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)

Chronic renal injury can be mediated by angiotensin II (ANG II) and prostanoids through hemodynamic and inflammatory mechanisms and attenuated by individual suppression of these mediators. In rats with (5/6) renal ablation (Nx), we investigated 1) the intrarenal distribution of COX-2, ANG II, and the AT(1) receptor (AT(1)R); 2) the renoprotective and antiinflammatory effects of an association between the AT(1)R blocker, losartan (Los), and the gastric sparing anti-inflammatory nitroflurbiprofen (NOF). Adult male Munich-Wistar rats underwent Nx or sham operation (S), remaining untreated for 30 days, after which renal structure was examined in 12 Nx rats (Nx(pre)). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: Nx(V) (vehicle), Nx(Los) (Los), Nx(NOF) (NOF), and Nx(Los/NOF) (Los/NOF). Nx(pre) rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion, and macrophage infiltration, accompanied by abnormal glomerular, vascular, and interstitial COX-2 expression. ANG II appeared in interstitial cells, in contrast to S, in which ANG II was virtually confined to afferent arterioles. Intrarenal AT(1)R distribution shifted from mostly tubular in S to predominantly interstitial in Nx(pre). All these changes were aggravated at 120 days and attenuated by Los and NOF monotherapies. Los/NOF treatment arrested renal structural injury and ANG II expression and reversed hypertension, albuminuria, and renal inflammation. In conclusion, abnormal expression of COX-2, ANG II, and AT(1)R may be key to development of renal injury in Nx. Concomitant COX-2 inhibition and AT(1)R blockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.
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PMID:Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory. 1507 90

Atherosclerosis and its complications such as coronary heart disease, myocardial infarction and stroke are the leading causes of death in the developed world. High blood pressure, diabetes, smoking and a diet high in cholesterol and lipids clearly increase the likelihood of premature atherosclerosis, albeit other factors, such as the individual genetic makeup, may play an additional role. Several epidemiological studies and intervention trials have been performed with vitamin E, and some of them showed that it prevents atherosclerosis. For a long time, vitamin E was assumed to act by decreasing the oxidation of LDL, a key step in atherosclerosis initiation. However, at the cellular level, vitamin E acts by inhibition of smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxLDL uptake and cytokine production, all reactions implied in the progression of atherosclerosis. Recent research revealed that these effects are not the result of the antioxidant activity of vitamin E, but rather of precise molecular actions of this compound. It is assumed that specific interactions of vitamin E with enzymes and proteins are at the basis of its non-antioxidant effects. Vitamin E influences the activity of several enzymes (e.g. PKC, PP2A, COX-2, 5-lipooxygenase, nitric oxide synthase, NADPH-oxidase, superoxide dismutase, phopholipase A2) and modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins). These interactions promise to reveal the biological properties of vitamin E and allow designing better strategies for the protection against atherosclerosis progression.
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PMID:Anti-atherosclerotic effects of vitamin E--myth or reality? 1509 Feb 61

Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin-angiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI2 in renovascular hypertension in vivo, employing mice lacking the PGI2 receptor (IP-/- mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP-/- mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP-/- mice than in WT mice. All these parameters were measured in mice lacking the four PGE2 receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI2 is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP-/- mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP-/- mice. These results indicate that PGI2 derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.
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PMID:Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP. 1537 97

The use of specific COX-2 inhibitors in place of standard nonsteroidals for the treatment of arthritis appears to reduce the risk of serious gastrointestinal toxicity in this group of patients. However, the role played by these inhibitors in the generation or exacerbation of ischaemic cardiovascular disease is less clear. Clinical studies demonstrate that hypertension can be induced or aggravated by COX-2 inhibitors to a degree similar to that which occurs with standard nonsteroidals. Endothelial dysfunction, an indicator of cardiac ischaemia, may also be exacerbated by specific COX-2 inhibition and there is much debate as to whether these changes lead to an absolute increase in ischaemic cardiac events. These effects on cardiovascular risk factors appear all the more important in patients with rheumatoid arthritis where there is an increase in the incidence of ischaemic heart disease. Here we review the available data on COX-2 inhibition and cardiovascular disease and conclude that all patients who started these agents should have a careful assessment and modification of any cardiovascular risk factors.
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PMID:Cardiovascular risk and COX-2 inhibition in rheumatological practice. 1538 47

The two cyclooxygenase isoforms (COX-1 and COX-2--coxibs) have overlapping functions and both are involved in the regulation of homeostatic and inflammatory processes in the various tissues. Treatment with highly selective COX-2 inhibitors is associated with significantly fewer serious adverse gastrointestinal events than is treatment with the dual inhibitors--the non-selective NSAIDs. Of the two coxibs, rofecoxib was shown to be much more selective than celecoxib and with less interaction with other drugs. Various clinical studies have demonstrated that the coxibs are equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator non-selective NSAIDs in osteoarthritis, rheumatoid arthritis, post surgery pain and dysmenorrhea. Perioperative use of coxibs reduces pain, opioid consumption and the risk of bleeding caused by the non-selective NSAIDs. The coxibs show similar tolerability for renal, liver and cardiothrombotic events as compared to the non-selective NSAIDs. Coxibs are contraindicated in pregnancy, in nursing mothers and pediatric patients and should be used with caution in patients with asthma. The impact of the coxibs on the cardiovascular system is controversial. However, coxibs should be used in caution and at the lowest recommended dose in patients with hypertension, ischemic heart disease and heart failure. These drugs do not interfere with the aspirin anti-platelet aggregation activity. Emerging evidence suggest that the coxibs may also find potential use as supportive therapy in various malignant tumors and intestinal polyps where COX-2 is overly expressed.
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PMID:[Is there a future for COX-2 inhibitors?]. 1560 72

The present study was undertaken to determine whether the severity of renal failure or hypertension in homozygous cyclooxygenase (COX)-2-deficient (COX-2-/-) mice affected by genetic background or gender. COX-2 deletion was introduced into three congenic genetic backgrounds, 129/Sv (129/COX-2-/-), C57/BL6 (C57/COX-2-/-), and BALB/c (BALB/COX-2-/-), by backcrossing the original mixed-background knockout mice with the respective inbred strains for 9 or 10 generations. Evaluation of the severity of hypertension and renal failure was performed in knockout and wild-type mice at the age of 2.5-3.5 mo. Blood pressure measured by tail-cuff plethysmography was significantly elevated in the male 129/COX-2-/- mice (165.8 +/- 9.2 vs. 116 +/- 5.1 mmHg, P < 0.05), and to a much lesser extent in the female 129/COX-2-/- mice (127.4 +/- 3.3 vs. 102.4 +/- 3.3), whereas it was unchanged in the C57- or BALB/COX-2-/- mice regardless of gender. Urinary excretion of albumin, determined by EIA, was remarkably increased in the 129/COX-2-/- (16.4 +/- 4.1 vs. 0.16 +/- 0.043 mg albumin/mg creatinine, P < 0.001), and to a lesser extent in the male C57/COX-2-/- mice (0.595 +/- 0.416 vs. 0.068 +/- 0.019). Albumin excretion was not elevated in the male BALB/COX-2-/- or in female COX-2-/- mice on any of the three genetic backgrounds. Histological analysis showed abundant protein casts, dilated tubules, and infiltration of inflammatory cells in the male 129/COX-2-/- mice, but not in COX-2-/- mice in other strains or gender. However, the presence of small glomeruli in the nephrogenic zone was observed in all strains of COX-2 knockout mice, regardless of genetic background and gender. Therefore, we conclude that the severity of hypertension and renal failure in COX-2-deficient mice is influenced by genetic background and gender, whereas the incomplete maturation of outer cortical nephrons appears to be independent of genetic background effects.
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PMID:Influence of genetic background and gender on hypertension and renal failure in COX-2-deficient mice. 1561 21

In view of the ongoing controversy of cardiorenal safety of selective COX-2 inhibitors (coxibs), the present study was designed to examine the effects of 2 different coxibs, celecoxib and rofecoxib, compared with a traditional NSAID, diclofenac, and placebo on renal morphology and function in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl-enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib), or placebo was added to chow from weeks 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. Renal cortex mRNA was isolated for determination of COX-2, eNOS, and CRP mRNA by real-time reverse-transcriptase polymerase chain reaction. Untreated hypertensive animals showed glomerular injury including collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops, and an especially high grade of glomerulosclerosis (P<0.05 versus DR-placebo) and CD8-positive and ED1-positive cells (P<0.01 versus DR-placebo), which was improved by celecoxib but not by diclofenac and rofecoxib. C-reactive protein mRNA in renal cortex was increased in DS-placebo animals (P<0.05 versus DR-placebo) and normalized by celecoxib (P<0.05 versus DS-placebo), whereas eNOS mRNA was decreased in the DS-rofecoxib group (P<0.05 versus DR-placebo, DS-celecoxib, and DS-diclofenac). Proteinuria was observed in hypertensive animals (P<0.0001 versus DR-placebo), increased by rofecoxib (P<0.05 versus DS-placebo), and normalized by celecoxib (P=0.0015 versus DS-placebo). This head-to-head comparison of selective and nonselective COX inhibitors demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertension.
Hypertension 2005 Feb
PMID:Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension. 1562 40

Owing to the selective inhibition of PGI2 synthesis, treatment with COX-2 inhibitors constitutes a potential risk for the increased occurrence of thrombotic cardiovascular incidents and of the first-time occurrence or a deterioration in pre-existing heart failure. Elderly patients, particularly those with a history of ischemic heart disease, hypertension or heart failure, are at risk. One key indication for selective COX-2 inhibitors is the chronic treatment of patients suffering from rheumatoid arthritis or osteoarthritis. However, these patients have an excess cardiovascular mortality, which relates particularly to cardiovascular incidents or heart failure. The use of nonselective antiphlogistic drugs and COX-2 inhibitors is associated with a higher potential risk in these patient groups. In essence, more than 80 million patients worldwide were treated with rofecoxib up to its voluntary withdrawal. The high number of patients who are still being treated with COX-2 inhibitors or for whom the use of COX-2 inhibitors is planned justifies the use of a biochemical marker which, as a screening instrument, is initially designed to recognize the patients who are "ill" despite the lack of symptoms. In asymptomatic patients with NT-proBNP levels below the cut-off, high-risk patients require further work-up. Recognition of these risk factors is easily accomplished considering the case history and the results of an established cardiovascular risk score (e.g. PROCAM score). These risk patients should then also be referred for intensive diagnostic work-up. On the other hand, symptomatic patients or those with high NT-proBNP levels should primarily be referred for more extensive cardiovascular diagnosis before a decision is taken concerning the use of COX-2 inhibitors. As an integral part of this extensive work-up the determination of NT-proBNP can help to improve the accuracy of diagnosis and prognostic assessment. With the exception of patients showing symptoms of an unstable coronary heart disease, imminent cerebral ischemia, uncontrolled arterial hypertension or decompensated heart failure, the use of a COX-2 inhibitor is possible provided special caution is exercised. Termination of treatment is advisable if there is a clinical deterioration of specific symptoms or signs in those patients (product information). Follow-up with NT-proBNP (monitoring) can be helpful in detecting imminent cardiac decompensation at an earlier stage in order to take suitable countermeasures.
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PMID:Rationale for testing the cardiovascular risk for patients with COX-2 inhibitors on the basis of biomarker NT-proBNP. 1571 8

Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6% of patients had taken rofecoxib 50 mg/day for longer than recommended. Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.
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PMID:Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? 1581 52

Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used medications worldwide to inhibiting COX activity for the treatment of pain and inflammation. Their nephrotoxicity has been well documented. With the development and clinical implementation of new COX-2 inhibitors, the safety, including the effects on renal function and blood pressure, is attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion and maintenance of renal blood flow. Similar to conventional NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in high-risk patients (including elderly and patients with volume depletion). Recently, agents with combined lipooxygenase/COX inhibition and agents that combine NSAIDs with a nitric oxide (NO) donor have been reported to reduce adverse renal effects.
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PMID:Renal effects of non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors. 1589 76

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