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)

Cyclooxygenase and lipoxygenase metabolism of arachidonic acid produces compounds important in cardiovascular control. Further, arachidonic acid can be metabolised by cytochrome p450 to produce epoxyeicosatrienoic acids (EETs). These derivatives are inactivated by soluble epoxide hydrolase (sEH). The potential role of these EETs in hypertension and cardiac remodelling has been determined using the selective sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Experiments were performed on male Wistar rats following uninephrectomy alone (UNX rats) or uninephrectomy with administration of DOCA (25 mg every fourth day subcutaneously) and 1% NaCl in drinking water (DOCA-salt rats). ADU (10 mg/kg/d subcutaneously) was administered for 2 wk starting 2 wk after surgery. Cardiovascular structure and function were determined using organ wet weights, histological analysis of collagen and inflammation, isolated heart and thoracic aortic ring preparations, and electrophysiological measurements. DOCA-salt hypertensive rats developed hypertension, hypertrophy, perivascular and interstitial fibrosis, endothelial dysfunction, and prolongation of the cardiac action potential duration within 4 wk. Administration of ADU prevented the further increase in systolic blood pressure and left-ventricular wet weight and normalized endothelial function. ADU treatment did not change inflammatory cell infiltration, collagen deposition, or cardiac action potential duration. EETs may be involved in the development of hypertension and endothelial dysfunction in DOCA-salt rats, but not in excessive collagen deposition or electrophysiological abnormalities.
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PMID:Prevention of hypertension in DOCA-salt rats by an inhibitor of soluble epoxide hydrolase. 1740 62

This study investigated whether production of reactive oxygen species by neutrophils differs between women with preeclampsia and those with essential hypertension. First, we assessed superoxide production by neutrophils during pregnancy and 4 weeks after delivery in 15 healthy pregnant women, 12 women with preeclampsia, and 7 pregnant women with essential hypertension. We then examined effects of serum from each subject on superoxide production by neutrophils obtained from healthy nonpregnant women. Neutrophil superoxide production was measured by cytochrome C reduction. N-formyl-methionyl-leucyl-phenylalanine-stimulated superoxide production was significantly increased in neutrophils from women with preeclampsia and women with essential hypertension compared with normal pregnant women. Four weeks postpartum, the level of superoxide production was significantly decreased in women with preeclampsia but not in women with either normal pregnancy or essential hypertension. When neutrophils obtained from nonpregnant women were preincubated with predelivery sera from each group, sera from women with preeclampsia significantly enhanced superoxide production compared with sera from the other 2 groups. When postpartum serum was used, enhancement of neutrophil superoxide production by serum from women with preeclampsia was significantly decreased compared with that by predelivery serum. In conclusion, increased neutrophil superoxide production resolved after delivery in preeclampsia, whereas activation persisted postpartum in women with essential hypertension. The different transition of neutrophil superoxide production in response to pregnancy appears to be that preeclampsia is characterized by the presence of serum factors that enhance neutrophil superoxide production. Thus, in preeclampsia, serum factors bear a more essential role producing superoxide than a behavior of neutrophils.
Hypertension 2007 Jun
PMID:Difference in neutrophil superoxide generation during pregnancy between preeclampsia and essential hypertension. 1789 68

In cardiovascular diseases e.g. heart failure and coronary artery disease gender differences are evident in etiology, pathophysiology, clinical presentation, prognosis and response to treatment. Diabetes and hypertension are the major risk factors in women. Mechanisms leading to apparent diabetes or its clinical pre-stage are different in women and men and according to this result in different therapeutic implications. Diastolic heart failure is more frequent in women and effects and side effects of important groups of active pharmaceutical substances are, at least to some extent, different. Atrial fibrillation and ventricular arrhythmia differ in frequency of occurrence; drug induced tachycardia with QT interval prolongation is particularly frequent in women. Underlying pathomechanisms responsible for gender differences in pharmacotherapy are on the one hand differences in pharmacokinetic mechanisms. Particularly drugs which are metabolised via cytochrome P 450 CYP 3A pathway show different kinetics in women and men. In addition, important differences are evident in pharmocodynamics caused by effects of sex steroid hormones or products of X-chromosomal genes. The evidence of estrogen and testosterone receptors in cardiomyocytes and the vascular system, interaction of sex steroid hormones with cellular pathways and the role of X-chromosomal genes are the focus of basic research. Interactions of sex steroid hormone receptors with other nuclear receptors e.g. PPARs ("peroxisome proliferator-activated receptors") are another important underlying mechanism. The knowledge of different pharmacokinetic mechanisms has to be taken into consideration in pharmacotherapy of cardiovascular diseases, for example by adjustment of drug dosages in women, necessary in different groups of pharmaceutical substances or in the long run, gender differences in effects and side effects of drugs. In drug development both aspects have to be considered. There is more than one good reason to intensify basic and clinical research and research on health care on gender differences in cardiovascular diseases.
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PMID:[Implications of gender-specific aspects in the therapy of cardiovascular diseases]. 1787 7

Ouabain is Na(+)/K(+)-ATPase inhibitor and an endogenous regulator of blood pressure, it has dual effect on vascular endothelial cells(VEC) cell growth and VEC apoptosis is contributed to vascular dysfunction involved in vascular remolding. However, the precise mechanisms of apoptosis induced by ouabain remained unclear. The objective of this study was to identify the differently expressed proteins involved in VEC apoptosis induced by ouabain in order to explore cellular and subcellular mechanisms related to ouabain actions. Human umbilical vein endothelial cells (HUVEC) were exposed to increasing concentrations (0.1 nM to 10 microM) of ouabain at 12-48 h intervals. Cell viability tests revealed that high concentrations of ouabain inhibited cell growth. Flow cytometry and caspase-3 activity analysis confirmed that apoptosis was primarily responsible for ouabain induced cell death. Two-dimensional electrophoresis in conjunction with mass spectrometry revealed that the ouabain-induced apoptosis was accompanied by regulated expression of programmed cell death protein 6, cytochrome C1, endothelin converting enzyme, claudin-1, reticulon-4, galectin-1, ras-related protein rab-11B, calnexin, profilin-1 and heat shock protein 60 (HSP60). Further study on cytochrome c and HSP60 demonstrated that levels of mitochondria and cytosol cytochrome c and HSP60 changed in response to ouabain treatment. Data showed that mitochondria proteins such as HSP60 interferes with HSP60-Bax interactions played an important role in ouabain induced apoptosis. These data bring new sights into physiological role for ouabain in VEC apoptosis and vascular remodeling, thus provide new strategies for new anti-cardiovascular disease drug development or the identification of biomarkers for vascular dysfunction in ouabain related hypertension.
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PMID:Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. 1824 27

Association of polymorphism of b1-adrenoreceptors gene and cytochrome 2D6 gene with efficacy of b-adrenoblocker betaxolol was studied in 81 patients with I and II degree arterial hypertension. Betaxolol (10-20 mg/day) was given for 4 weeks, its efficacy was assessed by office blood pressure (BP) measurements, 24-hour BP and ECG monitoring and standard exercise test. At the end of the study significant lowering of systolic and diastolic BP was noted by 11,8 +/- 2,47 (p=0,001) and 7,8 +/- 1,68 mm Hg (p=0,001), respectively. Heart rate (HR) at rest lowered by 19,8 +/- 1,96 beats/min (p=0,0001). At analysis of individual reaction of patients to treatment with betaxolol it turned out that decrease of BP and HR was variable, but their distribution in the group did not differ significantly from normal. Hypotensive activity and influence on HR were confirmed by results of all instrumental investigations. No significant differences were revealed in dynamics of systolic and diastolic BP both at rest and at effort between patients with different genotypes of polymorphic marker Gly389Arg of ADRB1 gene. Compared with carriers of genotype Ser/Ser carriers of genotype Ser/Pro of polymorphic marker Pro34Ser of Cyp2D6 gene had significantly more pronounced decrease of HR at the background of treatment with betaxolol: - 32,6 +/- 4,77 and - 18,4 +/- 2,01 beats/min (p=0,023) at rest and - 30,1 +/- 3,05 and - 24,0 +/- 2,59 beats/min (p=0,043) at maximal exercise, respectively. These patients had also more pronounced lowering of diastolic BP at maximal work load and more pronounced increase of exercise duration at the background of treatment. Thus efficacy of betaxolol in patients with hypertension was associated solely with genotype of polymorphic marker Ser34Pro of CYP2D6 gene. In patients having in genotype Pro allele of polymorphic marker Pro34Ser of CYP2D6 gene therapy with betaxolol is more effective, than in homozygote carriers of Ser allele. This can be related to low rate of metabolism of the preparation in these patients.
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PMID:[Genetic aspects of individual sensitivity to betaxolol in patients with arterial hypertension]. 1842 52

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants implicated in the development of pro-inflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. PCB exposure of endothelial cells results in increased cellular oxidative stress, activation of stress and inflammatory pathways leading to increased expression of cytokines and adhesion molecules and ultimately cell death, all of which can lead to development of atherosclerosis. To date no studies have been performed to examine the direct effects of PCB exposure on the vasculature relaxant response which if impaired may predispose individuals to hypertension, an additional risk factor for atherosclerosis. Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) following oxidative/nitrosative stress in endothelial cells and subsequent depletion of NADPH has been identified as a central mediator of cellular dysfunction. The aim therefore was to investigate whether 2,2',4,6,6'-pentachlorobiphenyl (PCB 104) directly causes endothelial cell dysfunction via increased oxidative stress and subsequent overactivation of PARP. Exposure of ex vivo rat aortic rings to PCB 104 impaired the acetylcholine-mediated relaxant response, an effect that was dependent on both concentration and exposure time. In vitro exposure of mouse endothelial cells to PCB 104 resulted in increased cellular oxidative stress through activation of the cytochrome p450 enzyme CYP1A1 with subsequent overactivation of PARP and NADPH depletion. Pharmacological inhibition of CYP1A1 or PARP protected against the PCB 104-mediated endothelial cell dysfunction. In conclusion, the environmental contaminants, PCBs, can activate PARP directly impairing endothelial cell function that may predispose exposed individuals to development of hypertension and cardiovascular disease.
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PMID:PCB-induced endothelial cell dysfunction: role of poly(ADP-ribose) polymerase. 1954 8

Fructose feeding has been shown to induce insulin resistance and hypertension. Renal protein expression for the cytochrome P (CYP) 450 arachidonic acid metabolizing enzymes has been shown to be altered in other models of diet-induced hypertension. Of special interest is CYP4A, which produces the potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid and CYP2C, which catalyzes the formation of the potent dilators epoxyeicosatrienoic acids as well as soluble epoxide hydrolase (sEH) which metabolizes the latter to dihydroxyeicosatrienoic acids. The RhoA/Rho kinase (ROCK) signaling pathway is downstream of arachidonic acid and is reported to mediate metabolic-cardio-renal dysfunctions in some experimental models of insulin resistance and diabetes. The aim of the present study was to determine the expression of CYP4A, CYP2C23, CYP2C11, sEH, RhoA, ROCK-1, ROCK-2, and phospho-Lin-11/Isl-1/Mec-3 kinase (LIMK) in kidneys of fructose-fed (F) rats. Male Wistar rats were fed a high fructose diet for 8 weeks. Body weight, systolic blood pressure, insulin sensitivity, and renal expression of the aforementioned proteins were assessed. No change was observed in the body weight of F rats; however, euglycemia and hyperinsulinemia implicating impaired glucose tolerance and significant elevation in systolic blood pressure were observed. Renal expression of CYP4A and CYP2C23 was significantly increased while that of CYP2C11 and sEH was not changed in F rats. Equal expression for RhoA in both control and F rats and an enhanced level of ROCK-1 and ROCK-2 constitutively activate 130 kDa cleavage fragments as well as phospho-LIMK. These data suggest that the kidneys could be actively participating in the pathogenesis of insulin resistance-induced hypertension through the arachidonic acid CYP 450-RhoA/Rho kinase pathway(s).
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PMID:Renal expression of arachidonic acid metabolizing enzymes and RhoA/Rho kinases in fructose insulin resistant hypertensive rats. 1963 17

The deficiency of 17 alpha-hydroxylase/17,20-lyase causes a rare autosomal recessive disorder presenting with congenital adrenal insufficiency (CAH) and sexual infantilism. Both 17 alpha-hydroxylase and 17,20-lyase reactions are catalyzed by a single polypeptide, cytochrome P450c17 (CYP17), which is encoded by the CYP17A1 gene. We describe the clinical, hormonal, and molecular findings of a 33-yr-old patient presenting with primary amenorrhea, late onset hypertension, and hypokalemic myopathy. The molecular analysis of CYP17A1 revealed a novel homozygous missense mutation resulting in the substitution of arginine to lysine at the amino acid position 21 (p.R21L).
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PMID:A novel mutation in the N-terminal region of the CYP17A1 gene in a patient with 17 alpha-hydroxylase/17,20-lyase deficiency. 1963 99

A case of colchicine-induced rhabdomyolysis is reported. A 48 year old African-American male with history of hypertension and chronic gout on colchicine 0.6 mg daily presented with symptoms of a community acquired pneumonia. The patient was started on 500 mg of clarithromycin orally twice daily and represented to the emergency room after 3 days complaining of severe muscle pain. His liver panel showed elevations in the serum aminotransferases; AST 513 mU/ml (nl 15-41) and ALT 182 mU/ml (nl 17-63). His complete blood count showed an elevated white blood cell count of 18,800/ml (nl 4,000-10,000/ml). Urine analysis was positive for myoglobin with no red cells present. Serum creatine kinase (CK) was 22,996 mU/ml (nl 31-221) with a normal troponin I 0.18 (nl <0.4).Investigations confirmed the presence of rhabdomyolysis and discontinuation of colchicine and clarithromycin resulted in resolution of clinical and biochemical features of rhabdomyolysis. By hospital day four, his muscle soreness had improved markedly. His serum CK improved to 3,389 mU/ml (nl 31-221 mU/ml) and serum creatinine improved to 1.5 mg/dl (nl 0.8-1.2). On hospital day five, the patient was discharged on oral anti-hypertensive medication and a ten-day course of doxycycline. Metabolism of colchicine by the cytochrome P450 3A4 system has been previously described, but this is the first published report of colchicine associated rhabdomyolysis secondary to drug metabolism interactions with an antibiotic. A review of medications that are metabolized via the cytochrome 3A4 and A-SLAVED-LIVER (Amiodarone, Simvastatin, Lovastatin, Atorvastatin, Verapamil, Erythromycin, Diltiazem, cLarithromycin, Itraconazole, Voriconazole, colchicinE, Ritonavir) pneumonic was established.
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PMID:Short term treatment with clarithromycin resulting in colchicine-induced rhabdomyolysis. 2541 92

Sesamin, the major lignan found in sesame, has been shown to increase vitamin E levels by inhibiting its metabolism via the cytochrome P450 isozyme CYP4F2. CYP4F2 and CYP4A11 are the predominant human isoforms that synthesize 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. Considerable evidence suggests that 20-HETE may play a role in the pathogenesis of hypertension. We hypothesized that sesamin could be an inhibitor of 20-HETE synthesis. This study investigated the effects of sesamin on 20-HETE synthesis in vitro and the effect of sesame supplementation on plasma and urinary 20-HETE concentrations in humans. Human microsomes were used to investigate the potency and selectivity of sesamin inhibition of 20-HETE synthesis. Sesamin inhibited human renal and liver microsome 20-HETE synthesis with IC50 <20 micromol/L. It was selective toward CYP4F2 (IC50: 1.9 micromol/L) and had reduced activity toward CYP4A11 (IC50: >150 micromol/L), as well as cytochrome P epoxygenation of arachidonic acid (IC50: >50 micromol/L). In a randomized, controlled crossover trial, overweight men and women (n=33) consumed 25 g/d of sesame (approximately 50 mg/d of sesame lignan) or an isocaloric matched control for 5 weeks each. Relative to control, sesame supplementation resulted in a 28% decrease in plasma and a 32% decrease in urinary 20-HETE (P<0.001). Urinary sodium, potassium, and blood pressure were not affected. This study demonstrates for the first time that sesame supplementation in humans reduces the plasma and urinary levels of 20-HETE, likely via inhibition of CYP4F2 by sesame lignans. These results suggest that sesame lignans could be used for the investigation of potential roles of 20-HETE in humans.
Hypertension 2009 Nov
PMID:Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: in vitro and human studies. 1978 46


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