injected i.p. with MONO (65 mg/kg). Taurine and GES were given as 1% solutions in drinking water beginning 14 days before administration of MONO and continuing for 14 days therafter, when the rats were killed. The MONO group had right ventricular hypertrophy and pulmonary hyperplasia. Compared with control, no significant changes in the right ventricle/left ventricle weight ratio, or the right ventricle/body weight ratio occurred in rats also given taurine of GES. Lung weights in these two groups were higher than in the control group, but below that of the MONO-alone group. The lethality of MONO over 14 days was decreased by taurine (LD50 for MONO alone 80 mg/kg; for MONO + taurine 121 mg/kg). Rats given only MONO had lower hepatic concentrations of GSH and cysteine (Cys), and higher activities of microsomal GSH transferase activity were no different from control. Gamma-Glutamylcysteine (Glu-Cys) synthetase and gamma-glutamyl transpeptidase activities were elevated. In MONO-injected rats given GES, hepatic GSH levels were higher and Cys levels were lower than in either the MONO alone or MONO + taurine groups. Gamma-Glu-Cys synthetase activity was depressed. Microsomal GSH transferase, GSH peroxidase and gamma-glutamyl transpeptidase activities were elevated. Livers of MONO-injected animals showed higher levels of serine (reversed by both taurine and GES) and glycine (Gly; reversed by GES) and lower levels of glutamine. Compared with control rats, the following changes occurred in serum amino acids: MONO alone: increased aspartate, taurine and lysine; taurine-supplemented: increased taurine, methionine (Met) and lysine, and decreased Gly; GES-supplemented: decreased asparagine, serine, Gly, arginine, taurine, and valine. Compared with the MONO-alone group, the taurine-supplemented group had higher glutamate (Glu), Met and alanine, and the GES-supplemented group higher alanine and lower serine, Gly, arginine and valine. We conclude that taurine protects against MONO-induced lethality and right ventricular hypertrophy. GES also protects against right ventricular hypertrophy. However, these agents act by different mechanisms, taurine preventing many of the biochemical changes induced by MONO, with GES inducing additional changes.
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PMID:Effects of taurine and guanidinoethane sulfonate on toxicity of the pyrrolizidine alkaloid monocrotaline. 857 99

Monocrotaline (MONO), a pyrrolizidine alkaloid, causes veno-occlusive disease of the liver, pulmonary arterial hypertension, and right ventricular hypertrophy. Toxicity is due to the hepatic formation of a pyrolic metabolite that can be detoxified by conjugation with glutathione (GSH). We have shown that the GSH content of the liver affects the quantity of the pyrrolic metabolite that is released from the liver. We have now examined whether MONO, in turn, affects GSH metabolism. Twenty-four hours after administration of MONO to rats (65 mg/kg, i.p.), the highest concentration of bound pyrrolic metabolites was found in the liver, followed by the lung and kidney. Heart and brain contained lower concentrations of these metabolites. Significantly higher levels of GSH were found in liver and lungs of MONO-treated rats than in saline-injected control animals. In the liver, activities of the following enzymes were elevated: gamma-glutamylcysteine synthetase, GSH synthetase, gamma-glutamyl transpeptidase, dipeptidase, and microsomal GSH transferase. The same changes were seen in the lung. In the heart, gamma-glutamyl transpeptidase activity was decreased markedly, and cytosolic GSH transferase activity was elevated. In the kidney, the activities of GSH synthetase, gamma-glutamyl transpeptidase, and cytosolic GSH transferase were increased. Our results establish a mutual interaction of MONO and sulfur metabolism. It appears that an early metabolic action of MONO is to modify sulfur amino acid metabolism, diverting cysteine metabolism from oxidation to taurine towards synthesis of GSH.
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PMID:Effects of monocrotaline, a pyrrolizidine alkaloid, on glutathione metabolism in the rat. 857 5


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