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)

In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in a restricted subpopulation of cells. The two sites of renal COX-2 localization detected in all species to date are the macula densa (MD) and associated cortical thick ascending limb (cTALH) and medullary interstitial cells (MICs). 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 generated by neuronal nitric oxide synthase is a positive modulator of COX-2 expression. Decreased extracellular chloride increases COX-2 expression in cultured cTALH, an effect mediated by increased p38 mitogen-activated protein 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 increases in MICs in response to a high-salt diet as well as water deprivation. Studies in cultured MICs have confirmed that expression is increased in response to hypertonicity and is mediated, at least in part, by nuclear factor-kappaB activation. COX-2 inhibition leads to apoptosis of MICs in response to hypertonicity in vitro and after 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:Physiological regulation of cyclooxygenase-2 in the kidney. 1139 41

Cyclooxygenase-2 (COX-2) is constitutively expressed in the macula densa of several laboratory animal species where it is considered to play a physiologic role in the regulation of basal renal function. Pertubations to normal homeostasis is shown to be associated with the upregulation of COX-2 in the macula densa of rats and dogs. In contrast, COX-2 has not been detected in the macula densa of normal adult human and non-human primate kidneys, suggesting a less prominent role of this isoform in normal renal function in these species. In this study, we characterized COX-2 expression in human kidneys collected from subjects with a clinical history indicative of compromised renal function associated with diabetic nephropathy (DN), hypertension, and congestive heart failure (CHF). COX-2 expression was evaluated by immunohistochemistry using isoform-specific antibodies and in situ hybridization. No COX-2 protein or mRNA was observed in the macula densa of normal kidneys (n= 11), whereas slight to moderate COX-2 expression was present in the macula densa of 7/15 subjects (46%) with DN, 5/11 (46%) subjects with hypertension, and 3/10 subjects (30%) with CHF. These results indicate that COX-2 is variably induced in the macula densa of the human kidney in compromised renal conditions and that COX-2-mediated prostaglandins may be involved in maintaining adequate renal functions in some patients with DN, hypertension, and CHF. This variability may be related to individual clinical status or synthesis of vasodilatory prostaglandins by cyclooxygenase-1 (COX-1).
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PMID:Expression of cyclooxygenase-2 in the macula densa of human kidney in hypertension, congestive heart failure, and diabetic nephropathy. 1149 48

The effects of short-term oral administration of red wine polyphenolic compounds on hemodynamic parameters and on vascular reactivity were investigated in rats. Endothelial function and vascular smooth muscle contractility were studied in association with the induction of gene expression in the vascular wall. Rats were treated daily for 7 days by intragastric administration of either 5% glucose or red wine polyphenolic compounds (20 mg/kg). Administration of these compounds produced a progressive decrease in systolic blood pressure, which became significantly different on day 4. Aortas from rats treated with red wine polyphenolic compounds displayed increased endothelium-dependent relaxation to acetylcholine that was related to increased endothelial NO activity and involved a mechanism sensitive to superoxide anion scavengers. However, no increase in whole-body oxidative stress has been observed in rats treated with red wine polyphenolic compounds, as shown by plasma glutathione assay. Also, in the aorta, red wine polyphenolic compounds increased the expression of cyclooxygenase-2 and increased the release of endothelial thromboxane A(2), which compensated for the extraendothelial NO-induced hyporeactivity in response to norepinephrine, resulting from enhanced inducible NO synthase expression. The present study provides evidence that short-term oral administration of red wine polyphenolic compounds produces a decrease in blood pressure in normotensive rats. This hemodynamic effect was associated with an enhanced endothelium-dependent relaxation and an induction of gene expression (of inducible NO synthase and cyclooxygenase-2) within the arterial wall, which together maintain unchanged agonist-induced contractility. These effects of red wine polyphenolic compounds may be a potential mechanism for preventing cardiovascular diseases.
Hypertension 2001 Aug
PMID:Wine polyphenols decrease blood pressure, improve NO vasodilatation, and induce gene expression. 1150 69

Primary cultures of medullary thick ascending limb (mTAL) cells retain the capacity to express calcium-sensing receptor (CaR) mRNA and protein. Increases in cyclooxygenase-2 (COX-2) mRNA accumulation, protein expression, and PGE(2) synthesis were observed in a dose- and time-dependent manner after exposure of these cells to extracellular calcium (Ca(o)(2+)). Moreover, transfection of mTAL cells with a CaR overexpression vector significantly enhanced COX-2 expression and PGE(2) production in response to calcium compared with cells transfected with an empty vector. Challenge with the CaR-selective agonist poly-L-arginine (PLA) also increased COX-2 mRNA accumulation, protein expression, and PGE(2) synthesis. Furthermore, Ca(o)(2+)- and PLA-mediated PGE(2) production was abolished in the presence of NS-398 or nimesulide, two different COX-2-selective inhibitors. These data suggest that intracellular signaling mechanisms initiated via activation of CaR contribute to COX-2-dependent PGE(2) synthesis in the mTAL. Because Ca(o)(2+) concentration varies along Henle's loop, calcium may contribute to salt and water balance via a COX-2- and CaR-dependent mechanism. Thus novel calcimimetics might be useful in conditions such as hypertension in which manipulation of extracellular fluid volume provides beneficial effects.
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PMID:CaR-mediated COX-2 expression in primary cultured mTAL cells. 1155 12

Cyclooxygenase-2 (COX-2) selective inhibitors are now extensively used for their anti-inflammatory and analgesic efficacy. Several large controlled trials provide evidence to support the proposition that they cause fewer major gastro-intestinal side effects and less toxicity than routine nonsteroidal anti-inflammatory drugs (NSAIDs). In view of the documented different localizations of the cyclooxygenase-1 and COX-2 enzymes in the kidney, it was initially hoped that COX-2 inhibitors would be associated with fewer renal side effects than other NSAIDs. This has not been borne out by subsequent studies. Like other NSAIDs, COX-2 inhibitors can cause salt and water retention, leading to edema and worsening hypertension. They can also cause acute declines in renal function and glomerular filtration rate. These events are, however, uncommon in large rheumatology populations and infrequently lead to discontinuation of the medications. Judicious use of COX-2 inhibitors in high-risk patients (such as those with chronic renal insufficiency, diabetes or congestive heart failure) will lead to a decreased incidence of adverse renal events.
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PMID:COX-2 inhibitors and the kidney. 1169 50

The ideal cyclooxygenase-2-specific inhibitor (coxib) would demonstrate efficacy comparable or superior to the best non-steroidal anti-inflammatory drug (NSAID) and, in addition to being substantially less gastrotoxic than the safest conventional NSAID, would have limited or no cardiovascular or renal toxicity and be generally tolerated as well as placebo. The contribution of the pharmacokinetic properties of a coxib to achieving this goal has been overlooked to some degree for available coxibs. Maximizing synovial compartment exposure while minimizing systemic exposure may deliver tolerability benefits, particularly with respect to rates of hypertension and cardiovascular and thrombotic adverse effects.
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PMID:Pharmacokinetic and pharmacodynamic aspects of the ideal COX-2 inhibitor: a rheumatologist's perspective. 1169 54

Selective inhibition of cyclooxygenase-2 (COX-2) was proposed as a novel anti-inflammatory and analgesic treatment with a reduced profile of gastrointestinal side effects compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Although perceived as an inducible enzyme by inflammatory and other stimuli, COX-2 is constitutively expressed in the kidney. In this review, we focus on renal and cardiovascular (CV) physiological and pathophysiological characteristics of COX-2 and renal and CV aspects of treatment with selective COX-2 inhibitors. Both clinical and experimental studies have shown that renal and CV effects of COX-2 inhibitors are similar to those of NSAIDs. These effects include sodium, potassium, and water retention and decreases in renal function, as well as mild to modest increases in blood pressure (BP) and edema. These deleterious effects are amplified in patients with volume and/or sodium depletion. The concomitant administration of COX-2 inhibitors may destabilize BP control in hypertensive patients treated with antihypertensive agents. In contrast to the normal kidney, which could constitute a target for adverse actions of COX-2 inhibitors, recent experimental studies showed increased renal COX-2 expression in several models of renal injury, such as the remnant kidney, renovascular hypertension, and diabetes, and implicated COX-2 in the progression of renal failure. This suggests that COX-2 inhibitors may confer a renoprotective effect in diverse renal disorders. These intriguing formulations must be delineated further in appropriately designed prospective clinical trials.
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PMID:Renal and cardiovascular effects of selective cyclooxygenase-2 inhibitors. 1172 45

Antirheumatic analgesic medications generally fall into one of the following categories: acetaminophen, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, traditional opioids, or adjunctive analgesics. This article does not discuss corticosteroids, opioids, or topical analgesics. Acetaminophen, usually indicated early for mild pain, is often used in combination with other drugs. It has established safety. Traditional NSAIDs are effective in relieving moderate pain in certain inflammatory and noninflammatory conditions. There are many effective choices, but as a class it is fraught with the risk of serious peptic ulcer disease and its complications. Cyclooxygenase-2 specific inhibitors are NSAIDS that reduce the gastrointestinal risk and platelet-mediated bleeding. All NSAIDs may produce peripheral edema, hypertension, and potentiate warfarin. The evidence that coxibs cause thrombotic heart disease is weak. Tramadol is an alternative to musculoskeletal pain management, particularly in patients with moderate to moderately severe pain who do not respond to or who cannot tolerate acetaminophen, NSAIDs, or opioids. The role of analgesic adjuvants is discussed.
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PMID:Use of nonopioid analgesics and adjunctive agents in the management of pain in rheumatic diseases. 1179 Sep 99

We have shown increased cyclooxygenase-2 (COX-2) expression in rats with kidney failure. Increased angiotensin II concentration, hypertension, and renal mass reduction have been described during development of kidney failure. Thus we explored each of these mechanisms, because any one of them could be responsible for COX-2 induction. Kidney failure increased systolic blood pressure from 104 +/- 5 to 138 +/- 2 mmHg, urinary PGE(2) from 74 +/- 17 to 185 +/- 25 ng/24 h, and COX-2 expression from 0.06 +/- 0.04 to 0.17 +/- 0.03 arbitraty units (AU). Treatment of the rats with ramipril or losartan prevented the increase in blood pressure, urinary PGE(2), and COX-2 expression in the rats with kidney failure. Infusion of angiotensin II increased blood pressure from 101 +/- 6 to 132 +/- 6 mm Hg, urinary PGE(2) excretion from 62 +/- 15 to 155 +/- 17 ng/24 h, and COX-2 expression from 0.23 +/- 0.01 to 1.6 +/- 0.3 AU. When the angiotensin II-infused rats were treated with nitrendipine, blood pressure decreased from 132 +/- 6 to 115 +/- 2 mm Hg, and urinary PGE(2) excretion decreased from 152 +/- 18 to 97 +/- 12 ng/24 h, whereas COX-2 expression was 1.6 +/- 0.7 and 1.7 +/- 0.5 AU for rats with and without nitrendipine. Blood pressure of the rats with renal pole resection was similar to that in sham rats (97 +/- 7 and 91 +/- 4 mmHg, respectively), whereas COX-2 expression was increased in rats with renal pole resection, from 0.06 +/- 0.04 to 0.12 +/- 0.03 AU. We suggest that in kidney failure, the increase in angiotensin II concentration regulates COX-2 expression, thereby increasing prostaglandin synthesis, which contributes to the development of kidney failure.
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PMID:Angiotensin II stimulates cyclooxygenase-2 mRNA expression in renal tissue from rats with kidney failure. 1188 Mar 19

The effect of high NaCl diet on resistance arteries is not yet fully documented. In order to assess the effect of NaCl on myogenic tone and flow-induced dilation independent of arterial blood pressure change, we used normotensive rats which did not develop hypertension upon high NaCl intake. Normotensive Wistar Kyoto Rats received a high (8%) or a normal NaCl diet (0.4%). Mesenteric resistance arteries (150 microm, internal diameter) were cannulated in an arteriograph to allow perfusion of arteries under controlled pressure and flow. Pressure-induced myogenic tone was lower in the high NaCl group than in the control group. Cyclooxygenase inhibition with indomethacin and (N-(2-cyclohexyloxy)-4-nitro-phenyl)-methanesulphonamide, 1 micromol/l) NS 398 (specific cyclooxygenase-2 inhibitor) similarly decreased myogenic tone in rats fed high NaCl but had no effect in those fed a normal NaCl diet. Flow-induced dilation was decreased in the high NaCl group. Inhibition of nitric oxide synthesis with N(G)-nitro-L-arginine methyl ester decreased flow-induced dilation in both groups. Indomethacin and NS 398 did not change flow-induced dilation. As shown by immunofluorescence COX-2 was present in the endothelium of arteries from rats with a high NaCl diet but not in those fed a normal NaCl diet. Thus, chronic high NaCl intake decreased both flow-induced dilation and myogenic tone in resistance arteries. The chronic high NaCl did not affect the participation of nitric oxide on flow-induced dilation, but induced the expression of cyclooxygenase-2, which participates in myogenic tone. These results suggest that high NaCl changes flow and pressure mechanosensing processes and strengthen the hypothesis that sodium ions have an important role in both pressure and flow-mechanotransduction in vascular cells.
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PMID:High NaCl intake decreases both flow-induced dilation and pressure-induced myogenic tone in resistance arteries from normotensive rats: involvement of cyclooxygenase-2. 1188 68


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