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 present study aimed to determine the relevance of cyclooxygenase-2 (COX-2)-derived prostanoids for the adverse effects of lipopolysaccharides (LPSs) on cardiovascular function. For this goal, male Sprague-Dawley rats received a single intravenous dose of LPS (10 mg/kg) and were treated with different cyclooxygenase inhibitors. Injection of LPS caused a marked decrease of systolic arterial pressure, from 128 to 79 mm Hg, and a concomitant increase of heart rate, from 380 to 530 minutes(-1). Both the decrease of systemic arterial pressure and the increase of heart rate induced by LPS were almost absent if the animals also received the COX-2 blocker rofecoxib (20 mg/kg), regardless whether the drug was given 1 hour before or 1 hour after LPS. Although plasma and organ levels of prostanoids were lowered by rofecoxib, the characteristic LPS-induced increases of NO synthase II and COX-2 gene expression, as well as of plasma and tissue nitrate/nitrite concentrations, were not affected by rofecoxib. Although rofecoxib treatment did also not change LPS-induced tissue cytokine concentrations, it markedly improved LPS-induced liver damage, as indicated by the decrease of transaminases. Moreover, the overall well-being of the LPS-injected animals improved on concomitant treatment with the COX-2 inhibitor. Taken together, our data suggest that COX-2-derived prostanoids are major mediators for the detrimental effects of LPS on cardiovascular and organ function.
Hypertension 2002 Dec
PMID:Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular failure. 1246 84

Abeta peptides are thought to be critical molecules in the pathophysiology of Alzheimer's disease (AD) and are the major protein constituents of senile plaques. In most AD cases, Abeta peptides also form some deposits in the cerebrovasculature, leading to cerebral amyloid angiopathy and hemorrhagic stroke. Regional cerebral hypoperfusion is one of the earlier clinical manifestations in both the sporadic and familial forms of AD. In addition, a variety of vascular risk factors of different etiologies (for instance, diabetes, hypertension, high cholesterol level, atherosclerosis, and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of Abeta on constrictor responses elicited by endothelin-1 in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized Abeta potentiates endothelin-1-induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoconstriction elicited by Abeta in these large human cerebral arteries appears to be completely antagonized by NS-398, a selective cyclooxygenase-2 inhibitor, or by SB202190, a specific p38 mitogen-activated protein kinase inhibitor, suggesting that Abeta vasoactivity is mediated via the stimulation of a proinflammatory pathway. In addition, a similar proinflammatory response appears to be mediated by Abeta in isolated human brain microvessels, resulting in an increased production of prostaglandin E(2) and F(2alpha). Using a scanner laser Doppler imager, we show a progressive decline with aging in cortical perfusion level in transgenic APPsw mice (line 2576) compared with age-matched control littermates. The relation between the acute proinflammatory and vasoactive properties of Abeta and the chronic progressive hypoperfusion seen in AD (and transgenic models thereof) is yet to be elucidated.
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PMID:Proinflammatory and vasoactive effects of Abeta in the cerebrovasculature. 1248 Jul 34

Analysis of results of randomized controlled studies revealed pronounced attenuation of vasodilating, natriuretic, and cardioprotective effects of angiotensin converting enzyme inhibitors (ACEI) by concomitant use with of indomethacin and aspirin in patients with hypertension, chronic heart failure, and acute myocardial infarction. In some studies beneficial effects of ACEI were shown to be weakened by concomitant use with of other nonsteroidal antiinflammatory drugs, including selective inhibitors of cyclooxygenase-2.
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PMID:[Interaction of angiotensin converting enzyme inhibitors with nonsteroidal antiinflammatory drugs]. 1249 16

The article is concerned with the effects of specific cyclooxygenase-2 (COX-2) inhibitors and their relationship to thrombotic cardiovascular events and to renal disease. Clinical and experimental aspects of COX-2-specific inhibitors are cited. A COX-2 inhibitor, celecoxib, interferes with myocardial prostacyclin production and also produces hypertension. Data have shown that in animal experiments, celecoxib also lowers myocardial prostaglandin concentration but fails to inhibit thromboxane concentration to the same degree. In the kidney, celecoxib can result in glomerular and interstitial nephritis or papillary necrosis. As in infarcted heart muscle, the COX-2-specific inhibitor celecoxib causes a significant decline in prostaglandin in the renal medulla. It was concluded from both clinical and experimental findings that COX-2 inhibitors can cause thrombotic cardiovascular events as well as renal disease. For these reasons, care should be exercised in administering specific COX-2 inhibitors to patients with pre-existing cardiac or renal disease.
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PMID:Cyclooxygenase-2 inhibitors: is there an association with coronary or renal events? 1257 96

The present study examined the role of cyclooxygenase-synthetized prostanoids in the pathogenesis of angiotensin-II-induced inflammatory response and vascular injury in transgenic rats harboring mouse renin-2 gene (mREN2 rats). Five- to six-week-old, heterozygous mREN2 rats received the following drug regimens for 8 weeks: (1) controls; (2) cyclooxygenase-2 inhibitor (MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2(5H)-furanone], 14 mg kg(-1) p.o.); (3) cyclooxygenase-1/cyclooxygenase-2 inhibitor (sulindac, 14 mg kg(-1) p.o.); (4) angiotensin II receptor antagonist (losartan 40 mg kg(-1) p.o.); (5) MF-tricyclic + losartan; (6) sulindac + losartan. Normotensive Sprague-Dawley rats served as controls. mREN2 rats developed pronounced hypertension, cardiac hypertrophy, and albuminuria as compared to normotensive Sprague-Dawley controls. mREN2 rats showed pronounced perivascular inflammation and morphological damage in the kidneys and the heart. Both MF-tricyclic and sulindac further increased blood pressure and albuminuria in mREN2 rats. Neither MF-tricyclic nor sulindac were able to prevent angiotensin-II-induced perivascular inflammation and morphological changes in the heart or in the kidneys. Myocardial and renal cyclooxygenase-2 mRNA expressions were decreased in mREN2 rats, whereas no difference was found in cyclooxygenase-1 mRNA expressions. Sulindac increased both cyclooxygenase-1 and cyclooxygenase-2 gene expressions, whereas MF-tricyclic increased only cyclooxygenase-2 gene expressions. Losartan normalized blood pressure, cardiac hypertrophy, albuminuria, inflammatory response and morphological changes in mREN2 rats, both in the presence and absence of cyclooxygenase inhibitors. Our findings indicate that cyclooxygenase does not play a central role in the pathogenesis of angiotensin-II-induced inflammatory response and vascular injury in mREN2 rats.
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PMID:Cardiovascular and renal effects of cyclooxygenase inhibition in transgenic rats harboring mouse renin-2 gene (TGR[mREN2]27). 1258 11

In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in restricted subpopulations of cells. High levels of expression can be detected in the macula densa (MD) and associated cortical thick ascending limb of Henle (cTALH) cells and medullary interstitial cells (MICs). In human biopsy specimens, COX-2 expression is also detected in glomerular podocytes and increased podocyte expression is seen in experimental models of progressive glomerular injury. Physiological regulation of COX-2 in these cellular compartments suggests functional roles for eicosanoid products of the enzyme. COX-2 expression increases in high-renin states (salt restriction, angiotensin-converting enzyme inhibition, renovascular hypertension) and selective COX-2 inhibitors significantly decrease plasma renin levels, renal renin activity and mRNA expression. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin II and by glucocorticoids and mineralocorticoids. Conversely, nitric oxide (NO) generated by neuronal nitric oxide synthase (nNOS) is a positive modulator of COX-2 expression. Decreased extracellular chloride increases COX-2 expression in cultured cTALH, an effect mediated by increased p38 MAP kinase activity and, in vivo, a sodium-deficient diet increases expression of activated p38 in MD/cTALH. In contrast to COX-2 in MD/cTALH, COX-2 expression in MICs increases in response to a high-salt diet, as well as water deprivation. Studies in cultured MICs confirm that expression is increased in response to hypertonicity, and expression is mediated at least in part by nuclear factor-kappaB (NFkappaB) activation. COX-2 inhibition leads to apoptosis of MICs in response to hypertonicity in vitro and following water deprivation in vivo. In addition, COX-2 metabolites appear to be important mediators of medullary blood flow and renal salt handling. Therefore, there is increasing evidence that COX-2 is an important physiological mediator of kidney function.
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PMID:Cyclooxygenase-2 and the kidney: functional and pathophysiological implications. 1268 21

Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-kappaB and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid-induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both n-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid-induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.
Hypertension 2003 Jun
PMID:Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. 1274 10

Lead exposure is a known cause of hypertension. Although most studies have focused on lead-induced endothelial dysfunction and on the involvement of reactive oxygen species (ROS), it has been recently demonstrated that the vascular wall of lead-exposed rats has both an altered the endothelium-independent relaxing response and a reduced expression of soluble guanylate cyclase (sGC). The aim of the present study was to determine in in vitro incubated rat isolated aortic segments if lead downregulates sGC expression, analyzing the involvement of ROS and cyclooxygenase-2 (COX-2). The experiments were performed in isolated aortic segments from Wistar rats that were incubated with lead for 24 h. Lead significantly reduced sGC-beta(1) subunit expression in a concentration-dependent manner. The maximal reduction in sGC-beta(1) subunit expression was achieved with 1 ppm lead. Vitamin C (30 micromol/L) partially restored sGC-beta( 1) subunit expression in lead (1 ppm)-exposed aortic segments. A similar protection of sGC-beta(1) subunit expression was obtained with both a protein kinase A inhibitor, H89 (1 micromol/L) and with rofecoxib (1 micromol/L), an inhibitor of COX-2 activity. Moreover, lead exposure increased COX-2 expression in the arterial wall. While vitamin C reduced both COX-2 expression and superoxide anion production related to lead exposure, rofecoxib failed to modify superoxide anion generation in lead-incubated aortic segments. In conclusion, the present results suggest the involvement of ROS and COX-2 in the downexpression of sGC-beta(1) subunit induced by lead in the rat vascular wall.
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PMID:Lead-induced downregulation of soluble guanylate cyclase in isolated rat aortic segments mediated by reactive oxygen species and cyclooxygenase-2. 1276 Dec 46

Hypertension is associated with endothelial dysfunction that is attributable to oxidative stress and a proinflammatory state. Under these conditions, enhanced expression of cyclooxygenase-2 might lead to increased production of vasoconstrictor prostanoids and reactive oxygen species that reduce the bioavailability of endothelium-derived nitric oxide. To investigate the contribution of cyclooxygenase-2 activity to endothelial dysfunction in human hypertension, we evaluated brachial artery vasodilator function by ultrasound in 29 hypertensive patients before and after treatment with the selective cyclooxygenase-2 inhibitor celecoxib or placebo in a randomized, double-blind study. Brachial artery flow-mediated dilation improved from a baseline of 7.9+/-4.5% to 9.9+/-5.1% (P=0.005) 3 hours after the first dose and to 10.1+/-6.1% (P=0.006) after 1 week of treatment with celecoxib. In contrast, placebo treatment had no significant effect on flow-mediated dilation (8.1+/-4.4%, 8.3+/-3.5%, and 8.0+/-3.2%, respectively). Neither treatment altered nitroglycerin-mediated dilation, extent of reactive hyperemia, or baseline arterial diameter. Celecoxib treatment had no significant effect on the urinary concentrations of F2 isoprostane or thromboxane metabolites. However, urinary concentrations of the prostacyclin metabolite 2,3-dinor-6-ketoprostglandin F1alpha were significantly lower after 1 week of celecoxib treatment. Thus, cyclooxygenase-2 products contribute to endothelial dysfunction in hypertension, and treatment with a cyclooxygenase-2 inhibitor could have a beneficial effect in this setting. However, cyclooxygenase-2 inhibition also has an adverse effect on prostacyclin production that could promote thrombosis, and the net clinical consequences of improved endothelial function versus loss of prostacyclin merits further investigation.
Hypertension 2003 Sep
PMID:Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension. 1287 94

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They regulate lipid metabolism, glucose homeostasis, cell proliferation, and differentiation and modulate inflammatory responses. We examined whether PPARgamma is functional in cultured neonatal ventricular myocytes and studied its role in inflammation. Western blots revealed PPARgamma in myocytes. When myocytes were transfected with a PPAR response element reporter plasmid (PPRE-TK-luciferase), the PPARgamma activator 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) increased promoter activity, whereas cotransfection of a dominant negative PPARgamma inhibited it. To determine the role of 15dPGJ2 in expression of proinflammatory genes, we tested its effect on interleukin-1beta induction of cyclooxygenase-2 (COX-2). 15dPGJ2 decreased interleukin-1beta stimulation of COX-2 by 40% and PGE2 production by 73%. We next questioned whether 15dPGJ2 was modulating the expression of inducible prostaglandin E2 synthase (PGES) and found that it completely blocked interleukin-1beta induction of PGES. Use of a second PPARgamma agonist, troglitazone, and the selective PPARgamma antagonist GW9662 demonstrated that the effects seen were PPARgamma-dependent. In addition, we found that 15dPGJ2 blocked interleukin-1beta stimulation of inducible nitric oxide synthase (iNOS). We concluded that 15dPGJ2 may play an anti-inflammatory role in a PPARgamma-dependent manner, decreasing COX-2, PGES, and PGE2 production, as well as iNOS expression.
Hypertension 2003 Oct
PMID:PPARgamma inhibition of cyclooxygenase-2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes. 1288 95


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