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)

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.
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PMID:Clinical aspects of reactive oxygen and nitrogen species. 1577 17

The dried roots of Scutellaria baicalensis (S. baicalensis) Georgi (common name: Huangqin in China) have been widely employed for many centuries in traditional Chinese herbal medicine as popular antibacterial and antiviral agents. They are effective against staphylococci, cholera, dysentery, pneumococci and influenza virus. Baicalein, one of the major flavonoids contained in the dried roots, possesses a multitude of pharmacological activities. The glycoside of baicalein, baicalin is a potent anti-inflammatory and anti-tumor agent. This review describes the biological properties of baicalein (Table 1), which are associated with the prevention and treatment of cardiovascular diseases. Baicalein is a potent free radical scavenger and xanthine oxidase inhibitor, thus improving endothelial function and conferring cardiovascular protective actions against oxidative stress-induced cell injury. Baicalein lowers blood pressure in renin-dependent hypertension and the in vivo hypotensive effect may be partly attributed to its inhibition of lipoxygenase, resulting in reduced biosynthesis and release of arachidonic acid-derived vasoconstrictor products. On the other hand, baicalein enhances vasoconstricting sensitivity to receptor-dependent agonists such as noradrenaline, phenylephrine, serotonin, U46619 and vasopressin in isolated rat arteries. The in vitro effect is likely caused by inhibition of an endothelial nitric oxide-dependent mechanism. The anti-thrombotic, anti-proliferative and anti-mitogenic effects of the roots of S. baicalensis and baicalein are also reported. Baicalein inhibits thrombin-induced production of plasminogen activator inhibitor-1, and interleukin-1beta- and tumor necrosis factor-alpha-induced adhesion molecule expression in cultured human umbilical vein endothelial cells. The pharmacological findings have highlighted the therapeutic potentials of using plant-derived baicalein and its analogs for the treatment of arteriosclerosis and hypertension.
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PMID:Biological properties of baicalein in cardiovascular system. 1585 50

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxide-producing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases.
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PMID:Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. 1587 5

The current study was designed to determine the effects of a dietary astaxanthin (ASX-O) on vascular reactivity in spontaneously hypertensive rats (SHR), in order to verify its antihypertensive action mechanism. We evaluated contractions induced by phenylephrine (Phe), angiotensin II (Ang II) and the xanthine/xanthine oxidase (Xan/XOD) system, and relaxations induced by sodium nitroprusside (SNP) as well as endothelium-dependent relaxations mediated by acetylcholine (ACh) in thoracic aorta of the SHR, with and without ASX-O intervention. We also investigated the effects of ASX-O on blood rheology using a microchannel array system. In this study, ASX-O showed a significant modulatory effect on nitric oxide (NO)-induced vasorelaxation by the NO-donor SNP (p<0.05). However, it did not show significant effects in restoring the impaired endothelium-dependent relaxation to ACh in the SHR. On the other hand, the constrictive effects by Phe, Ang II and Xan/XOD were ameliorated by ASX-O (p<0.05). ASX-O also demonstrated significant hemorheological effect by decreasing the microchannel transit time of whole blood. In conclusion, the results suggest that ASX-O may act in modulating the blood fluidity in hypertension, and that the antihypertensive effects of ASX-O may be exerted through mechanisms including normalization of the sensitivity of the adrenoceptor sympathetic pathway, particularly [alpha]-adrenoceptors, and by restoration of the vascular tone through attenuation of the Ang II- and reactive oxygen species (ROS)-induced vasoconstriction.
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PMID:Antihypertensive potential and mechanism of action of astaxanthin: II. Vascular reactivity and hemorheology in spontaneously hypertensive rats. 1593 Jul 28

Heart failure is the major cause of hospitalization, morbidity and mortality worldwide. Previous experimental and clinical studies have suggested that there is an increased production of reactive oxygen species (ROS: superoxide, hydrogen peroxide, hydroxyl radical) both in animals and in patients with acute and chronic heart failure. The possible source of increased ROS in the failing myocardium include xanthine and NAD(P)H oxidoreductases, cyclooxygenase, the mitochondrial electron transport chain and activated neutrophils among many others. The excessively produced nitric oxide (NO) derived from NO synthases (NOS) has also been implicated in the pathogenesis of chronic heart failure (CHF). The combination of NO and superoxide yields peroxynitrite, a reactive oxidant, which has been shown to impair cardiac function via multiple mechanisms. Increased oxidative and nitrosative stress also activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which importantly contributes to the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Recent studies have demonstrated that pharmacological inhibition of xanthine oxidase derived superoxide formation, neutralization of peroxynitrite or inhibition of PARP provide significant benefit in various forms of cardiovascular injury. This review discusses the role of oxidative/nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure.
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PMID:Role of oxidative-nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure. 1602 19

To investigate if increased lipid peroxidation is involved in hypercholesterolemia-induced hypertension and renal injury, we examined the effects of allopurinol, a xanthine oxidase inhibitor, on these conditions. Groups of male Sprague--Dawley rats were fed for 8 weeks with a high-cholesterol diet (4% cholesterol), a high-cholesterol plus allopurinol (10 mg/kgBW/day) diet or a normal diet. Systolic blood pressure (SBP), serum lipids, uric acid (UA) and malondialdehyde (MDA) as a measure of lipid peroxides, and urinary excretion of protein (UP) were measured after 0, 4 and 8 weeks. Urinary excretion of nitrite plus nitrate (UNOx) and iron (UFe), and MDA in the kidney were measured after 8 weeks. The renal injury was evaluated by the glomerular sclerosis score (SS). The high-cholesterol diet increased SBP, serum total cholesterol and UA, MDA in the serum and kidney, UP, UNOx, UFe and SS. Allopurinol ameliorated cholesterol-induced elevation in serum UA, MDA in the serum and kidney, UP, UNOx, UFe and SS, but did not affect SBP. Hence, our results suggest that lipid peroxidation may be involved in hypercholesterolemia-induced renal injury, and that suppression of lipid peroxidation can reduce such injury.
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PMID:Effects of allopurinol, a xanthine oxidase inhibitor, on renal injury in hypercholesterolemia-induced hypertensive rats. 1603 90

Cyclosporin A (CsA) generates superoxide in smooth muscle cells. Our earlier studies have demonstrated that the increase in the vasopressin type 1 receptor induced in vascular smooth muscle cells in the presence of CsA is probably due to superoxide (Krauskopf et al., J Biol Chem 278, 41685-41690, 2003). This increase in vasopressin receptor is likely at the base of increased vascular responsiveness to vasoconstrictor hormones and hypertension induced by CsA. Here, we demonstrate that CsA produces superoxide. In addition, our data show that superoxide generation does not originate from the major cellular superoxide generating systems NAD(P)H oxidase or xanthine oxidase. Our results suggest that the side effects of CsA could be diminished with the help of SOD mimetic drugs.
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PMID:Cyclosporin A generates superoxide in smooth muscle cells. 1608 72

We have demonstrated recently [Callera, Touyz, Teixeira, Muscara, Carvalho, Fortes, Schiffrin and Tostes (2003) Hypertension 42, 811-817] that increased vascular oxidative stress in DOCA (deoxycorticosterone acetate)-salt rats is associated with activation of the ET (endothelin) system via ETA receptors. The exact source of ET-1-mediated oxidative stress remains unclear. The aim of the present study was to investigate whether ET-1 increases generation of ROS (reactive oxygen species) in DOCA-salt hypertension through NADPH-oxidase-dependent mechanisms. Xanthine oxidase, eNOS (endothelial nitric oxide synthase) and COX-2 (cyclo-oxygenase-2) were also examined as potential ET-1 sources of ROS as well as mitochondrial respiration. DOCA-salt and control UniNX (uninephrectomized) rats were treated with the ETA antagonist BMS182874 (40 mg.day(-1).kg(-1) of body weight) or vehicle. Plasma TBARS (thiobarbituric acid-reacting substances) were increased in DOCA-salt compared with UniNX rats. Activity of NADPH and xanthine oxidases in aorta, mesenteric arteries and heart was increased in DOCA-salt rats. BMS182874 decreased plasma TBARS levels without influencing NADPH and xanthine oxidase activities in DOCA-salt rats. Increased p22(phox) protein expression and increased p47(phox) membrane translocation in arteries from DOCA-salt by rats were not affected by BMS182874 treatment. Increased eNOS and COX-2 expression, also observed in aortas from DOCA-salt rats, was unaltered by BMS182874. Increased mitochondrial generation of ROS in DOCA-salt rats was normalized by BMS182874. ETA antagonism also increased the expression of mitochondrial MnSOD (manganese superoxide dismutase) in DOCA-salt rats. In conclusion, activation of NADPH oxidase does not seem to be the major source of oxidative stress induced by ET-1/ETA in DOCA-salt hypertension, which also appears to be independent of increased activation of xanthine oxidase or eNOS/COX-2 overexpression. Mitochondria may play a role in ET-1-driven oxidative stress, as evidenced by increased mitochondrial-derived ROS in this model of hypertension.
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PMID:Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms. 1632 76

Dahl salt-sensitive (SS) rats exhibit increased renal medullary oxidative stress and blood pressure salt-sensitivity compared with consomic, salt-resistant SS-13BN rats, despite highly similar genetic backgrounds. The present study examined potential sources of renal medullary superoxide in prehypertensive SS rats fed a 0.4% NaCl diet by assessing activity and protein levels of superoxide producing and scavenging enzymes. Superoxide production was nearly doubled in SS rats compared with SS-13BN rats as determined by urinary 8-isoprostane excretion and renal medullary oxy-ethidium microdialysate levels. Medullary superoxide production in tissue homogenates was greater in SS rats, and the NADPH oxidase inhibitor diphenylene iodonium preferentially reduced SS levels to those found in SS-13BN rats. Dinitrophenol, a mitochondrial uncoupler, eliminated the remaining superoxide production in both strains, whereas inhibition of xanthine oxidase, NO synthase, and cycloxygenase had no effect. L-arginine, NO synthase, superoxide dismutase, catalase, and glutathione peroxidase activities between SS and SS-13BN rats did not differ. Chronic blood pressure responses to a 4% NaCl diet were then determined in the presence or absence of the NADPH oxidase inhibitor apocynin (3.5 microg/kg per minute), chronically delivered directly into the renal medulla. Apocynin infusion reduced renal medullary interstitial superoxide from 1059+/-130 to 422+/-80 (oxyethidium fluorescence units) and mean arterial pressure from 175+/-4 to 157+/-6 mm Hg in SS rats, whereas no effects on either were observed in the SS-13(BN). We conclude that excess renal medullary superoxide production in SS rats contributes to salt-induced hypertension, and NADPH oxidase is the major source of the excess superoxide.
Hypertension 2006 Apr
PMID:NADPH oxidase in the renal medulla causes oxidative stress and contributes to salt-sensitive hypertension in Dahl S rats. 1650 10

Substantial evidence suggests the involvement of oxidative stress in the pathophysiology of congestive heart failure and its antecedent conditions such as cardiac hypertrophy and adverse remodelling after MI. Oxidative stress describes an imbalance between antioxidant defences and the production of reactive oxygen species (ROS), which at high levels cause cell damage but at lower levels induce subtle changes in intracellular signalling pathways (termed redox signalling). ROS are derived from many sources including mitochondria, xanthine oxidase, uncoupled nitric oxide synthases and NADPH oxidases. The latter enzymes are especially important in redox signalling, being implicated in the pathophysiology of hypertension and atherosclerosis, and activated by diverse pathologically relevant stimuli. We review the contribution of ROS to heart failure pathophysiology and discuss potential therapies that may specifically target detrimental redox signalling. Indeed, drugs such as ACE inhibitors and statins may act in part through such mechanisms. A better understanding of redox signalling mechanisms may enable the development of new targeted therapeutic strategies rather than the non-specific antioxidant approaches that have to date been disappointing in clinical trials.
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PMID:Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. 1667 Jan


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