UMLS:C0020538 - FACTA Search

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

Kallikrein/kinin has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of kallikrein gene transfer in cerebral ischemia. Adult, male Sprague-Dawley rats were subjected to a 1-hour occlusion of the middle cerebral artery followed by intracerebroventricular injection of adenovirus harboring either the human tissue kallikrein gene or the luciferase gene. Kallikrein gene transfer significantly reduced ischemia-induced locomotor deficit scores and cerebral infarction after cerebral ischemia injury. Expression of recombinant human tissue kallikrein was identified and localized in monocytes/macrophages of rat ischemic brain by double immunostaining. Morphological analyses showed that kallikrein gene transfer enhanced the survival and migration of glial cells into the ischemic penumbra and core, as identified by immunostaining with glial fibrillary acidic protein. Cerebral ischemia markedly increased apoptotic cells, and kallikrein gene delivery reduced apoptosis to near-normal levels as seen in sham control rats. In primary cultured glial cells, kinin stimulated cell migration but inhibited hypoxia/reoxygenation-induced apoptosis in a dose-dependent manner. The effects of kinin on both migration and apoptosis were abolished by icatibant, a bradykinin B2 receptor antagonist. Enhanced cell survival after kallikrein gene transfer occurred in conjunction with markedly increased cerebral nitric oxide levels and phospho-Akt and Bcl-2 levels but reduced caspase-3 activation, NAD(P)H oxidase activity, and superoxide production. These results indicate that kallikrein gene transfer provides neuroprotection against cerebral ischemia injury by enhancing glial cell survival and migration and inhibiting apoptosis through suppression of oxidative stress and activation of the Akt-Bcl-2 signaling pathway.
Hypertension 2004 Feb
PMID:Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. 1469 96

Excess production of superoxide anion in response to angiotensin II plays a central role in the transduction of signal molecules and the regulation of vascular tone. We examined the ability of insulin resistance to stimulate superoxide anion production and investigated the identity of the oxidases responsible for its production. Rats were fed diets containing 60% fructose (fructose-fed rats) or 60% starch (control rats) for 8 weeks. In aortic homogenates from fructose-fed rats, the superoxide anion generated in response to NAD(P)H was more than 2-fold higher than that of control rats. Pretreatment of the aorta from fructose-fed rats with inhibitors of NADPH oxidase significantly reduced superoxide anion production. In the isolated aorta, contraction induced by angiotensin II was more potent in fructose-fed rats compared with control rats. Losartan normalized blood pressure, NAD(P)H oxidase activity, endothelial function, and angiotensin II-induced vasoconstriction in fructose-fed rats. To elucidate the molecular mechanisms of the enhanced constrictor response to angiotensin II, expressions of angiotensin II receptor and subunits of NADPH oxidase were examined with the use of angiotensin II type 1a receptor knockout (AT1a KO) mice. Expression of AT1a receptor mRNA was enhanced in fructose-fed mice, whereas expression of either AT1b or AT2 was unaltered. In addition, protein expression of each subunit of NADPH oxidase was increased in fructose-fed mice, whereas the expression was significantly decreased in fructose-fed AT1a KO mice. The novel observation of insulin resistance-induced upregulation of AT1 receptor expression could explain the association of insulin resistance with endothelial dysfunction and hypertension.
Hypertension 2004 Feb
PMID:Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. 1469 97

Clinical and experimental evidence suggests that the pathways by which hypertension and dyslipidemia lead to vascular disease may overlap and that angiotensin II (Ang II) is involved in restructuring of the arterial wall in both atherosclerosis and hypertension. Ang II represents a potent proinflammatory agent promoting recruitment of monocytes into the vascular intima. Ang II also indirectly facilitates transformation of macrophages and smooth muscle cells into foam cells by promoting superoxide radical formation (via NADP/NADPH oxidase stimulation). The oxidative stress produced by Ang II leads to enhanced low-density lipoprotein oxidation and degradation of nitric oxide, an important vascular protective molecule capable of retarding atherosclerosis progression. The importance of the renin-angiotensin system (RAS) in atherogenesis is highlighted by studies in animal models as well as human beings indicating that inhibition of angiotensin-converting enzyme or blockade of type 1 Ang II receptors retards the development of atherosclerotic lesions. In light of a causal and central role of Ang II in atherogenesis, blockade of the RAS represents an important therapeutic consideration in the prevention and treatment of atherosclerotic disease.
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PMID:Renin-angiotensin system as a therapeutic target in managing atherosclerosis. 1470 95

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

To determine the role of endogenous superoxide (O2-) in the kidney, we assessed renal hemodynamics and excretory function in gp91(PHOX) (a NAD(P)H oxidase subunit) gene knockout (KO) mice and compared these findings with those of wild-type (WT) strain C57BL/6 mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances respectively in anesthetized mice (n=8 in each group). There were higher baseline RBF (4.3+/-0.4 versus 2.5+/-0.2 mL/min per gram; P<0.002) and lower renal vascular resistance (RVR) (16+/-1.4 versus 29+/-2.3 mm Hg/mL/min per gram; P<0.0001) in KO compared with WT without a significant difference in mean arterial pressure (MAP) (67+/-2 versus 71+/-2 mm Hg) and GFR (0.66+/-0.09 versus 0.73+/-0.05 mL/min per gram) between the strains. Intravenous infusion of angiotensin II (Ang II) (2 ng/min per gram of body weight) for 30 minutes caused a lesser degree of decreases in RBF (-8% versus -33%) and of increases in RVR (+73% versus +173%) in KO compared with WT. GFR was increased (43%) in KO but not in WT during Ang II infusion. Urinary excretion of nitrate/nitrite was higher in conscious KO (n=5) than in WT (n=5), indicating an increase in nitric oxide bioavailability that could be the cause of high RBF and low RVR in KO. These data indicate that gp91(PHOX), a subunit of NAD(P)H oxidase, plays a regulatory role in the maintenance of renal vascular tone. These results also suggest that the mechanism of Ang II-mediated renal vascular action involves concomitant generation of O2-.
Hypertension 2004 Feb
PMID:Assessment of renal functional phenotype in mice lacking gp91PHOX subunit of NAD(P)H oxidase. 1471 66

Hypertension is a risk factor for cardiovascular and cerebrovascular outcome. Hypertension is associated with oxidative stress. Alteration in endothelial function is an initial step in the pathogenesis of atherosclerosis. A balance between ambient levels of super oxide and released nitric oxide(NO) plays an important role in the maintenance of endothelial function. It is well known that reactive oxygen species, including hydroxy radicals, directly scavenge NO and produce toxic peroxynitrite. Angiotensin II and mechanical stress generate the reactive oxygen species through the activation of NADH/NADPH oxidase in hypertension. Several investigators have shown that oxidative stress is involved in enhanced vascular growth, vascular inflammation, and impaired endothelium-dependent in hypertension. In this review, we would like to explain the role of oxidative stress in hypertensive organ damages.
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PMID:[Oxidative stress, reactive oxygen species]. 1473 35

Patients with uncontrolled essential hypertension have elevated concentrations of superoxide anion (O(2)(-*)), hydrogen peroxide (H(2)O(2)), lipid peroxides, endothelin, and transforming growth factor-beta (TGF-beta) with a simultaneous decrease in endothelial nitric oxide (eNO), superoxide dismutase (SOD), vitamin E, and long-chain polyunsaturated fatty acids (LCPUFAs). Physiological concentrations of angiotensin II activate NAD(P)H oxidase and trigger free radical generation (especially that of O(2)(-*)). Normally, angiotensin II-induced oxidative stress is abrogated by adequate production and release of eNO, which quenches O(2)(-*) to restore normotension. Angiotensin II also stimulates the production of endothelin and TGF-beta. TGF-beta enhances NO generation, which in turn suppresses TGF-beta production. Thus, NO has a regulatory role on TGF-beta production and is also a physiological antagonist of endothelin. Antihypertensive drugs suppress the production of O(2)(-*) and TGF-beta and enhance eNO synthesis to bring about their beneficial actions. LCPUFAs suppress angiotensin-converting enzyme (ACE) activity, reduce angiotensin II formation, enhance eNO generation, and suppress TGF-beta expression. Perinatal supplementation of LCPUFAs decreases insulin resistance and prevents the development of hypertension in adult life, whereas deficiency of LCPUFAs in the perinatal period results in raised blood pressure later in life. Patients with essential hypertension have low concentrations of various LCPUFAs in their plasma phospholipid fraction. Based on this, it is proposed that LCPUFAs serve as endogenous regulators of ACE activity, O(2)(-*), eNO generation, and TGF-beta expression. Further, LCPUFAs have actions similar to statins, inhibit (especially omega-3 fatty acids) cyclooxygenase activity and suppress the synthesis of proinflammatory cytokines, and activate the parasympathetic nervous system, all actions that reduce the risk of major vascular events. Hence, it is proposed that availability of adequate amounts of LCPUFAs during the critical periods of growth prevents the development of hypertension in adulthood.
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PMID:Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-beta to prevent human essential hypertension. 1474 37

Accumulating evidence indicates that vascular dysfunction in atherosclerosis, hypertension, and diabetes is either caused by or accompanied by oxidative stress in the vessel wall. In particular, the role of redox processes as mediators of vascular repair and contributors to post-angioplasty restenosis is increasingly evident. Yet the pathophysiology of such complex phenomena is still unclear. After vascular injury, activation of enzymes such as NADPH oxidase leads to a marked increase in superoxide generation, proportional to the degree of injury, which rapidly subsides. Such early superoxide production is significantly greater after stent deployment, as compared to balloon injury. Recent data suggest the persistence of low levels of oxidant stress during the vascular repair reaction in neointimal and medial layers. Despite the compensatory increase in expression of iNOS and nNOS, nitric oxide bioavailability is reduced because of increased reaction rates with superoxide, yielding as by-products reactive nitrogen/oxygen species that induce protein nitration. Concurrently, the activity of vascular superoxide dismutases exhibits a sustained decrease following injury. This decreased activity appears to be a key contributor to vasoconstrictive remodeling and a major determinant of the occurrence of nitrative/oxidative stress. Replenishment of superoxide dismutase (SOD), as well as treatment with vitamins C and E or the lipid-lowering drug probucol and its analogs, led to decrease in constrictive remodeling and improved vessel caliber. Better understanding of the redox pathophysiology of vascular repair should help clarify the pathogenesis of many other vascular conditions and may provide novel therapeutic strategies to prevent vascular lumen loss.
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PMID:Redox processes underlying the vascular repair reaction. 1496 Nov 89

Until recently elevated blood pressure was considered as a hemodynamic entity representing an increase in workload for the heart and the arterial tree. Control of hypertension meant hemodynamic unloading, through inhibition of vasoconstrictor pathways, principally renin-angiotensin system and sympathetic system. In recent years however a new pharmacological approach has evolved as a result of (i) the dissociation of endothelial dysfunction and vascular pathology from increased blood pressure; (ii) the recognition that endothelial dysfunction regards not only the vascular reactivity, but also promotes atherosclerosis and thrombosis; and (iii) an improved understanding of the complexity of local-tissue renin angiotensin system and of the vasodilatory and cytoprotective role of natriuretic peptides. This has led to a reconsideration of existing medicines in terms of specification on endothelial function, more rationalized application of drugs and search for new compounds targeting both vasodilatory and anti-proliferative pathways. Examples include beta1-adrenergic antagonists, such as Nebivolol and Carvedilol, and vasopeptidase inhibitors, such as Omapatrilat, that inhibit simultaneously the angiotensin converting enzyme and neutral endopeptidase. Furthermore the identification of genetic polymorphisms in the effectors involved in the pathophysiology of hypertension or in the response to anti-hypertensive drugs, such as the p22phox subunit of NADPH oxidase, alpha-adducin or adrenergic receptors, has promoted the prospective of both better understanding of hypertension and individualized strategies for its treatment.
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PMID:The shift in the "paradigm" of the pharmacology of hypertension. 1496 15

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