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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although active oxygen species play important roles in the pathogenesis of various diseases, the molecular mechanism for oxygen toxicity in vascular diseases remains to be elucidated. Since endothelium-derived relaxing factor (EDRF) is inactivated by superoxide radicals in vitro, oxidative stress in and around vascular endothelial cells may affect the circulatory status of animals. To study the role of superoxide radicals and related enzymes, such as superoxide dismutase (SOD), in vascular diseases, we have developed a fusion protein (HB-SOD) consisting of human Cu/Zn-type SOD and a C-terminal basic peptide with high affinity for heparan sulfate on endothelial cells. When injected intravenously, HB-SOD bound to vascular endothelial cells, underwent transcellular transport, and localized within vascular walls by a heparin-inhibitable mechanism. The blood pressure of spontaneously hypertensive rats (SHR) but not normal animals was decreased significantly by HB-SOD. Heparin inhibited the depressor effect of HB-SOD. In contrast, native SOD had no effect on blood pressure of either SHR or normal rats. Neither H2O2-inactivated HB-SOD nor the C-terminal heparin-binding peptide showed such a depressor effect, suggesting that the catalytic function of HB-SOD is responsible for its depressor action. To know the source of superoxide radicals, we determined xanthine oxidase activity in the aorta and uric acid levels in the plasma. Although no appreciable difference in xanthine oxidase activity was found between the two animal groups, uric acid levels were significantly higher in SHR than in normal rats. Oxypurinol, a potent inhibitor of xanthine oxidase, also decreased the blood pressure of SHR but not of normal rats. These findings indicate that superoxide radicals in and around vascular endothelial cells play critical roles in the pathogenesis of hypertension of SHR.
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PMID:Does superoxide underlie the pathogenesis of hypertension? 165 94

Indapamide, a nonthiazide diuretic, exhibits direct vasodilator action as well as natriuretic and diuretic effects. Although calcium antagonist-like activity has been addressed so far, the mechanisms for vasodilator effect are still uncertain. To understand the wide range of indapamide actions, we examined the effects of indapamide on the vascular eicosanoid generation and investigated its mechanisms by using rat vascular smooth muscle cells in culture. Indapamide uniquely increased the prostacyclin generation in the vascular smooth muscle cells in a dose-dependent manner, whereas it did not affect the vasoconstrictor thromboxane A2. Thiazide diuretics lowered the prostacyclin generation, while nonthiazide derivatives did not affect the biosynthesis. Enzymatic analysis revealed that indapamide affected neither [14C]arachidonate liberation nor prostacyclin synthase of the smooth muscle cells. Indapamide eliminated a stable free radical in a cell-free system, lowered the formation of malondialdehyde from lipid peroxides in rat brain homogenate, and reduced lipid peroxidation by the free radical generating system of xanthine-xanthine oxidase. Indeed, the scavenging action of indapamide significantly attenuated the inhibitory activity of 15-hydroperoxy-arachidonate to prostacyclin synthase activity. These results indicate that indapamide diuretic increases prostacyclin generation in the vascular smooth muscle cells possibly through antioxidant effects and that the enhanced prostacyclin generation is partly responsible for its direct vasodilator action.
Hypertension 1990 Feb
PMID:Radical scavengers of indapamide in prostacyclin synthesis in rat smooth muscle cell. 210 10

Endothelium-dependent contractions to acetylcholine and endothelium-independent contractions to oxygen-derived free radicals in the aorta of the spontaneously hypertensive rat (SHR) are mediated by an unidentified product of the cyclooxygenase pathway of arachidonic acid metabolism. To determine the role of thromboxane A2 (TXA2) or prostaglandin H2 (PGH2) in these contractions, rings of the thoracic aorta of SHR were suspended in organ chambers for measurement of isometric force. Acetylcholine caused endothelium-dependent contractions in quiescent rings from SHR aortas. Oxygen-derived free radicals generated with xanthine plus xanthine oxidase caused contractions in rings without endothelium. Dazoxiben (thromboxane synthetase inhibitor) did not affect contractions evoked by acetylcholine. AH 23,848, SQ 29,548, or R 68,070 (TXA2/PGH2 receptor antagonists) inhibited contractions to U 46,619 (a TXA2/PGH2 receptor agonist), acetylcholine, and oxygen-derived free radicals. Acetylcholine stimulated the release of prostacyclin from Wistar-Kyoto (WKY) rat and SHR aortas but not the release of other prostaglandins (PGE2, PGF2 alpha, TXA2). Oxygen-derived free radicals did not stimulate the release of prostaglandins from either SHR or WKY rat aortas. These results demonstrate that stimulation of TXA2/PGH2 receptors probably by PGH2 might be involved in endothelium-dependent contractions. Oxygen-derived free radicals, which might be an endothelium-derived contracting factor or factors, ultimately cause contraction by stimulation of TXA2/PGH2 receptors.
Hypertension 1990 Jun
PMID:Thromboxane A2 receptor antagonists inhibit endothelium-dependent contractions. 214 Oct 3

Clinical and experimental evidence demonstrates that hypertrophied cardiac tissue is more sensitive to ischemic injury than is normal myocardium. Recent studies indicate that cardiac ischemia-reperfusion injury involves the generation of toxic oxygen free radicals. We used the spontaneously hypertensive rat (SHR) model, with its otherwise genetically identical control (the Wistar-Kyoto [WKY] rat), to investigate the potential role of enzymes that generate and detoxify oxygen radicals in the sensitivity of hypertrophied heart to ischemia and reperfusion. Because hypertension develops progressively with age in SHRs, we assayed xanthine oxidase, superoxide dismutase, catalase, and glutathione peroxidase at three different time points and found significant fluctuations at different ages. At age 26 weeks, physiological measurements demonstrated hypertension and increased sensitivity to ischemia and reperfusion, measured as significantly decreased left ventricular recovery after injury. At this age, xanthine oxidase, which may generate oxygen radicals, was significantly increased in SHR compared with WKY rats (p = 0.003). Superoxide dismutase, which is a principal step in oxygen-radical detoxification, was significantly lower (p = 0.044). These data suggest that differences in the constitutive levels of oxygen-radical metabolic pathways are different in hypertrophied myocardium, and it is suggested that this finding may play a role in the response of these hearts to ischemia-reperfusion injury.
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PMID:Response to ischemia-reperfusion injury in hypertrophic heart. Role of free-radical metabolic pathways. 253 7

To determine if oxygen-derived free radicals are mediators of endothelium-dependent contractions to acetylcholine in the aorta of spontaneously hypertensive rats (SHR), the mechanism of contraction to xanthine plus xanthine oxidase was studied. Rings, with and without endothelium, of thoracic aorta from normotensive Wistar-Kyoto (WKY) rats and SHR were suspended in organ chambers for isometric tension recording. Oxygen-derived free radicals caused concentration-dependent contractions; these contractions were twice as large in the aortas of SHR than in WKY rats. Deferoxamine reversed the response to xanthine oxidase to a small relaxation. Either allopurinol, superoxide dismutase, or catalase, or the combination of superoxide dismutase plus catalase reduced the contractions. Diltiazem inhibited the response to xanthine oxidase; in contrast, phentolamine plus propranolol did not affect it. Indomethacin and meclofenamate, but not tranylcypromine or dazoxiben blocked the contractions. Endothelium-dependent contractions to acetylcholine in aortas from the SHR were not affected by deferoxamine or superoxide dismutase plus catalase. These data suggest that hydroxyl radicals cause contractions in the rat aorta, which are dependent on extracellular calcium and mediated by activation of the cyclooxygenase in the vascular smooth muscle. The augmented contractions in the hypertensive strain are due to an increased reactivity of the smooth muscle to oxygen-derived free radicals. However, the lack of effect of the scavengers on endothelium-dependent contractions to acetylcholine suggests that the endothelium-derived contracting factor is chemically different from oxygen-derived free radicals.
Hypertension 1989 Jun
PMID:Contractions to oxygen-derived free radicals are augmented in aorta of the spontaneously hypertensive rat. 256 6

The effects of topical application of agents which produce oxygen radicals on cerebral arterioles were studied in anesthetized cats. Xanthine oxidase plus xanthine, which produced superoxide anion radical, hydrogen peroxide, and hydrogen peroxide plus ferrous sulfate, which produced the free hydroxyl radical, induced sustained dilation, reduced responsiveness to the vasoconstrictor effect of hypocapnia, and destructive lesions of the endothelium and of the vascular smooth muscle. Similar effects were produced by arachidonate, 15-HPETE, and PGG2. The effect of arachidonate was inhibited by mannitol, a free hydroxyl radical scavenger, the effect of PGG2 was inhibited by SOD, the effect of 15-HPETE was inhibited by either catalase or SOD. These results suggest that these cerebral vascular abnormalities were produced by a single destructive free radical, probably the hydroxyl free radical, generated via interaction of superoxide and hydrogen peroxide. Cerebral vascular abnormalities similar to those produced by oxygen radicals were also seen after experimental concussive brain injury or after acute hypertension. After brain injury, activation of phospholipase C and increased brain prostaglandin concentration were demonstrated. The vascular effects of brain injury and acute hypertension were inhibited by free radical scavengers. The results suggest that, in these conditions, vascular damage is induced by oxygen radicals generated from arachidonate in association with increased prostaglandin synthesis.
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PMID:Oxygen radicals and vascular damage. 640 99

In addition to the hemodynamic components, the roles of various humoral factors have been emphasized in the progression of vascular and renal injury in hypertension. Radical scavenging properties have attracted much attention in this field. This article discusses the implication of antioxidant properties of the antihypertensive diuretic indapamide on renal injury in Dahl salt-sensitive (Dahl S) rats. Hydroxyl radicals, oxygen radicals toxic to cellular membranes, are eradicated by indapamide in different assay systems, e.g., reduction of alpha-alpha-diphenyl-beta-picrylhydrazyl, rat brain homogenate, or xanthine-xanthine oxidase systems. Such antioxidant effects of indapamide are primarily due to inhibition of lipid peroxidation induced by hydroxyl radicals, and this mechanism may stimulate prostacyclin generation through activation of prostacyclin synthase. In fact, the antioxidant properties of indapamide are well expressed in vivo as well; indapamide treatment reduced oxygen radicals in the kidney of Dahl S rats with hypertension. This was accompanied by a functional improvement of the kidney; decreases in urinary protein and n-acetylglucosaminidase excretion and an increase in glomerular filtration rate were observed. In addition, indapamide morphologically ameliorated the renal injury, and decreased glomerular sclerosis score, arterial injury, and renal tubular injury. Trichloromethiazide reduces blood pressure similar to that produced by indapamide. However, trichloromethiazide did not lead to reduction of oxygen radicals in the kidney, and did not improve the functional disturbance or morphological injury seen in Dahl S rats. These results indicate that indapamide has antioxidant properties, and in addition to blood pressure reduction, such radical scavenging effects may contribute to its beneficial effects on renal function in vivo.
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PMID:Oxygen radical scavengers and renal protection by indapamide diuretic in salt-induced hypertension of Dahl strain rats. 750 60

Gout is a common disease with a worldwide distribution. The major risk factor for the development of gout is sustained asymptomatic hyperuricaemia. Although pharmacological therapy of asymptomatic hyperuricaemia is not recommended, primary prevention of gout can be achieved through lifestyle changes including weight loss, restricting protein and calorie intake, limiting alcohol consumption, avoiding the use of diuretics in the treatment of hypertension, and avoiding occupational exposure to lead. The arthritis of gout can be readily managed with the use of nonsteroidal anti-inflammatory drugs (NSAIDs); systemic steroids or corticotrophin (adrenocorticotrophic hormone; ACTH) should be used in patients with contraindications to NSAIDs, or who are intolerant of them. Because of potential toxicity, colchicine should not be used to treat acute gout, but should be used in low dosage (0.6 to 1.2 mg/day) for prophylaxis of recurrent attacks of gout. The other cornerstone of prevention of recurrent gouty attacks is control of hyperuricaemia, which can be effectively accomplished with antihyperuricaemic therapy. The choice of agents, either uricosuric drugs or xanthine oxidase inhibitors, is based on the level of urinary uric acid excretion, renal function, age of patient, history of renal calculi and presence of tophi. Treatment and prevention of gout are exceedingly effective and patients can usually be managed by their primary care physician.
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PMID:Prevention and management of gout. 768 72

The factors that predispose to the accelerated organ injury that accompanies the hypertensive syndrome have remained speculative and without a firm experimental basis. Indirect evidence has suggested that a key feature may be related to an enhanced oxygen radical production. The purpose of this study was to refine and use a technique to visualize evidence of spontaneous microvascular oxidative stress in vivo in the spontaneously hypertensive rat (SHR) compared with its normotensive control, the Wistar-Kyoto rat (WKY). We investigated the effects of adrenal glucocorticoids on the microvascular oxidative stress sequence. The mesentery was superfused with hydroethidine, a reduced, nonfluorescent precursor of ethidium bromide. In the presence of oxidative challenge, hydroethidine is transformed intracellularly into the fluorescent compound ethidium bromide, which binds to DNA and can be detected by virtue of its red fluorescence. The fluorescent light emission from freshly exteriorized and otherwise unstimulated mesentery microvessels was recorded by digital microscopy. The number of ethidium bromide-positive nuclei along the arteriolar and venular walls in SHR was found to be significantly increased above the level exhibited by WKY. The elevation in ethidium bromide fluorescence in SHR arterioles could be attenuated by a synthetic glucocorticoid inhibitor and in rats subjected to adrenalectomy. The administration of glucocorticoids after adrenalectomy by injection of dexamethasone restored the oxidative reaction in SHR arterioles. Treatment with dimethylthiourea and with a xanthine oxidase inhibitor attenuated the superoxide formation. Although a nitric oxide synthase inhibitor (NG-nitro-L-arginine methyl ester) enhanced the ethidium bromide staining in WKY, it did not affect that in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 May
PMID:In vivo evidence for microvascular oxidative stress in spontaneously hypertensive rats. Hydroethidine microfluorography. 773 20

Much interest in cicletanine, a novel antihypertensive drug, has grown because it uniquely stimulates prostacyclin (PGI2) production and may, thereby, provide further cardiovascular protection. We postulated that cicletanine may be an antioxidant, and assessed its ability to protect the kidney in Dahl salt-sensitive (Dahl S) rats on a high salt diet. Cicletanine eradicated in vitro a stable radical, DPPH, and decreased the lipid peroxidation both in rat brain homogenate and in a xanthine-xanthine oxidase (X-XOD) superoxide generating system. Furthermore, cicletanine attenuated the inhibition of PGI2 synthase activity by 15HPETE. However, cicletanine did not exhibit superoxide dismutase-like activity in X-XOD system, suggesting that it behaves primarily as a hydroxy radical scavenger. A 6 week cicletanine treatment reduced blood pressure in Dahl S rats fed a high salt diet, and ameliorated functional and morphological injury to the kidney. This attenuation of glomerular sclerosis correlated with the attenuation of lipid peroxidation in the kidney homogenate. These data indicate that cicletanine is an antioxidant that protects the kidney from salt-induced hypertension in Dahl salt-sensitive strain rats.
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PMID:Possible radical scavenging properties of cicletanine and renal protection in Dahl salt sensitive rats. 834 28


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