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)

One-kidney, 1-clip rats (1K1C) or uninephrectomized controls were treated with either the superoxide dismutase mimetic tempol (0.5 mmol. kg(-1). d(-1)), angiotension type 1 receptor inhibitor losartan (50 mmol. L(-1). kg(-1). d(-1)), or both (n=6 per group) for 2 weeks. At the end of the study, systolic blood pressure (BP) decreased on average by 21% in tempol-treated and 29% in losartan-treated versus untreated 1K1C (217+/-4.4 mm Hg) and was normalized in the losartan plus tempol group. Mean BP also decreased from 159+/-3.7 mm Hg in 1K1C to 93+/-2.8 mm Hg in the losartan plus tempol group. Also, aortic wall area was reduced by 18% in losartan- or tempol-treated 1K1C and by 30% in losartan plus tempol rats compared with untreated 1K1C. Plasma renin activity was increased from 4.8+/-0.3 in untreated 1K1C to 15.9+/-0.9 ng. mL(-1). h(-1) in losartan-treated but not tempol-treated 1K1C. Superoxide generation by the isolated aortic rings assessed by lucigenin chemiluminescence was significantly decreased (by approximately 40%) in all losartan, tempol, and losartan plus tempol groups compared with untreated 1K1C. Nitrotyrosine ELISA in the kidney displayed a significant reduction, from 59+/-13 ng/mg of protein in 1K1C to 12.5+/-5 ng/mg of protein in the losartan plus tempol 1K1C. Western blotting for nNOS in kidney cortex and medulla showed a protein increase in both fractions of 1K1C versus controls and was normalized by losartan plus tempol treatment. Collectively, data show a synergistic effect of losartan and tempol on BP reduction in 1K1C rats. The mechanism may involve reduced superoxide production and nitrotyrosine formation in kidney and decreased kidney neuronal-type NO synthase expression in treated animals. This status in the oxidative balance seems to affect BP in the renal hypertensive rats.
Hypertension 2001 Sep
PMID:Role of angiotensin II and free radicals in blood pressure regulation in a rat model of renal hypertension. 1156 5

Augmentation of superoxide levels has been linked to impaired relaxation in hypertension, diabetes and hypercholesterolaemia. Purified endothelial nitric oxide synthase (eNOS) generates superoxide under limited availability of 5,6,7,8-tetrahydrobiopterin (BH(4)). Thus alterations in endothelial BH(4) levels have been postulated to stimulate superoxide production from eNOS. This possibility was examined by determining the concentration-dependent effects of BH(4), and its analogues, on superoxide formation by eNOS. Superoxide was quantified by EPR spin trapping, which is the only available technique to quantify superoxide from eNOS. Using 5-ethoxycarbonyl-5-methyl-pyrroline N-oxide, we show that only fully reduced BH(4) diminished superoxide release from eNOS, with efficiency BH(4)>6-methyl-BH(4)>5-methyl-BH(4). In contrast, partially oxidized BH(4) analogues, 7,8-dihydrobiopterin (7,8-BH(2)) and sepiapterin had no effect. Neither l-arginine nor N(G)-nitro-l-arginine methyl ester (l-NAME) abolished superoxide formation. Together, BH(4) and l-arginine stimulated .NO production at maximal rates of 148 nmol/min per mg of protein. These results indicate that BH(4) acts as a "redox switch", decreasing superoxide release and enhancing .NO formation. This role was verified by adding 7,8-BH(2) or sepiapterin to fully active eNOS. Both 7,8-BH(2) and sepiapterin enhanced superoxide release while inhibiting (.)NO formation. Collectively, these results indicate that the ratio between oxidized and reduced BH(4) metabolites tightly regulates superoxide formation from eNOS. The pathological significance of this scenario is discussed.
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PMID:The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. 1187 2

The present study was designed to evaluate the possible antioxidant effect of pergolide, a DA-2 receptor agonist, in deoxycorticosterone acetate (DOCA)-salt hypertension and its role in endogenous endothelin-1 (ET- 1) production and organ hypertrophy. Male Sprague-Dawley rats were uninephrectomized (UNx) or uninephrectomized, and received subcutaneous implants of DOCA and drank 1% sodium chloride (DOCA). DOCA rats were treated daily for 3 weeks with pergolide (1 mg/kg, i.p.) or vitamin C (1 mg/rat, orally). DOCA-salt treatment increased systolic blood pressure (SBP) in UNx rats by 45 +/- 2 mmHg from 117 +/- 5 to 162 +/- 10 mmHg (p < 0.05), an effect blunted by pergolide and vitamin C. Superoxide generation was not increased in DOCA rats; however, both pergolide and vitamin C significantly reduced superoxide generation by 49 +/- 7% and 52 +/- 13%, respectively (p < 0.05). Plasma ET-1 levels increased twofold in UNx rats but was reduced to 42 +/- 7% (p < 0.05) in DOCA compared to UNx rats. Pergolide and vitamin C reduced plasma ET-1 levels further by 43 +/-10% (p < 0.05) and 46 +/- 8% (p < 0.05), respectively. Pergolide increased urinary Na+ excretion but did not alter urinary protein excretion or the left ventricular and aortic hypertrophy in DOCA rats. These data suggest that the reduction of SBP by pergolide in DOCA-salt hypertension may be attributed to its natriuretic ability, not its ability to reduce superoxide generation or ET- 1 production.
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PMID:Effects of pergolide on blood pressure and tissue injury in DOCA-salt hypertension. 1203 71

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
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PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

Apoptosis of vascular smooth muscle cells (VSMCs) is an integral part of cardiovascular diseases including atherosclerosis, hypertension and restenosis. Here we studied the fate of VSMCs in response to intracellular superoxide stimulation. Diethyldithiocarbamic acid (DDC) was used to inhibit copper-zinc superoxide dismutase thereby increasing intracellular superoxide levels. The results show that DDC at a dose from 25-100 micro M is able to induce VSMC apoptosis. Superoxide was found to be responsible for DDC-induced apoptosis. In the apoptotic process mitochondrial membrane potential was decreased and caspase-3, -8 and -9 were activated. Surprisingly, neither cytochrome c release nor Bid cleavage could be observed. These data suggest a role for intracellular superoxide in the regulation of VSMCs apoptosis.
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PMID:Intracellular superoxide induces apoptosis in VSMCs: role of mitochondrial membrane potential, cytochrome C and caspases. 1237 Apr 93

The present study evaluated whether reactive oxygen species-induced alterations in bioavailability of 20-HETE in the kidney contribute to the antihypertensive and renoprotective actions of antioxidant therapy with Tempol in the Dahl salt-sensitive (DS) rat. Superoxide inhibited the synthesis of 20-HETE by renal cortical microsomes and enhanced breakdown of 20-HETE to a more polar product. Addition of Tempol (1 mmol/L) to the drinking water reduced mean arterial pressure from 187+/-9 to 160+/-3 mm Hg in DS rats fed an 8%-NaCl diet for 2 weeks. 20-HETE excretion rose from 117+/-11 to 430+/-45 ng/day, and 8-isoprostane excretion fell from 14+/-1 to 8+/-1 ng/day. Tempol also increased creatinine clearance and reduced the severity of renal damage in DS rats fed a high-salt diet. Blockade of NO synthase with NG-nitro-L-arginine methyl ester (25 mg/kg per day) did not attenuate the antihypertensive or renoprotective actions of Tempol in DS rats. However, chronic blockade of the formation of 20-HETE with N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) blunted the antihypertensive and renoprotective effects of Tempol. These findings indicate that the antihypertensive and renoprotective effects of reducing oxidative stress with Tempol depends in part on increasing the bioavailability of 20-HETE in the kidney.
Hypertension 2003 Mar
PMID:Contributions of 20-HETE to the antihypertensive effects of Tempol in Dahl salt-sensitive rats. 1262 82

Overproduction of oxygen free radicals, which is mainly mediated by superoxide, occurs in human hypertension and a wide variety of animal models. There are several important enzymatic sources of superoxide production, including NADPH oxidase, xanthine oxidase and uncoupled nitric oxide synthase. Superoxide levels are also controlled through endogenous antioxidant systems and superoxide dismutase is the primary antioxidant in the vascular system. Strategies have therefore focused on combating hypertension and vascular disease through the inhibition of superoxide-generating enzymes, and scavenging superoxide. While results from animal studies are promising, no consensus has been reached on identifying a drug target for the reliable and effective treatment of oxidative stress in hypertension.
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PMID:Targeting sources of superoxide and increasing nitric oxide bioavailability in hypertension. 1273 29

The endothelial cell layer displays the features of a distributed organ and has a variety of biological functions such as keeping the balance between coagulation and fibrinolysis, expression of adhesion molecules for cells in the immune system, metabolism of noradrenaline and 5-hydroxytryptamine, and conversion of angiotensin I and bradykinin. The endothelium also regulates the underlying smooth muscle layer and vascular tone by release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) as well as vasoconstricting factors such as endothelin, superoxide (O(2)(-)), and thromboxane. We have reviewed the nature, mechanisms of action, and role of these factors in regulation of vascular tone, with special emphasis on NO. By a process catalyzed by NO synthase, NO and citrulline is formed from the substrates molecular O(2) and L-arginine. The main receptor for NO is guanylyl cyclase leading to formation of smooth muscle cyclic guanosinmonophosphate and relaxation. EDHF is an endothelium-derived factor causing vasorelaxation of the underlying smooth muscle layer by hyperpolarization. The nature of EDHF is still unknown, but several candidates for EDHF have been proposed such as potassium ions, hydrogen peroxide, and epoxyeicosatrienoic acids. Prostaglandins such as prostacyclin and prostaglandin E2 binds to specific receptors followed by increases in cyclic adenosinmonophosphate and vasorelaxation, while contractile prostaglandins constrict vessels by activation of thromboxane and endoperoxidase receptors. Superoxide anions induce contraction of vascular smooth muscles cells by scavenging NO. Endothelin is a potent endothelium-derived contractile factor. The synthesis of endothelin-1 is induced by hypoxia, thrombin, interleukin-1, transforming growth factor-beta1, vasopressin, and catecholamines. Cardiovascular risk factors like age, hypertension, and hyperlipidemia are associated with impaired endothelium-dependent vasodilation either as a consequence of increased inactivation of endothelium-derived vasodilators or increased formation of endothelium-derived contracting factors. This imbalance of endothelium-derived factors plays a role for development of atheroslerosis and ischemic vascular diseases.
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PMID:[Role of nitric oxide and other endothelium-derived factors]. 1273 1

Treatment with cyclosporine A (CysA), a potent immunosuppressive agent, is associated with systemic and renal vasoconstriction, leading to hypertension. The present study was conducted to elucidate the contribution of angiotensin II (Ang II) to CysA-induced hypertension and reactive oxygen species (ROS) generation. CysA (30 mg/kg per day SC), given for 3 weeks in rats, increased systolic blood pressure (SBP) from 119+/-2 to 145+/-3 mm Hg (n=7). Plasma and kidney Ang II levels were significantly higher in CysA-treated rats (136+/-10 fmol/mL and 516+/-70 fmol/g) than in vehicle-treated (1 mL olive oil) rats (76+/-10 fmol/mL and 222+/-21 fmol/g, n=7). CysA treatment increased AT1 receptor protein expression in the aorta (by 251+/-35%), whereas it was reduced in the kidney (by -32+/-4%). Superoxide anion production in aortic segments and kidney thiobarbituric acid-reactive substance (TBARS) contents were higher in CysA-treated rats (26+/-2 counts/min per milligram and 37+/-3 nmol/g) than in vehicle-treated rats (17+/-1 counts/min per milligram and 24+/-3 nmol/g). Concurrent administration of an AT1 receptor antagonist, valsartan (30 mg/kg per day, in drinking water), to CysA-treated rats (n=7) significantly decreased SBP (113+/-4 mm Hg) and prevented increases in vascular superoxide (16+/-2 counts/min per milligram) and kidney TBARS contents (21+/-3 nmol/g). Similarly, treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (Tempol; 3 mmol/L in drinking water, n=7), prevented CysA-induced increases in SBP (115+/-3 mm Hg), vascular superoxide (16+/-1 counts/min per milligram), and kidney TBARS contents (19+/-2 nmol/g). These data suggest that ROS generation induced by augmented Ang II levels contributes to the development of CysA-induced hypertension.
Hypertension 2003 Oct
PMID:Role of angiotensin II and reactive oxygen species in cyclosporine A-dependent hypertension. 1287 88

Endothelium-dependent relaxation (EDR) in the blood vessels of spontaneously hypertensive rats (SHR) and the role of nitric oxide (NO) in the initiation of hypertension are reviewed. EDR was impaired in blood vessels of SHR depending on age and degree of hypertension when compared with those of normotensive rats. The cause of the impairment varied among the type of blood vessels: a decrease in the production of NO and endothelium-derived relaxing factor (EDRF) and an increase in the production of endothelium-derived contracting factor (EDCF) are the main causes of the impairment in large arteries, while a decrease in endothelium-dependent hyperpolarization and increased release of EDCF are the main causes of the impairment in small arteries. Interactions among these endothelium-derived factors and changes in the interactions are also causes of impairment. Superoxide may be involved in the impairment of EDR by destroying NO. The endothelium depresses smooth muscle contraction, including spontaneous tone developed in vascular smooth muscle, and the depressing effect of the endothelium is impaired in the preparations from SHR. The endothelium of blood vessels of SHR are structurally injured as demonstrated by scanning electron microscopy. Antihypertensive treatment prevented these functional and structural changes. Chronic treatment with inhibitors of NO production in normotensive rats impaired EDR and elevated blood pressure. The impairment of EDR is a secondary change due to continued hypertension, and early initiation of antihypertensive therapy is recommended.
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PMID:[Endothelium-derived factors in hypertensive blood vessels, especially nitric oxide and hypertension]. 1287 34


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