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)

The hypothesis that O(2)(.-) enhances angiotensin II (AngII)-induced vasoconstriction and impairs acetylcholine-induced vasodilation of afferent arterioles (Aff) in AngII-induced hypertension was investigated. Rabbits (n = 6 per group) received 12 to 14 d of 0.154 M NaCl (Sham), subpressor AngII (60 ng/kg per min; AngII 60) or slow pressor AngII (200 ng/kg per min; AngII 200). Individual Aff were perfused in vitro at 60 mmHg. AngII 200 increased mean arterial pressure (mean +/- SD; 103 +/- 9 versus 73 +/- 6 mmHg; P < 0.01), plasma lipid peroxides (2.6 +/- 0.3 versus 2.0 +/- 0.3 nM; P < 0.05), renal cortical NADPH- and NADH-dependent O(2)(.-) generation, and Aff mRNA for p22(phox) 5-fold (P < 0.001) but decreased that for AT(1)-receptor 2.4-fold (P < 0.01). AngII 60 increased only NADH-dependent O(2)(.-) generation by renal cortex. Aff from AngII 200 rabbits had diminished acetylcholine relaxations (+50 +/- 4 versus +85 +/- 6%; P < 0.001), but these became similar in the presence of nitro-L-arginine (10(-4) M). Aff from AngII 60 and AngII 200 rabbits had unchanged norepinephrine contractions (10(-7) M) but significantly (P < 0.05) enhanced AngII contractions (10(-8) M: Sham -52 +/- 5 versus AngII 60 to 77 +/- 5 versus AngII 200 to 110 +/- 10%). The superoxide dismutase mimetic tempol (10(-4) M) moderated the AngII responses of Aff from AngII 200 rabbits to levels of AngII 60 rabbits (-64 +/- 7%). The AngII slow pressor response enhances renal cortical O(2)(.-) and p22(phox) expression. Increased O(2)(.-) generation in Aff mediates an impaired nitric oxide synthase-dependent endothelium-derived relaxing factor response and paradoxically enhances contractions to AngII despite downregulation of the mRNA for AT(1) receptors. A subpressor dose of AngII enhances Aff responses to AngII independent of O(2)(.-).
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PMID:Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin II of afferent arterioles from rabbits infused with angiotensin II. 1456 11

The present studies were undertaken to investigate the potential effect of a calcium channel blocker (CCB) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular injury and the cellular mechanism of the effect of CCB on vascular remodeling. In polyethylene cuff-induced vascular injury of the mouse femoral artery, proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation associated with activation of extracellular signal-regulated kinase (ERK), and tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, inflammatory response assessed by monocyte chemoattractant protein-1 and tumor necrosis factor-alpha expression, as well as oxidative stress such as expression of NADH/NADPH oxidase p22(phox) subunit and superoxide production, were less in AT1a receptor null mice. Administration of nonhypotensive doses of a CCB, azelnidipine (0.5 or 1 mg/kg per day) attenuated these parameters in wild-type and AT1a receptor null mice. Coadministration of lower doses of an ARB, olmesartan (0.5 mg/kg per day), and azelnidipine (0.1 mg/kg per day), which did not affect vascular remodeling, significantly inhibited these parameters in wild-type mice. Moreover, the effective dose of azelnidipine (1 mg/kg per day) exaggerated the inhibitory action of olmesartan at effective doses of 1 or 3 mg/kg per day on VSMC proliferation in the injured arteries. These results suggest that azelnidipine could inhibit vascular injury at least partly independent of the inhibition of AT1 receptor activation and that azelnidipine could exaggerate the vascular protective effects of olmesartan, suggesting clinical possibility that the combination of CCB and ARB could be more effective in the treatment of vascular diseases.
Hypertension 2004 Feb
PMID:Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan. 1470 52

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men, 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Val279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia.
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PMID:Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. 1470 72

Oxidative stress (OxSt) is a major damaging factor in arterial hypertension and its long-term complications. This is why considerable attention is paid to the possible effects of antihypertensive drugs on OxSt. Manidipine is a dihydropiridine calcium channel blocker with reported nephroprotective activities, but no information is available on its effect on OxSt and related mechanisms. This study assessed the effect of manidipine on normal subjects' monocyte gene and protein expression of OxSt-related proteins such as p22(phox), a NAD(P)H oxidase system subunit, critical in generating O2-, and heme oxygenase-1 (HO-1), induced by and protective from OxSt, and compared manidipine with the ACE inhibitor captopril and the calcium channel blocker nifedipine, in the presence and absence of sodium arsenite (NaAsO2) as an inducer of OxSt.Co-incubation of manidipine with NaAsO2 dose-dependently decreased p22(phox) mRNA production from basal: 0.87 +/- 0.1 d.u., 0.69 +/- 0.06 and 0.66 +/- 0.09 at 100, 300 and 500 nM respectively versus 0.99 +/- 0.2, P < 0.04, while HO-1 mRNA production was increased by the same concentrations of the drug: 0.87 +/- 0.1 d.u., 0.92 +/- 0.1, 0.98 +/- 0.1 respectively versus 0.63 +/- 0.07; P < 0.03. Monocyte p22(phox) mRNA production was reduced both by manidipine and captopril: 0.48 +/- 0.04 d.u. and 0.43 +/- 0.08, respectively versus 0.58 +/- 0.07, P < 0.006, while no changes were induced by nifedipine (0.61 +/- 0.07, P = ns). Manidipine increased monocyte HO-1 mRNA production (1.6 +/- 0.4 versus 1.2 +/- 0.4, P < 0.008), while nifedipine and captopril showed no effect (1.2 +/- 0.3 and 1.1 +/- 0.3, respectively). The effects of M on p22(phox) and HO-1 gene expression in the presence of OxSt were also paralleled by the same effects at protein level. In conclusion, manidipine decreases p22(phox) and increases HO-1 mRNA production and protein level. The manidipine-induced increase of HO-1 gene and protein expression seems to be a peculiar effect of this drug since it is not observed with captopril and nifedipine. This effect, together with the reduction of p22(phox) mRNA production, could play a role in its protective mechanism against OxSt.
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PMID:Effect of manidipine on gene expression and protein level of oxidative stress-related proteins: p22phox and HO-1: relevance for antihypertensive and anti-remodeling effects. 1508 64

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA.
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PMID:Genetic risk for restenosis after coronary balloon angioplasty. 1513 68

We tested the hypothesis that superoxide anion (O(2)(-).) generated in the kidney by prolonged angiotensin II (ANG II) reduces renal cortical Po(2) and the use of O(2) for tubular sodium transport (T(Na):Q(O(2))). Groups (n = 8-11) of rats received angiotensin II (ANG II, 200 ng.kg(-1).min(-1) sc) or vehicle for 2 wk with concurrent infusions of a permeant nitroxide SOD mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol, 200 nmol.kg(-1).min(-1)) or vehicle. Rats were studied under anesthesia with measurements of renal oxygen usage and Po(2) in the cortex and tubules with a glass electrode. Compared with vehicle, ANG II increased mean arterial pressure (107 +/- 4 vs. 146 +/- 6 mmHg; P < 0.001), renal vascular resistance (42 +/- 3 vs. 65 +/- 7 mmHg.ml(-1).min(-1).100 g(-1); P < 0.001), renal cortical NADPH oxidase activity (2.3 +/- 0.2 vs. 3.6 +/- 0.4 nmol O(2)(-)..min(-1).mg(-1) protein; P < 0.05), mRNA and protein expression for p22(phox) (2.1- and 1.8-fold respectively; P < 0.05) and reduced the mRNA for extracellular (EC)-SOD (-1.8 fold; P < 0.05). ANG II reduced the Po(2) in the proximal tubule (39 +/- 1 vs. 34 +/- 2 mmHg; P < 0.05) and throughout the cortex and reduced the T(Na):Q(O(2)) (17 +/- 1 vs. 9 +/- 2 mumol/mumol; P < 0.001). Tempol blunted or prevented all these effects of ANG II. The effects of prolonged ANG II to cause hypertension, renal vasoconstriction, renal cortical hypoxia, and reduced efficiency of O(2) usage for Na(+) transport, activation of NADPH oxidase, increased expression of p22(phox), and reduced expression of EC-SOD can be ascribed to O(2)(-). generation because they are prevented by an SOD mimetic.
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PMID:Angiotensin-induced defects in renal oxygenation: role of oxidative stress. 1559 67

We have investigated the antioxidant effect of adrenomedullin (AM) on endothelial function in the Dahl salt-sensitive (DS) rat hypertension model. Dahl salt-resistant (DR) and DS rats were fed an 8% NaCl diet. In addition, the DS rats were subcutaneously infused with either saline or recombinant human AM for 4 weeks. Although systolic blood pressures measured weekly in AM- and saline-infused rats did not significantly differ, aortic O2*- levels were significantly (P<0.01) higher in the latter. Likewise, both endothelial nitric oxide synthase (eNOS) mRNA and protein were significantly higher in saline-infused DS rats. Infusion of AM reduced both O2*- and eNOS expression to levels comparable to those seen in DR rats. AM infusion also upregulated the gene expression of guanosine-5'-triphosphate cyclohydrolase I and downregulated the expression of p22(phox), suggesting that AM increased the NOS coupling and bioavailability of NO. AM possesses significant antioxidant properties that improve endothelial function.
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PMID:Beyond vasodilation: the antioxidant effect of adrenomedullin in Dahl salt-sensitive rat aorta. 1591 62

Although angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are known to reduce both reactive oxygen species (ROS) generated by activated NAD(P)H oxidase and vascular remodeling in hypertension, the effects of AT1 receptor antagonists or ACE inhibitors on ROS-scavenging enzymes remain unclear. We hypothesized that AT1 receptor antagonists or ACE inhibitors may modulate vascular remodeling via superoxide dismutase (SOD) in hypertension. Male stroke-prone spontaneously hypertensive rats (SHRSP) were treated for 6 weeks with a vehicle, an AT1 receptor antagonist (E4177; 30 mg/kg/day), or an ACE inhibitor (cilazapril; 10 mg/kg/day). We evaluated protein expression using immunoblots, determined SOD activities with a spectrophotometric assay, and measured NAD(P)H oxidase activity by a luminescence assay. The two drugs showed equipotent effects on blood pressure, left ventricular hypertrophy and fibrosis, and endothelial NO synthase in the SHRSP hearts. The wall-to-lumen ratio of the intramyocardial arteries and the NAD(P)H oxidase essential subunit p22(phox) and its activity were significantly reduced, whereas Cu/Zu-containing SOD (Cu/ZnSOD) expression and activity were significantly increased in the SHRSP hearts. Furthermore, E4177 reduced vascular remodeling more than did cilazapril not only by reducing p22(phox) expression and NAD(P)H oxidase activity but also by upregulating the Cu/ ZnSOD expression and its activity in the SHRSP hearts. Thus, both the AT1 receptor antagonist and the ACE inhibitor inhibited vascular remodeling and reduced ROS in SHRSP via not only a reduction in NAD(P)H oxidase but also an upregulation of Cu/ZnSOD.
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PMID:Angiotensin II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously hypertensive rats. 1596 57

There is growing evidence that oxidative stress contributes to hypertension. Oxidative stress can precede the development of hypertension. In almost all models of hypertension, there is oxidative stress that, if corrected, lowers BP, whereas creation of oxidative stress in normal animals can cause hypertension. There is overexpression of the p22(phox) and Nox-1 components of NADPH oxidase and reduced expression of extracellular superoxide dismutase (EC-SOD) in the kidneys of ANG II-infused rodents, whereas there is overexpression of p47(phox) and gp91(phox) and reduced expression of intracellular SOD with salt loading. Several mechanisms have been identified that can make oxidative stress self-sustaining. Reactive oxygen species (ROS) can enhance afferent arteriolar tone and reactivity both indirectly via potentiation of tubuloglomerular feedback and directly by microvascular mechanisms that diminish endothelium-derived relaxation factor/nitric oxide responses, generate a cyclooxygenase-2-dependent endothelial-derived contracting factor that activates thromboxane-prostanoid receptors, and enhance vascular smooth muscle cells reactivity. ROS can diminish the efficiency with which the kidney uses O(2) for Na(+) transport and thereby diminish the P(O(2)) within the kidney cortex. This may place a break on further ROS generation yet could further enhance vasculopathy and hypertension. There is a tight relationship between oxidative stress in the kidney and the development and maintenance of hypertension.
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PMID:Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? 1618 28

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


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