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

Endothelium-derived relaxing factor (EDRF) is a substance that is released by the vascular endothelium and mediates vasodilator responses induced by various substances including acetylcholine (AC). Superoxide anion (O2-) inactivates EDRF. It is well known that the endothelium-dependent vascular relaxations to AC are depressed in the aorta of spontaneously hypertensive rats (SHR). We studied the role of O2- on onset and maintenance of hypertension in SHR. Male 4- and 17-week old SHR (4SHR, 17SHR), and enalapril treated 17-week old SHR (5 mg/kg/day for 4 weeks: ETSHR), and age-matched normotensive Wistar-Kyoto rats (WKY; 4WKY, 17WKY) were used. Relaxation responses to AC or superoxide dismutase (SOD) were measured in isolated aortae from rats. Mean arterial pressure (MAP) was measured after injection of SOD in rats under conscious state. Systolic blood pressure of 4SHR, 17SHR, ETSHR, 4WKY, and 17WKY were 129 +/- 2 mmHg, 203 +/- 3 mmHg, 158 +/- 3 mmHg, 97 +/- 1 mmHg, and 138 +/- 2 mmHg, respectively. Although relaxation responses to AC were decreased in aortae from 4SHR, 17SHR, and ETSHR compared with those from age-matched WKY, relaxation responses to SOD dit not differ between SHR and corresponding WKY. Whereas the injection of SOD(10000 U/kg) elicited a significant reduction of MAP in 4SHR (-11 +/- 3 mmHg) and 17SHR (-24 +/- 5 mmHg), it has no effect in WKY. These data suggest that AC mediated endothelium-dependent relaxation is attenuated in SHR and that excessive O2- in the endothelium resulted from hypertension may contributes the decreased response in SHR.
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PMID:[Role of superoxide anion on onset and maintenance of hypertension in spontaneously hypertensive rats]. 133 77

This review attempts to summarize the available data regarding the vascular actions of free oxygen radicals. Studies on blood vessels in situ and in vitro demonstrate that free oxygen radicals can evoke both vasodilation and vasoconstriction. Free oxygen radicals can modulate the tone of vascular smooth muscle by acting directly on the smooth muscle cells, and also via indirect mechanisms by changes in the production or biological activity of vasoactive mediators. The individual oxygen radicals may have different (sometimes opposite) vascular effects. Superoxide anion inactivates endothelium-derived relaxing factor and the adrenergic neurotransmitter norepinephrine. Hydrogen peroxide and the hydroxyl radical evoke vasodilation by acting directly on vascular smooth muscle and also by stimulating the synthesis/release of endothelium-derived relaxing factor. In acute arterial hypertension or experimental brain injury oxygen radicals are important mediators of vascular damage. Production of oxygen-derived free radicals by activated neutrophils may be responsible for vasodilation and increased permeability of capillary membrane during the acute inflammatory process. Free oxygen radicals also play an important role in reperfusion injury of various organs, and vascular actions of the free radicals may contribute to the damage of parenchymal tissues.
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PMID:Vascular effects of oxygen-derived free radicals. 327 50

The appearance of superoxide anion radical in cerebral extracellular space during and after acute hypertension induced by intravenous norepinephrine was investigated in anesthetized cats equipped with cranial windows. Superoxide was detected by demonstrating the presence of superoxide dismutase-inhibitable reduction of nitroblue tetrazolium. The superoxide dismutase-inhibitable rate of reduction of nitroblue tetrazolium was 4.1 +/- 1.61 nM/min per cm2 during hypertension and 4.55 +/- 0.62 nM/min per cm2 one hour after hypertension had subsided. During norepinephrine administration in the absence of hypertension, the superoxide dismutase-inhibitable rate of reduction of nitroblue tetrazolium was 0.44 +/- 0.17 nM/min per cm2. The reduction of nitroblue tetrazolium during hypertension was also inhibited by prior treatment of the brain surface with phenylglyoxal at pH 10, to induce irreversible inhibition of the anion channel. The results show that acute hypertension is associated with the generation of superoxide which enters the extracellular space of the brain via the anion channel. Following hypertension, the sustained vasodilation caused by acute hypertension was inhibited significantly by topical application of superoxide dismutase and catalase, showing that it was due in part to superoxide and other radicals derived from it. The vasodilator response of cerebral arterioles to topical acetylcholine was converted to vasoconstriction following acute hypertension, and restored to vasodilation following topical application of superoxide dismutase and catalase. The results show that superoxide and other radicals generated after acute hypertension interfere with acetylcholine-induced endothelium-dependent vasodilation, probably because they destroy the endothelium-derived relaxant factor.
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PMID:Superoxide generation and reversal of acetylcholine-induced cerebral arteriolar dilation after acute hypertension. 405 9

Possible involvement of reactive oxygen species and nitric oxide in the pathogenesis of human essential hypertension was investigated. It was observed that both superoxide anion and hydrogen peroxide production by polymorphonuclear leukocytes and the plasma levels of lipid peroxides are higher in uncontrolled essential hypertension compared with normal controls. Nitric oxide levels measured as its stable metabolite nitrite, as an index of nitric oxide synthesis, revealed its levels to be low in hypertensive patients. Superoxide anion, hydrogen peroxide, lipid peroxides and nitric oxide levels reverted to normal values after the control of hypertension by drugs. The concentrations of anti-oxidants such as vitamin E and superoxide dismutase were found to be decreased in patients with uncontrolled hypertension. Several anti-hypertensive drugs inhibited lipid peroxidation in vitro. Angiotensin-II, a potent vasoconstrictor, stimulated free radical generation in normal leukocytes which could be blocked by calmodulin antagonists. These results suggest that an increase in free radical generation and a simultaneous decrease in the production of nitric oxide and anti-oxidants such as SOD and vitamin E occurs in essential hypertension. This increase in free radical generation can inactivate prostacyclin and nitric oxide and decrease their half life which can lead to an increase in peripheral vascular resistance and hypertension.
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PMID:Are free radicals involved in the pathobiology of human essential hypertension? 822 35

Calcium antagonists are well accepted in the prevention of ischaemia in patients with chronic stable angina, unstable angina, variant angina, and silent ischaemia, and in the treatment of hypertension. Although all of these compounds increase myocardial oxygen supply by reducing coronary tone and decrease myocardial oxygen demand by reducing systolic pressure and myocardial contractility, the magnitude of these effects may differ from one agent to another. Some calcium antagonists, such as verapamil and diltiazem, reduce heart rate and attenuate heart rate increases in response to stress, while in contrast, dihydropyridine calcium antagonists such as nifedipine may cause reflex increases in heart rate. These differences may be of importance in light of epidemiologic evidence that lower heart rates are associated with a reduced long-term risk of cardiovascular mortality, and experimental data showing that a lower heart rate may protect against the development of atherosclerosis. Calcium antagonists also inhibit platelet aggregation and thrombus formation which may contribute to their anti-ischaemic effects. Clinical trial data suggest that calcium antagonists may stay the progression of atherosclerosis. Mechanisms underlying an anti-atherosclerotic effect may include attenuation of endothelial dysfunction, prevention of LDL, peroxidation, stimulation of LDL receptor activity, inhibition of superoxide radical generation, and inhibition of vascular smooth muscle cell growth. Heart-rate-controlling calcium antagonists, such as verapamil and diltiazem, may reduce reinfarction rates following acute myocardial infarction and thus may have a role in post-infarction patients who do not show evidence of heart failure. Their use in heart failure patients receiving an angiotension-converting enzyme inhibitor (ACE-I) is under investigation in several large trials. Because calcium antagonists have a mechanism of action different from ACE-I, the pairing of a heart-rate-controlling calcium antagonist with an ACE-I might be expected to offer additive cardioprotective and vascular protective effects.
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PMID:The role of calcium antagonists in ischaemic heart disease. 884 1

Hypertension is an important risk factor for the development of atherosclerosis. Traditional antihypertensive therapy is not fully effective in prevention of cardiovascular abnormalities of hypertension. Two classes of hypotensive drugs, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors, reduce atherosclerosis in several experimental models in animals. Anti-atherosclerotic effects of calcium antagonists include attenuation of endothelial dysfunction, prevention of LDL modification, stimulation of LDL receptor activity, inhibition of superoxide radical generation and inhibition of vascular smooth muscle cells proliferation and migration. In large angiographic trials calcium antagonists reduced the development of new atherosclerotic plaques. ACE inhibitors also lead to the lower incidence of atherosclerosis in experimental animals. They inhibit migration and proliferation of vascular smooth muscle cells, reduce macrophage-derived foam cell accumulation, preserve protective endothelium function, reduce LDL modification and increase fibrinolytic activity. It depends on reduced angiotensin II synthesis, increased concentration of kinins, substance P and angiotensin-(1-7), inhibition of leukotriene B4 formation and improvement of insulin action. In some studies they also reduce plasma lipids concentration, including lipoprotein (a). ACE inhibitors were found to be ineffective in prevention of restenosis after PTCA in human but data derived from large, multicenter trials indicate that they are effective in the secondary prevention of myocardial infarction.
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PMID:[Anti-atherosclerotic action of hypotensive drugs]. 924 14

Nitric oxide (NO) is a labile radical gas that is widely acclaimed as one of the most important molecules in biology. Through covalent modifications of target proteins and redox reactions with oxygen and superoxide radical and transition metal prosthetic groups, NO plays a critical role in many vital biological processes, including the control of vascular tone, neurotransmission, ventilation, hormone secretion, inflammation, and immunity. Moreover, NO has been shown to influence a host of fundamental cellular functions, such as RNA synthesis, mitochondrial respiration, glycolysis, and iron metabolism. NO is formed from L-arginine by NO synthases (NOSs), a family of related enzymes encoded by separate unlinked genes. The different NOS isozymes exhibit disparate tissue and intrarenal distributions and are governed by unique regulatory mechanisms. In the kidney, NO participates in several vital processes, including the regulation of glomerular and medullary hemodynamics, the tubuloglomerular feedback response, renin release, and the extracellular fluid volume. While NO serves beneficial roles as a messenger and host defense molecule, excessive NO production can be cytotoxic, the result of NO's reaction with reactive oxygen and nitrogen species, leading to peroxynitrite anion formation, protein tyrosine nitration, and hydroxyl radical production. Indeed, NO may contribute to the evolution of several commonly encountered renal diseases, including immune-mediated glomerulonephritis, postischemic renal failure, radiocontrast nephropathy, obstructive nephropathy, and acute and chronic renal allograft rejection. Moreover, impaired NO production has been implicated in the pathogenesis of volume-dependent hypertension. This duality of NO's beneficial and detrimental effects has created extraordinary interest in this molecule and the need for a detailed understanding of NO biosynthesis.
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PMID:Nitric oxide in renal health and disease. 929 59

Superoxide anion (O2-) plays a key role in the endogenous suppression of endothelium-derived nitric oxide (NO) bioactivity and has been implicated in the development of hypertension. In previous studies, we found that O2- is produced predominantly in the adventitia of isolated rabbit aorta and acts as a barrier to NO. In the present studies, we characterize the enzyme responsible for O2- production in the adventitia and show that this enzyme is a constitutively active NADPH oxidase with similar composition as the phagocyte NADPH oxidase. Constitutive O2--generating activity was localized to aortic adventitial fibroblasts and was enhanced by the potent vasoconstrictor angiotensin II. Immunohistochemistry of aortic sections demonstrated the presence of p22(phox), gp91(phox), p47(phox), and p67(phox) localized exclusively in rabbit aortic adventitia, coincident with the site of staining for O2- production. Furthermore, immunodepletion of p67(phox) from adventitial fibroblast particulates resulted in the loss of NADPH oxidase activity, which could be restored by the addition of recombinant p67(phox). Further study into the regulation of this adventitial source of O2- is important in elucidating the mechanisms regulating the bioactivity of NO and may contribute to our understanding of the pathogenesis of hypertension.
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PMID:Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. 940 39

Superoxide radical (O2-) is increased in the vessel wall of spontaneously hypertensive rats (SHR) where its blockade potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of O2- in the hypertension and renal vasoconstriction of SHR and its interaction with nitric oxide (NO). Baseline mean arterial pressure (MAP) and renal vascular resistance were markedly elevated in SHR (n=6) compared with Wistar-Kyoto rats (WKY; n=6) (145+/-4 versus 118+/-4 mmHg, P<0.05, and 24+/-3 versus 17+/-1 mmHg x mL(-1) x min(-1), respectively; P<0.05). The stable membrane-permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (tempol; 72 micromol/kg i.v.) normalized MAP (103+/-9 versus 96+/-6 mm Hg for SHR and WKY, respectively) and RVR (17+/-2 versus 15+/-1 mm Hg x mL(-1) x min(-1)) of SHR. The MAP of SHR was more sensitive and responsive to graded infusions of tempol (0, 1.8, 18, 180, and 1800 micromol x kg(-1) x h(-1) i.v.) than that of WKY. To determine whether O2- increases MAP by inactivation of NO, its synthesis was blocked in SHR with NW-nitro-L-arginine methyl ester (L-NAME, 11 micromol x kg(-1) x min(-1) i.v., n=6). Whereas tempol alone significantly reduced MAP by 32% (184+/-12 to 121 +/- 18 mm Hg, P<0.05, n=6), L-NAME infusion abolished the MAP response to tempol (187+/-8 to 186+/-4 mm Hg, n=5). In contrast, tempol did reduce MAP of SHR (188+/-7 to 161+/-7 mm Hg, P<0.05) where MAP was elevated by norepinephrine (31 nmol x kg(-1) x min(-1) i.v., n=6). Finally, to determine the longer-term effect of O2-, tempol (1.5 mmol x kg(-1) x d(-1) i.p.) was given for 7 days. Tempol had no effect on MAP in WKY (96+/-1 to 97+/-1 mmHg, n=7) but significantly decreased MAP in SHR (133+/-2 to 120+/-3 mm Hg, P<0.05, n=7). These data implicate O2- in the hypertension of SHR in vivo. The antihypertensive action of tempol depends on NO synthesis presumably because O2- inactivates NO and thus diminishes its vasodilatory actions.
Hypertension 1998 Jul
PMID:Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide. 967 38

Superoxide radical (O2-) is ubiquitously critical to the bioactivity of endothelial nitric oxide. In angiotensin-dependent hypertension, vascular O2- levels rise and impede endothelium/nitric oxide-dependent vascular relaxation. We have reported that the major O2- source in the rabbit aorta is adventitial fibroblast phagocyte-like NADPH oxidase and shown that angiotensin (Ang) II treatment of adventitial fibroblasts causes a concentration-dependent increase in particulate NADPH-dependent O2-. From cultured rabbit aortic adventitial fibroblasts treated or not treated with Ang II, we prepared particulate fractions and measured lucigenin-enhanced chemiluminescence. Because [Sar1,Thr8]-Ang II, a generalized antagonist of Ang II and plausible inhibitor of the conversion of Ang II, reversed Ang II (10 nmol/L)-induced NADH- and NADPH-dependent O2- to basal levels, we tested the effect of the inhibitor of aminopeptidase N, amastatin (10 micromol/L), and found no effect on Ang II-stimulated O2-. Ang(1-7), Ang III, and Ang IV also were not effective in stimulating O2- levels at concentrations similar to those of Ang II. Kinetic analysis showed a rise in NADPH oxidase O2- production in response to Ang II, which peaks at 3 hours and returns to basal levels by 16 hours. p67phox, a cytosolic factor, appears to be affected at both the level of transcription and protein synthesis because actinomycin and cycloheximide individually inhibited the observed effect. A partial sequence of p67phox was recovered by reverse transcriptase from mRNA harvested from cultured rabbit aortic adventitial fibroblasts. Furthermore, the p67phox mRNA transcript in aortic fibroblasts is induced by Ang II before the peak of NADPH oxidase by Northern analysis and ribonuclease protection assays. These data suggest that Ang II stimulates NAD(P)H oxidase O2- generation in fibroblasts of aortic adventitia via transcriptional activation of p67phox. These data also provide preliminary evidence for the regulation of factors of the NADPH oxidase and potentially provide a novel means by which to abrogate the development of O2(-)-dependent hypertension.
Hypertension 1998 Aug
PMID:Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. 971 63


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