Mini-Reviews

Update on Cyclooxygenase-2 Inhibitors

Raymond C. Harris and Matthew D. Breyer
CJASN March 2006, 1 (2) 236-245; DOI: https://doi.org/10.2215/CJN.00890805

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Abstract

Nonsteroidal anti-inflammatory drugs represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described side effects can limit their use. Cyclooxygenase-2 (COX-2) inhibitors were initially touted as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of nonspecific nonsteroidal anti-inflammatory drugs. However, 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. This review summarizes the current state of knowledge about both renal and cardiovascular side effects that are attributed to COX-2 selective inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAID) are the most commonly used class of medications for the treatment of pain and inflammation and represent one of the most common classes of medications used worldwide, with an estimated usage of >30 million per day (1). Nonselective NSAID inhibit both constitutive cyclooxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2), the rate-limiting enzymes that are involved in production of prostaglandins and thromboxane. In addition to their role in inflammation, prostaglandins are important regulators of vascular tone, salt and water balance, and renin release, and nonselective NSAID exhibit adverse effects, including salt retention and reduced GFR, which may elevate BP or make pre-existing hypertension worse (2). It has been estimated that as many as 2.5 million Americans experience NSAID-mediated renal effects yearly (3). Risk factors that predispose to NSAID-induced renal functional alterations include age >65 yr, cardiovascular disease, diabetes, male gender, high NSAID dosage, and concurrent use of other nephrotoxic drugs (3). Up to 20% of patients who take nonselective NSAID and have more than one of these risk factors may manifest alterations in renal function.

In addition to renal side effects, nonselective NSAID have long been known to predispose to gastrointestinal (GI) toxicity. It has been estimated that one third of patients who taking long-term nonselective NSAID develop endoscopically proven gastric or duodenal ulcers (4). The risk for serious bleeding from these lesions is somewhat lower, with approximately 100,000 hospitalizations for GI complications of NSAID (5). One study estimated that nonselective NSAID–induced GI abnormalities constitute the 15th leading cause of death in the United States (6). The premise that COX-1 performs cellular “housekeeping” functions for normal physiologic activity and is the predominant isoform expressed in platelets and the GI tract, whereas COX-2 acts at inflammatory sites, led to the development of COX-2 selective inhibitors. It also was originally hypothesized that the renal effects of nonselective NSAID were also linked to COX-1 inhibition, but the widespread use of selective COX-2 inhibitors has indicated important roles for COX-2 metabolites in both physiologic and pathophysiologic modulation of renal and cardiovascular function, as highlighted by recent restrictions in the marketing and availability of these agents.

It is important to recognize that there is a wide range in the relative selectivity of various agents to inhibit COX-1 and COX-2. For example, in vivo, low-dose aspirin has greater relative COX-1 inhibitory selectivity, acting presystemically at relatively higher concentrations on the COX-1–rich platelet as it passes through the portal circulation, as the aspirin is absorbed (7,8). At high doses, aspirin inhibits both COX isoforms. The relative selectivity of different agents can be measured by ex vivo assays of prostaglandin production in whole blood, with the ratio of the concentrations producing 50% inhibition of COX-2 versus COX-1 as a measure of selectivity. For such agents, the following COX-2 selectivity ratio can be inferred: Etoricoxib > valdecoxib > rofecoxib > celecoxib > nimesulide > etodolac > meloxicam = diclofenac > indomethacin (9,10).

Expression of COX-1 and COX-2 in the Kidney

COX-1 is expressed constitutively in the kidney and has been localized to mesangial cells, arteriolar smooth muscle and endothelial cells, parietal epithelial cells of Bowman’s capsule, and cortical and medullary collecting ducts (11,12). COX-2 is inducible in most tissues in response to injury or inflammation, but COX-2 mRNA and immunoreactive protein are present at detectable levels in normal adult mammalian kidney. In the renal cortex, there is localized expression of COX-2 mRNA and immunoreactive protein in the cells of the macula densa (MD) and in scattered cells in the cortical thick ascending limb cells immediately adjacent to the MD (13–18) (Figure 1A). In human kidney, COX-2 expression also has been reported to be present in podocytes and arteriolar smooth muscle cells (12,14,19).

Figure 1.
Figure 1.

Effect of alterations in dietary sodium on cortical (left) and medullary (right) cyclooxygenase 2 (COX-2) expression. Cortical COX-2 expression is localized to the macula densa and surrounding cTALH cells and increases with a low-salt diet. Medullary COX-2 expression is localized to interstitial cells and increases with a high-salt diet.

COX-2 expression is also abundant in the lipid-laden medullary interstitial cells in the inner medulla and papilla (13,15) (Figure 1B). Some investigators have reported that COX-2 may also be expressed in inner medullary collecting duct cells or intercalated cells in the renal cortex (20,21). Nevertheless constitutively expressed COX-1 is clearly the most abundant isoform in the collecting duct, so the expression and physiologic significance of COX-2 co-expression in these cells remains uncertain. A recent report in human kidney has suggested that there is also significant COX-2 expression in the medullary vasa recta (19).

Effect of COX-2 Inhibitors on Salt and Water Homeostasis and BP

Nonselective NSAID have been reported to induce peripheral edema in up to 5% of the general population (22). Medullary prostaglandin E2 (PGE2) plays an important role in regulating NaCl and water reabsorption in the medullary thick ascending limb and collecting duct (23,24). Because COX-1 is abundantly and constitutively expressed in both cortical and medullary collecting duct, COX-1–derived prostanoids have been hypothesized to be involved in the natriuretic response, and in this regard, acutely increasing renal interstitial hydrostatic pressure by direct renal interstitial volume expansion will induce increased sodium excretion, which is blunted by infusion of nonselective NSAID but not COX-2 inhibitors (25). Furthermore, in a rat model of cirrhosis and ascites, a COX-1 selective inhibitor but not a COX-2 selective inhibitor decreased sodium excretion and impaired the diuretic and natriuretic responses to furosemide (26). Other studies in normal mice also suggest that COX-1 inhibition does not promote natriuresis and may actually promote sodium retention, so the role of renal COX-1 in modulating sodium excretion may be context dependent (27,28).

It is now increasingly apparent that medullary COX-2 plays a critical role in promoting natriuresis when dietary sodium intake is high. Recent compelling evidence indicates that the renal medulla is a critical site of intrarenal COX-2 activity’s protection against the development of systemic hypertension during high-salt intake (29). These studies showed that selective intramedullary infusion of a COX-2 inhibitor or COX-2 antisense oligonucleotides caused animals to develop hypertension when they were placed on a high-salt diet. Because renal medullary COX-2 is expressed primarily in medullary interstitial cells (15,28,30), these studies suggest a critical role for the medullary interstitial cell in maintaining systemic BP.

Renal medullary interstitial cells (RMIC) represent a unique stromal cell that resides between tubule epithelial cells of thick limbs and collecting ducts (31,32) and vasa rectae in the renal medulla. RMIC are morphologically distinguished by the presence of abundant lipid-rich intracellular droplets that are composed of long-chain unsaturated fatty acids, including arachidonate (31,32). RMIC are also distinguished by their robust PGE2 production rates (30). This locally produced PGE2 is able to exert its well-described dilator effects on the vasa rectae (33,34) and inhibit salt absorption by the thick ascending limb and collecting ducts via basolateral PGE2 receptors (35,36). Thus, RMIC-derived PGE2 is positioned at a nexus of physiologic control and can modulate renal salt excretion by affecting both the tone of the vasa recta and epithelial salt absorption. In the context of the current knowledge, RMIC COX-2 seems to be the critical synthetic step for this production of PGE2 and possibly other natriuretic eicosanoids that are derived from RMIC.

High-salt diet markedly increases renal medullary COX-2 expression both in vivo and in vitro (37,38). This may be via a direct effect of increased interstitial concentration because it has been shown that high extracellular NaCl but not urea potently induces RMIC COX-2 expression (38). When considered together with studies that show that COX-2 inhibition reduces urine salt excretion (39–41) and the findings that the intramedullary COX-2 inhibition produces salt-dependent hypertension (29), a physiologic feedback system can be constructed whereby increased salt intake augments RMIC COX-2 expression and PG production, thereby promoting increased renal salt excretion, maintaining normal total body sodium content.

COX-2 inhibitors will cause sodium retention occasionally in humans without renal impairment (42–45), and in balance studies that were performed in a clinical research center environment, administration of COX-2 inhibitors consistently decreased urinary sodium excretion for the first 72 h of administration (41,46,47). The relative amount of lower extremity edema has been documented to be greater with 25 mg/d rofecoxib than with 200 mg/d of celecoxib (48). Whether these findings are a result of greater potency of this dose of rofecoxib or of its greater selectivity for COX-2 versus COX-1 or other factors remains undetermined.

Nonselective NSAID may elevate BP and antagonize the BP-lowering effect of antihypertensive medications, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, and β blockers, to an extent that may potentially increase hypertension-related morbidity (49,50). COX-2 inhibitors also have been shown to affect BP. In studies that involved experimental animals, rofecoxib was shown to elevate significantly systolic BP in SHR or WKY rats that were fed a normal-salt or high-salt diet but not a low-salt diet, which suggests that the hypertension that is induced by COX-2 inhibition can occur independent of a genetic predisposition to hypertension and can be prevented by salt deprivation (51). In mice, COX-2 inhibition enhances the pressor effect of angiotensin II (Ang II) (28).

In double-blind, randomized, controlled clinical trials, conflicting results have been obtained about the influence of COX-2 inhibitor treatment on BP. It is somewhat difficult to compare these trials, because there are variations in design, subject characteristics, end points, and methods of BP measurement. In this regard, the two large trials that investigated the safety of COX-2 inhibitors, the Celecoxib Long-term Arthritis Safety Study (CLASS; Celecoxib) and Vioxx Gastrointestinal Outcome Study (VIGOR; Rofecoxib), both found in a minority of subjects evidence for increased BP less than or equal to (CLASS) or greater than (VIGOR) the NSAID comparators (44,52,53). In a review of clinical studies that involved >13,000 subjects, Whelton et al. (54) found that the overall incidence of renal adverse events that were induced by celecoxib was greater than that seen with placebo and was similar to the effects of the NSAID comparators. Because of the high prevalence of NSAID use among people 65 yr old or older, subsequent studies (SUCCESS VI [55] and VII [56]) compared the renal safety in older hypertensive patients with osteoarthritis (890 and 1092 patients in VI and VII, respectively) and found that at week 6, rofecoxib was more likely to increase the systolic BP than celecoxib. Similarly, in patients with type II diabetes and hypertension, ambulatory BP monitoring indicated that unlike celecoxib and the nonselective NSAID comparator naproxen, rofecoxib led to significant increases in 24-h systolic BP, although all three drugs induced some destabilization of BP control (57). Rofecoxib caused the greatest increase in systolic BP in patients who received ACE inhibitors or β blockers, whereas those who were on calcium channel antagonists or diuretic monotherapy and received either celecoxib or rofecoxib showed no significant increases in BP. However, in a randomized, double-blind, placebo-controlled, parallel-group clinical trial that involved 178 patients with essential hypertension and that used 24-h ambulatory recordings and high doses (400 mg/d, twice the recommended dose) of celecoxib, there was no evidence of any significant alteration of the antihypertensive effect of the ACE inhibitor lisinopril during a 4-wk period (58). Interpretation of these studies is complicated by uncertainty about comparisons of equivalence of potency and duration of action of the two coxibs (rofecoxib and celecoxib).

Effects of COX-2 Inhibitors on Renin and Renal Hemodynamics

In the mammalian kidney, the MD is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na+/K+/2Cl− co-transport (59,60). COX-2 expression increases in the MD in response to a salt-deficient diet and decreases in response to a high-salt diet (13,37). MD sensing of luminal chloride concentration is dependent on net apical transport, mediated by the luminal Na+/K+/2Cl− co-transport (61). Ion substitution experiments of tubular perfusate have shown that low extracellular chloride leads to increased renin secretion (62). Decreased extracellular chloride also has been demonstrated to upregulate COX-2 expression in MD/cortical thick ascending limb, primarily through a mitogen-activated protein kinase–dependent pathway (63,64) via NF-κB activation (65). In addition, reducing luminal [Cl−] in microperfused cortical thick limb has been found to be associated with increased COX-2–dependent basolateral PGE2 release from the MD, further suggesting that COX-2–derived metabolites exert paracrine effects on renin release and arteriolar tone in the neighboring juxtaglomerular apparatus (66).

Measurements in vivo in isolated perfused rat kidney and in isolated perfused juxtaglomerular (JG) preparations all indicated that administration of nonspecific COX inhibitors prevents the increases in renin release that are mediated by MD sensing of decreases in luminal NaCl (reviewed in [67,68]). Studies using experimental animals have indicated that selective COX-2 inhibitors can significantly decrease plasma renin levels, renal renin activity, and mRNA expression under certain high-renin states (69–75). Most (43,64,66,69,70,76–78) but not all experimental studies (79,80) have indicated a role for COX-2 in MD mediation of renin release. Randomized crossover studies in healthy humans who were administered furosemide and/or a low-sodium diet demonstrated inhibition of renin release by the COX-2 inhibitors rofecoxib (43) and meloxicam (81). In addition, in patients with hyperprostaglandin E syndrome/antenatal Bartter’s syndrome, who have genetic abnormalities in thick limb/MD NaCl reabsorption, rofecoxib administration suppresses hyperreninemia as effectively as indomethacin, further supporting a role for COX-2 metabolites in mediation of renin release (82,83).

Studies of prostanoid-dependent control of renal blood flow (RBF) and GFR by the MD indicate that both vasodilator and vasoconstrictor prostanoids may contribute to regulation of tubuloglomerular feedback (60,84–86). In addition, COX-2–derived prostanoids from vascular endothelium may directly modulate afferent arteriolar tone. Vasodilatory PG seem to be critical for maintaining RBF and GFR during volume-depleted states associated with increased circulating vasoconstrictors, such as Ang II or norepinephrine, by blunting constriction of the afferent arteriole (87). By inhibiting the production of PG that contribute to maintenance of vasodilation of adjacent afferent arterioles, COX-2 inhibition may contribute to the decline in GFR that is observed in patients who take NSAID or selective COX-2 inhibitors (88). In anesthetized dogs, nimesulide administration increased arterial pressure and decreased RBF, urine flow rate, and fractional lithium excretion in those that were on a low-sodium diet (89,90). Similar findings were reported in isolated perfused rat kidney (73). When renal cortical blood flow (CBF) and medullary blood flow (MBF) were selectively measured in mice, it was found that acute infusion of a COX-1 selective inhibitor did not affect either CBF or MBF. In contrast, a COX-2 selective inhibitor significantly reduced MBF without altering CBF; chronic pretreatment with a COX-1 inhibitor did not modify the effect of Ang II infusion, whereas Ang II significantly reduced MBF in mice that were pretreated with a COX-2 inhibitor or in COX-2 knockout mice (28). In healthy humans who were on normal-sodium diets, COX-2 inhibitors had minimal effects on renal hemodynamics (41,42). However, COX-2 inhibitors significantly decreased GFR in salt-depleted subjects (39,40,46,91). As further evidence of an important role for COX-2 in regulation of renal hemodynamics and renin production, acute ischemic renal insufficiency and hyperkalemia/type IV renal tubular acidosis have been reported as acute nephrotoxic effects of COX-2 inhibitors, especially in the older adults (88,92–95).

Other Renal Complications of COX-2 Inhibitors

Recently, tubulointerstitial injury also was reported with COX-2 inhibitors. One case of celecoxib-related renal papillary necrosis was reported (96), as well as cases of tubulointerstitial nephritis (97,98). A potential interaction between lithium and celecoxib also has been described (99,100).

Effects of COX-2 Inhibitors in Proteinuric States

NSAID have been reported to be effective in reducing proteinuria in patients with refractory nephrotic syndrome (101–104). Selective increases in renal cortical COX-2 expression can be detected in the region of the MD in rat remnant kidneys without significant alterations in COX-1 expression (105–107) and from kidneys with streptozotocin-induced diabetes (108,109). Isolated glomeruli from remnant kidneys also demonstrated selective increases in COX-2 immunoreactivity and increased PGE2 production, which was inhibited by a COX-2 selective inhibitor (105). Komers et al. (108) found that in rats with moderately controlled streptozotocin-induced diabetes, GFR was increased, and acute administration of a selective COX-2 inhibitor returned the GFR to control levels. In hyperfiltering states, tubuloglomerular feedback is reset at a higher distal tubular flow rate (110–112), and there is decreased myogenic tone of the afferent arteriole, which is corrected by inhibition of COX activity (113,114). Although we have not yet determined the signals that mediate increased COX-2 expression in this diabetic model, it is worth noting that recent studies indicated that glomerular hyperfiltration in diabetic rats occurs as compensation for increased proximal fractional reabsorption and a decrease in electrolyte load to the distal nephron, resulting in resetting of tubuloglomerular feedback to a higher single nephron GFR (115,116); this increased proximal reabsorption and resultant decrease in distal nephron electrolyte presentation would also be expected to increase MD COX-2 expression. The vasodilatory component of tubuloglomerular feedback is inhibited by the selective COX-2 inhibition, suggesting that COX-2–mediated prostanoids may be essential for arteriolar vasodilation (117,118).

Chronic administration of a selective COX-2 inhibitor significantly decreased proteinuria and inhibited development of glomerular sclerosis in rats with reduced functioning renal mass (105,106,119). These effects were seen in the absence of any detectable changes in systemic BP, suggesting that any “renoprotective” effects that were seen with the COX-2 inhibitor were not secondary to modulation of systemic BP (105,120). In a model of diabetes with superimposed DOCA/salt hypertension, chronic administration of a selective COX-2 inhibitor also significantly decreased proteinuria and reduced extracellular matrix deposition, as indicated by decreases in immunoreactive fibronectin expression and mesangial matrix expansion. In addition, COX-2 inhibition reduced expression of TGF-β, plasminogen activator inhibitor 1, and vascular endothelial growth factor in the kidneys of the diabetic hypertensive animals (109). Obviously, more studies are needed before any recommendation that these drugs be used clinically for these indications.

To summarize the renal side effects of COX-2 inhibitors, it now is evident that similar to nonselective NSAID, selective COX-2 inhibition may cause edema, hypertension, and even acute renal failure in a minority of patients. COX-2 inhibitors also may exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Special caution should be taken in patients with volume depletion or decreased organ perfusion. Although all COX-2 inhibitors that have been marketed have demonstrated the same spectrum of renal side effects, the number and the severity of the side effects has tended to be greater with rofecoxib than with celecoxib. The effective half-life of the former drug is longer, which may be responsible for the increased side effects when both drugs are administered once per day. However, it also is possible that non-“class” effects of the drugs may be a factor because the chemical structures are different, with celecoxib being a sulfonamide and rofecoxib a sulfone (121). Further modifications of these drugs in the future may provide agents with fewer renal side effects.

Recently, nitric oxide donors were shown to prevent renal depletion of prostacyclin during either nonselective or selective COX-inhibitor administration (122). Their combination with NSAID may reduce adverse renal effects. Several distinct agents with balanced inhibitory actions on the COX and lipoxygenase pathways also have been synthesized and are in various phases of preclinical or clinical development (123,124), and recently, a clinical trial indicated that the lipoxygenase/COX inhibitor licofelone could provide as effective pain relief as celecoxib but with less edema (125).

Cardiovascular Effects of COX-2 Inhibitors

Effects of COX-2 Inhibition on Vascular Tone

In addition to their propensity to reduce renal salt excretion and decrease MBF, NSAID and selective COX-2 inhibitors have been shown to exert direct effects on systemic resistance vessels. The acute pressor effect of Ang infusion in humans was significantly increased at all Ang II doses studied by indomethacin pretreatment (126), an NSAID that nonselectively inhibits both COX-1 and COX-2 (127). More recently, administration of selective COX-2 inhibitors or COX-2 gene knockout has been shown to accentuate the pressor effects of Ang II in mice (28). These studies also showed that the ability of Ang II infusion to produce an increase in BP was markedly reduced by administration of a selective COX-1 inhibitor or COX-1 gene knockout (28). These findings support the conclusion that COX-1–derived PG participate in and are integral to the pressor activity of Ang II, whereas COX-2–derived PG are vasodilators that oppose and mitigate the pressor activity of Ang II. Other animal studies showed that both NSAID and COX-2 inhibitors blunt arteriolar dilation and decrease flow through resistance vessels (128–130).

Increased Cardiovascular Thrombotic Events

COX-2 is known to be induced in vascular endothelial cells in response to shear stress (131), and selective COX-2 inhibition reduces circulating prostacyclin levels in normal humans (132). Therefore, since the development of COX-2 selective antagonists, it has been suggested that these agents might carry increased thrombogenic risks as a result of selective inhibition of the endothelial-derived anti-thrombogenic prostacyclin without any inhibition of the prothrombotic platelet-derived thromboxane generated by COX-1 (133). Although animal studies have provided conflicting results about the role of COX-2 inhibition on development of atherosclerosis (134–138), there are recent indications that COX-2 inhibition may destabilize atherosclerotic plaques (139), as suggested by studies indicating increased COX-2 expression and co-localization with microsomal PGE synthase-1 and metalloproteinases-2 and -9 in carotid plaques from individuals with symptomatic disease before endarterectomy (140–142).

Recently, the cardiovascular risks of COX-2 inhibition were front-page news in both medical and lay media, which has led to considerable confusion and angst among patients and practitioners alike. The first intimation that COX-2 inhibitors could predispose to increased cardiovascular risk arose from VIGOR, which compared GI toxicity in patients who had osteoarthritis or rheumatoid arthritis and received either rofecoxib (50 mg/d) or the nonselective NSAID comparator naproxen (1000 mg/d). The rofecoxib-treated patients were found to have a 2.38 relative risk for serious thrombotic cardiovascular effects (143). Although low-dose aspirin was omitted from this study, the increased risk with rofecoxib was observed regardless of whether the patients had preexisting cardiovascular risks that would have qualified for aspirin. Although these findings elicited considerable attention (144), the interpretation of the results was controversial for a number of reasons, including that a similar study in osteoarthritis patients that compared celecoxib with other nonspecific comparator NSAID (CLASS) did not detect an increased cardiovascular risk of the COX-2 selective agent (111) and the suggestion that the apparent increased cardiovascular risk seen in VIGOR with rofecoxib was actually due to a preferential beneficial effect of naproxen to inhibit platelet aggregation as a result of naproxen’s long half-life (145).

More definitive conclusions about increased cardiovascular risk with rofecoxib were subsequently reported from the Adenomatous Polyp Prevention by Vioxx trial (APPROVe), which compared rofecoxib (25 mg/d) with placebo in patients who had a history of colorectal adenomas. In this study, the rofecoxib group manifested an excess risk for thrombotic cardiovascular events after 18 mo of daily rofecoxib treatment (relative risk 1.92; 95% confidence interval 1.19 to 3.11; P < 0.008; Figure 2) (146). In anticipation of the release of these results, Merck voluntarily withdrew rofecoxib from the market in September 2004. The pathophysiologic mechanisms underlying increased cardiovascular risk associated with long-term rofecoxib use remain undetermined but could include increased atherosclerosis, associated hypertension, or other, as yet undetermined concomitant cardiovascular changes.

Figure 2.
Figure 2.

Increased cardiovascular risk with Rofexicab treatment in the APPROVe trial. (Top) Kaplan-Meier estimates of the cumulative incidence of confirmed serious thrombotic events. (Bottom) Estimates of congestive heart failure, pulmonary edema, or cardiac failure. Reprinted with permission from reference (146).

Subsequent to the release of the results from APPROVe, two NIH-sponsored trials that examined celecoxib were halted in late 2004 because of concerns about cardiovascular risk. In the Adenoma Prevention with Celecoxib study, a similar trial to APPROVe that studied prevention of colorectal adenoma formation, an independent Data Safety Monitoring Board concluded that continued exposure to the COX-2 inhibitor would place the patients at increased risk for cardiovascular events (147). In contrast, a study of possible beneficial effects of long-term administration of either naproxen or celecoxib in Alzheimer’s disease (Alzheimer’s Disease Anti-Inflammatory Prevention Trial) reported a possible increased risk in both cardiovascular and cerebrovascular events in the naproxen-treated group, although this naproxen-induced increase has been questioned (148). Two other epidemiologic studies also highlighted a potential cardiovascular risk of nonselective NSAID as well as COX-2 selective drugs. A study from Denmark reported that there was increased incidence of first-time hospitalization for myocardial infarction in patients who were taking all classes of nonaspirin NSAID (149), and an analysis of 468 practice groups in England reported an increased risk for myocardial infarction in patients who were taking either COX-2 selective or nonselective NSAID (150).

The Food and Drug Administration (FDA) convened a special advisory committee meeting in February 2005 to address these issues. After a contentious three-day meeting, the advisory committee voted (by a vote of 31 to 1) to recommend that celecoxib be retained on the market, by a vote of 17 to 13 that valdecoxib be retained, and by a vote of 17 to 15 that rofecoxib be retained. To date, however, rofecoxib remains off the market, and on April 7, 2005, the FDA ruled that the overall risk-to-benefit profile for valdecoxib was unfavorable and furthermore that valdecoxib did not have any marked advantage over other NSAID. The FDA therefore requested that Pfizer, valdecoxib’s manufacturer, voluntarily withdraw it from the market. In the same ruling, the FDA requested that the labeling of celecoxib, as well as 18 other nonselective NSAID, be modified to highlight the increased risk for cardiovascular events, with a medication guide informing patients to accompany all prescriptions.

Acknowledgments

This work was supported by National Institutes of Health grants DK39261 and DK62794 and funds from the Veterans Administration.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

References

  1. ↵
    Singh G, Triadafilopoulos G: Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol 26[Suppl 56]: 18–24, 1999
    OpenUrl
  2. ↵
    Johnson AG: NSAIDs and increased blood pressure. What is the clinical significance? Drug Saf 17: 277–289, 1997
    OpenUrlPubMed
  3. ↵
    Sandhu GK, Heyneman CA: Nephrotoxic potential of selective cyclooxygenase-2 inhibitors. Ann Pharmacother 38: 700–704, 2004
    OpenUrlCrossRefPubMed
  4. ↵
    Ofman JJ, MacLean CH, Straus WL, Morton SC, Berger ML, Roth EA, Shekelle P: A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. J Rheumatol 29: 804–812, 2002
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Singh G: Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 105: 31S–38S, 1998
    OpenUrlCrossRefPubMed
  6. ↵
    Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340: 1888–1899, 1999
    OpenUrlCrossRefPubMed
  7. ↵
    FitzGerald GA, Lupinetti M, Charman SA, Charman WN: Presystemic acetylation of platelets by aspirin: Reduction in rate of drug delivery to improve biochemical selectivity for thromboxane A2. J Pharmacol Exp Ther 259: 1043–1049, 1991
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Pedersen AK, FitzGerald GA: Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med 311: 1206–1211, 1984
    OpenUrlCrossRefPubMed
  9. ↵
    Chan CC, Boyce S, Brideau C, Charleson S, Cromlish W, Ethier D, Evans J, Ford-Hutchinson AW, Forrest MJ, Gauthier JY, Gordon R, Gresser M, Guay J, Kargman S, Kennedy B, Leblanc Y, Leger S, Mancini J, O’Neill GP, Ouellet M, Patrick D, Percival MD, Perrier H, Prasit P, Rodger I, et al.: Rofecoxib [Vioxx, MK-0966; 4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. J Pharmacol Exp Ther 290: 551–560, 1999
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Riendeau D, Percival MD, Brideau C, Charleson S, Dube D, Ethier D, Falgueyret JP, Friesen RW, Gordon R, Greig G, Guay J, Mancini J, Ouellet M, Wong E, Xu L, Boyce S, Visco D, Girard Y, Prasit P, Zamboni R, Rodger IW, Gresser M, Ford-Hutchinson AW, Young RN, Chan CC: Etoricoxib (MK-0663): Preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther 296: 558–566, 2001
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Smith WL, Bell TG: Immunohistochemical localization of the prostaglandin-forming cyclooxygenase in renal cortex. Am J Physiol 235: F451–F457, 1978
    OpenUrlPubMed
  12. ↵
    Komhoff M, Grone HJ, Klein T, Seyberth HW, Nusing RM: Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: Implication for renal function. Am J Physiol 272: F460–F468, 1997
    OpenUrlPubMed
  13. ↵
    Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD: Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 94: 2504–2510, 1994
    OpenUrlCrossRefPubMed
  14. ↵
    Nantel F, Meadows E, Denis D, Connolly B, Metters KM, Giaid A: Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly. FEBS Lett 457: 475–477, 1999
    OpenUrlCrossRefPubMed
  15. ↵
    Guan Y, Chang M, Cho W, Zhang Y, Redha R, Davis L, Chang S, DuBois RN, Hao CM, Breyer M: Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells. Am J Physiol 273: F18–F26, 1997
    OpenUrlPubMed
  16. Khan KN, Venturini CM, Bunch RT, Brassard JA, Koki AT, Morris DL, Trump BF, Maziasz TJ, Alden CL: Interspecies differences in renal localization of cyclooxygenase isoforms: Implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol 26: 612–620, 1998
    OpenUrlAbstract/FREE Full Text
  17. Khan KN, Stanfield KM, Harris RK, Baron DA: Expression of cyclooxygenase-2 in the macula densa of human kidney in hypertension, congestive heart failure, and diabetic nephropathy. Ren Fail 23: 321–330, 2001
    OpenUrlCrossRefPubMed
  18. ↵
    Komhoff M, Jeck ND, Seyberth HW, Grone HJ, Nusing RM, Breyer MD: Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int 58: 2420–2424, 2000
    OpenUrlCrossRefPubMed
  19. ↵
    Adegboyega PA, Ololade O: Immunohistochemical expression of cyclooxygenase-2 in normal kidneys. Appl Immunohistochem Mol Morphol 12: 71–74, 2004
    OpenUrlPubMed
  20. ↵
    Yang T, Schnermann JB, Briggs JP: Regulation of cyclooxygenase-2 expression in renal medulla by tonicity in vivo and in vitro. Am J Physiol 277: F1–F9, 1999
    OpenUrlPubMed
  21. ↵
    Ferguson S, Hebert RL, Laneuville O: NS-398 upregulates constitutive cyclooxygenase-2 expression in the M-1 cortical collecting duct cell line. J Am Soc Nephrol 10: 2261–2271, 1999
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Whelton A, Hamilton CW: Nonsteroidal anti-inflammatory drugs: Effects on kidney function. J Clin Pharmacol 31: 588–598, 1991
    OpenUrlCrossRefPubMed
  23. ↵
    Smith WL, Sonnenburg WK, Allen ML, Watanabe T, Zhu J, el-Harith EA: The biosynthesis and actions of prostaglandins in the renal collecting tubule and thick ascending limb. Adv Exp Med Biol 259: 131–147, 1989
    OpenUrlPubMed
  24. ↵
    Stokes JB: Integrated actions of renal medullary prostaglandins in the control of water excretion. Am J Physiol 240: F471–F480, 1981
    OpenUrlPubMed
  25. ↵
    Gross JM, Dwyer JE, Knox FG: Natriuretic response to increased pressure is preserved with COX-2 inhibitors. Hypertension 34: 1163–1167, 1999
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Lopez-Parra M, Claria J, Planaguma A, Titos E, Masferrer JL, Woerner BM, Koki AT, Jimenez W, Altuna R, Arroyo V, Rivera F, Rodes J: Cyclooxygenase-1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites. Br J Pharmacol 135: 891–900, 2002
    OpenUrlCrossRefPubMed
  27. ↵
    Athirakul K, Kim HS, Audoly LP, Smithies O, Coffman TM: Deficiency of COX-1 causes natriuresis and enhanced sensitivity to ACE inhibition. Kidney Int 60: 2324–2329, 2001
    OpenUrlCrossRefPubMed
  28. ↵
    Qi Z, Hao CM, Langenbach RI, Breyer RM, Redha R, Morrow JD, Breyer MD: Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin Invest 110: 61–69, 2002
    OpenUrlCrossRefPubMed
  29. ↵
    Zewde T, Mattson DL: Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension. Hypertension 44: 424–428, 2004
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Zusman RM, Keiser HR: Prostaglandin biosynthesis by rabbit renomedullary interstitial cells in tissue culture. Stimulation by angiotensin II, bradykinin, and arginine vasopressin. J Clin Invest 60: 215–223, 1977
    OpenUrlCrossRefPubMed
  31. ↵
    Nissen HM: On lipid droplets in renal interstitial cells. I. A histochemical study. Z Zellforsch Mikrosk Anat 83: 76–81, 1967
    OpenUrlCrossRefPubMed
  32. ↵
    Nissen HM, Andersen H: On the activity of prostaglandin-dehydrogenase system in the kidney. A histochemical study during hydration-dehydration and salt-repletion-salt-depletion. Histochemie 17: 241–247, 1969
    OpenUrlCrossRefPubMed
  33. ↵
    Silldorff EP, Yang S, Pallone TL: Prostaglandin E2 abrogates endothelin-induced vasoconstriction in renal outer medullary descending vasa recta of the rat. J Clin Invest 95: 2734–2740, 1995
    OpenUrlCrossRefPubMed
  34. ↵
    Pallone T: Vasoconstriction of outer medullary vasa recta by angiotensin II is modulated by prostaglandin E2. Am J Physiol 266: F850–F857, 1994
    OpenUrlPubMed
  35. ↵
    Stokes JB, Kokko JP: Inhibition of sodium transport by prostaglandin E2 across the isolated, perfused rabbit collecting tubule. J Clin Invest 59: 1099–1104, 1977
    OpenUrlPubMed
  36. ↵
    Hebert RL, Jacobson HR, Breyer MD: Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium. J Clin Invest 87: 1992–1998, 1991
    OpenUrlCrossRefPubMed
  37. ↵
    Yang T, Singh I, Pham H, Sun D, Smart A, Schnermann JB, Briggs JP: Regulation of cyclooxygenase expression in the kidney by dietary salt intake. Am J Physiol 274: F481–F489, 1998
    OpenUrlPubMed
  38. ↵
    Hao CM, Yull F, Blackwell T, Komhoff M, Davis LS, Breyer MD: Dehydration activates an NF-kappaB-driven, COX2-dependent survival mechanism in renal medullary interstitial cells. J Clin Invest 106: 973–982, 2000
    OpenUrlCrossRefPubMed
  39. ↵
    Swan SK, Rudy DW, Lasseter KC, Ryan CF, Buechel KL, Lambrecht LJ, Pinto MB, Dilzer SC, Obrda O, Sundblad KJ, Gumbs CP, Ebel DL, Quan H, Larson PJ, Schwartz JI, Musliner TA, Gertz BJ, Brater DC, Yao SL: Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med 133: 1–9, 2000
    OpenUrlPubMed
  40. ↵
    Rossat RJ, Maillard M, Nussberger J, Brunner HR, Burnier M: Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 66: 76–84, 1999
    OpenUrlCrossRefPubMed
  41. ↵
    Catella-Lawson F, McAdam B, Morrison BW, Kapoor S, Kujubu D, Antes L, Lasseter KC, Quan H, Gertz BJ, FitzGerald GA: Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 289: 735–741, 1999
    OpenUrlAbstract/FREE Full Text
  42. ↵
    Svendsen KB, Bech JN, Sorensen TB, Pedersen EB: A comparison of the effects of etodolac and ibuprofen on renal haemodynamics, tubular function, renin, vasopressin and urinary excretion of albumin and alpha-glutathione-S-transferase in healthy subjects: A placebo-controlled cross-over study. Eur J Clin Pharmacol 56: 383–388, 2000
    OpenUrlCrossRefPubMed
  43. ↵
    Kammerl MC, Nusing RM, Schweda F, Endemann D, Stubanus M, Kees F, Lackner KJ, Fischereder M, Kramer BK: Low sodium and furosemide-induced stimulation of the renin system in man is mediated by cyclooxygenase 2. Clin Pharmacol Ther 70: 468–474, 2001
    OpenUrlCrossRefPubMed
  44. ↵
    Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284: 1247–1255, 2000
    OpenUrlCrossRefPubMed
  45. ↵
    Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, Isakson PC, Verburg KM, Yu SS, Zhao WW, Geis GS: Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: A randomized controlled trial. JAMA 282: 1921–1928, 1999
    OpenUrlCrossRefPubMed
  46. ↵
    Whelton A, Schulman G, Wallemark C, Drower EJ, Isakson PC, Verburg KM, Geis GS: Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med 160: 1465–1470, 2000
    OpenUrlCrossRefPubMed
  47. ↵
    Schwartz JI, Vandormael K, Malice MP, Kalyani RN, Lasseter KC, Holmes GB, Gertz BJ, Gottesdiener KM, Laurenzi M, Redfern KJ, Brune K: Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet. Clin Pharmacol Ther 72: 50–61, 2002
    OpenUrlCrossRefPubMed
  48. ↵
    Whelton A: COX-2-specific inhibitors and the kidney: Effect on hypertension and oedema. J Hypertens 20[Suppl 6]: S31–S35, 2002
    OpenUrl
  49. ↵
    Johnson AG, Nguyen TV, Day RO: Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 121: 289–300, 1994
    OpenUrlCrossRefPubMed
  50. ↵
    de Leeuw PW: Nonsteroidal anti-inflammatory drugs and hypertension. The risks in perspective. Drugs 51: 179–187, 1996
    OpenUrlPubMed
  51. ↵
    Hocherl K, Endemann D, Kammerl MC, Grobecker HF, Kurtz A: Cyclo-oxygenase-2 inhibition increases blood pressure in rats. Br J Pharmacol 136: 1117–1126, 2002
    OpenUrlCrossRefPubMed
  52. ↵
    Bombardier C: An evidence-based evaluation of the gastrointestinal safety of coxibs. Am J Cardiol 89: 3D–9D, 2002
    OpenUrlPubMed
  53. ↵
    FDA, Arthritis, Advisory, Committee, Meeting, February 2001. Available: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_01_merck.pdf. Accessed December 2001
  54. ↵
    Whelton A, Maurath CJ, Verburg KM, Geis GS: Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J Ther 7: 159–175, 2000
    OpenUrlPubMed
  55. ↵
    Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM: Cyclooxygenase-2–specific inhibitors and cardiorenal function: A randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 8: 85–95, 2001
    OpenUrlCrossRefPubMed
  56. ↵
    Whelton A, White WB, Bello AE, Puma JA, Fort JG: Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 90: 959–963, 2002
    OpenUrlCrossRefPubMed
  57. ↵
    Sowers JR, White WB, Pitt B, Whelton A, Simon LS, Winer N, Kivitz A, van Ingen H, Brabant T, Fort JG: The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med 165: 161–168, 2005
    OpenUrlCrossRefPubMed
  58. ↵
    White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A: Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 39: 929–934, 2002
    OpenUrlAbstract/FREE Full Text
  59. ↵
    Persson AE, Salomonsson M, Westerlund P, Greger R, Schlatter E, Gonzalez E: Macula densa cell function. Kidney Int Suppl 32: S39–S44, 1991
    OpenUrlPubMed
  60. ↵
    Schnermann J: Juxtaglomerular cell complex in the regulation of renal salt excretion. Am J Physiol 274: R263–R279, 1998
    OpenUrlPubMed
  61. ↵
    Salomonsson M, Gonzalez E, Westerlund P, Persson AE: Chloride concentration in macula densa and cortical thick ascending limb cells. Kidney Int Suppl 32: S51–S54, 1991
    OpenUrlPubMed
  62. ↵
    Lorenz JN, Weihprecht H, Schnermann J, Skott O, Briggs JP: Renin release from isolated juxtaglomerular apparatus depends on macula densa chloride transport. Am J Physiol 260: F486–F493, 1991
    OpenUrlPubMed
  63. ↵
    Cheng HF, Wang JL, Zhang MZ, McKanna JA, Harris RC: Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride. J Clin Invest 106: 681–688, 2000
    OpenUrlCrossRefPubMed
  64. ↵
    Yang T, Park JM, Arend L, Huang Y, Topaloglu R, Pasumarthy A, Praetorius H, Spring K, Briggs JP, Schnermann JB: Low chloride stimulation of PGE2 release and COX-2 expression in a mouse macula densa cell line. J Biol Chem 275: 37922–37929, 2000
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Cheng HF, Harris RC: Cyclooxygenase-2 expression in cultured cortical thick ascending limb of Henle increases in response to decreased extracellular ionic content by both transcriptional and post-transcriptional mechanisms. Role of p38-mediated pathways. J Biol Chem 277: 45638–45643, 2002
    OpenUrlAbstract/FREE Full Text
  66. ↵
    Peti-Peterdi J, Komlosi P, Fuson AL, Guan Y, Schneider A, Qi Z, Redha R, Rosivall L, Breyer MD, Bell PD: Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells. J Clin Invest 112: 76–82, 2003
    OpenUrlCrossRefPubMed
  67. ↵
    Harris RC: The macula densa: Recent developments. J Hypertens 14: 815–822, 1996
    OpenUrlPubMed
  68. ↵
    Harris RC, Zhang MZ, Cheng HF: Cyclooxygenase-2 and the renal renin-angiotensin system. Acta Physiol Scand 181: 543–547, 2004
    OpenUrlCrossRefPubMed
  69. ↵
    Wang JL, Cheng HF, Harris RC: Cyclooxygenase-2 inhibition decreases renin content and lowers blood pressure in a model of renovascular hypertension. Hypertension 34: 96–101, 1999
    OpenUrlAbstract/FREE Full Text
  70. ↵
    Traynor TR, Smart A, Briggs JP, Schnermann J: Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2. Am J Physiol 277: F706–F710, 1999
    OpenUrlPubMed
  71. Harding P, Carretero OA, Beierwaltes WH: Chronic cyclooxygenase-2 inhibition blunts low sodium-stimulated renin without changing renal haemodynamics. J Hypertens 18: 1107–1113, 2000
    OpenUrlCrossRefPubMed
  72. Cheng HF, Wang JL, Zhang MZ, Wang SW, McKanna JA, Harris RC: Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition. Am J Physiol Renal Physiol 280: F449–F456, 2001
    OpenUrlAbstract/FREE Full Text
  73. ↵
    Castrop H, Schweda F, Schumacher K, Wolf K, Kurtz A: Role of renocortical cyclooxygenase-2 for renal vascular resistance and macula densa control of renin secretion. J Am Soc Nephrol 12: 867–874, 2001
    OpenUrlAbstract/FREE Full Text
  74. Cheng HF, Wang SW, Zhang MZ, McKanna JA, Breyer R, Harris RC: Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1. Am J Physiol Regul Integr Comp Physiol 283: R638–R646, 2002
    OpenUrlAbstract/FREE Full Text
  75. ↵
    Mertz HL, Liu J, Valego NK, Stallings SP, Figueroa JP, Rose JC: Inhibition of cyclooxygenase-2: Effects on renin secretion and expression in fetal lambs. Am J Physiol Regul Integr Comp Physiol 284: R1012–R1018, 2003
    OpenUrlAbstract/FREE Full Text
  76. ↵
    Harding P, Sigmon DH, Alfie ME, Huang PL, Fishman MC, Beierwaltes WH, Carretero OA: Cyclooxygenase-2 mediates increased renal renin content induced by low-sodium diet. Hypertension 29: 297–302, 1997
    OpenUrlAbstract/FREE Full Text
  77. Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, Harris RC: Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. J Clin Invest 103: 953–961, 1999
    OpenUrlCrossRefPubMed
  78. ↵
    Stubbe J, Jensen BL, Bachmann S, Morsing P, Skott O: Cyclooxygenase-2 contributes to elevated renin in the early postnatal period in rats. Am J Physiol Regul Integr Comp Physiol 284: R1179–R1189, 2003
    OpenUrlAbstract/FREE Full Text
  79. ↵
    Hocherl K, Kammerl M, Kees F, Kramer BK, Grobecker HF, Kurtz A: Role of renal nerves in stimulation of renin, COX-2, and nNOS in rat renal cortex during salt deficiency. Am J Physiol Renal Physiol 282: F478–F484, 2002
    OpenUrlAbstract/FREE Full Text
  80. ↵
    Kammerl MC, Nusing RM, Seyberth HW, Riegger GA, Kurtz A, Kramer BK: Inhibition of cyclooxygenase-2 attenuates urinary prostanoid excretion without affecting renal renin expression. Pflugers Arch 442: 842–847, 2001
    OpenUrlCrossRefPubMed
  81. ↵
    Stichtenoth DO, Wagner B, Frolich JC: Effect of selective inhibition of the inducible cyclooxygenase on renin release in healthy volunteers. J Investig Med 46: 290–296, 1998
    OpenUrlPubMed
  82. ↵
    Reinalter SC, Jeck N, Brochhausen C, Watzer B, Nusing RM, Seyberth HW, Komhoff M: Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int 62: 253–260, 2002
    OpenUrlCrossRefPubMed
  83. ↵
    Kleta R, Basoglu C, Kuwertz-Broking E: New treatment options for Bartter’s syndrome. N Engl J Med 343: 661–662, 2000
    OpenUrlCrossRefPubMed
  84. ↵
    Schnermann J: Cyclooxygenase-2 and macula densa control of renin secretion. Nephrol Dial Transplant 16: 1735–1738, 2001
    OpenUrlFREE Full Text
  85. Welch WJ, Wilcox CS: Macula densa arginine delivery and uptake in the rat regulates glomerular capillary pressure. Effects of salt intake. J Clin Invest 100: 2235–2242, 1997
    OpenUrlPubMed
  86. ↵
    Welch WJ, Wilcox CS: Potentiation of tubuloglomerular feedback in the rat by thromboxane mimetic. Role of macula densa. J Clin Invest 89: 1857–1865, 1992
    OpenUrlPubMed
  87. ↵
    Dunn MJ: Prostaglandin I2 and the kidney. Arch Mal Coeur Vaiss 82[Spec No 4]: 27–31, 1989
    OpenUrl
  88. ↵
    Perazella MA, Tray K: Selective cyclooxygenase-2 inhibitors: A pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs. Am J Med 111: 64–67, 2001
    OpenUrlPubMed
  89. ↵
    Rodriguez F, Llinas MT, Gonzalez JD, Rivera J, Salazar FJ: Renal changes induced by a cyclooxygenase-2 inhibitor during normal and low sodium intake. Hypertension 36: 276–281, 2000
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Roig F, Llinas MT, Lopez R, Salazar FJ: Role of cyclooxygenase-2 in the prolonged regulation of renal function. Hypertension 40: 721–728, 2002
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Chen BH: COX-2 inhibitors and renal function in elderly people. CMAJ 163: 604, 2000
    OpenUrlFREE Full Text
  92. ↵
    Ahmad SR, Kortepeter C, Brinker A, Chen M, Beitz J: Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf 25: 537–544, 2002
    OpenUrlCrossRefPubMed
  93. Woywodt A, Schwarz A, Mengel M, Haller H, Zeidler H, Kohler L: Nephrotoxicity of selective COX-2 inhibitors. J Rheumatol 28: 2133–2135, 2001
    OpenUrlAbstract/FREE Full Text
  94. Phelan KM, Mosholder AD, Lu S: Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry 64: 1328–1334, 2003
    OpenUrlCrossRefPubMed
  95. ↵
    Papaioannides D, Bouropoulos C, Sinapides D, Korantzopoulos P, Akritidis N: Acute renal dysfunction associated with selective COX-2 inhibitor therapy. Int Urol Nephrol 33: 609–611, 2001
    OpenUrlCrossRefPubMed
  96. ↵
    Akhund L, Quinet RJ, Ishaq S: Celecoxib-related renal papillary necrosis. Arch Intern Med 163: 114–115, 2003
    OpenUrlCrossRefPubMed
  97. ↵
    Rocha JL, Fernandez-Alonso J: Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 357: 1946–1947, 2001
    OpenUrlCrossRefPubMed
  98. ↵
    Ortiz M, Mon C, Fernandez MJ, Sanchez R, Mampaso F, Alvarez Ude F: [Tubulointerstitial nephritis associated with treatment with selective Cox-2 inhibitors, celecoxib and rofecoxib]. Nefrologia 25: 39–43, 2005
    OpenUrlPubMed
  99. ↵
    Gunja N, Graudins A, Dowsett R: Lithium toxicity: A potential interaction with celecoxib. Intern Med J 32: 494, 2002
    OpenUrlCrossRefPubMed
  100. ↵
    Slordal L, Samstad S, Bathen J, Spigset O: A life-threatening interaction between lithium and celecoxib. Br J Clin Pharmacol 55: 413–414, 2003
    OpenUrlCrossRefPubMed
  101. ↵
    Bergstein JM: Prostaglandin inhibitors in the treatment of nephrotic syndrome. Pediatr Nephrol 5: 335–338, 1991
    OpenUrlCrossRefPubMed
  102. Dunn MJ: Prostaglandins, angiotensin II, and proteinuria. Nephron 55: 30–37, 1990
    OpenUrlCrossRefPubMed
  103. Vriesendorp R, Donker AJ, de Zeeuw D, de Jong PE, van der Hem GK, Brentjens JR: Effects of nonsteroidal anti-inflammatory drugs on proteinuria. Am J Med 81: 84–94, 1986
    OpenUrlCrossRefPubMed
  104. ↵
    Heeg JE, de Jong PE, Vriesendorp R, de Zeeuw D: Additive antiproteinuric effect of the NSAID indomethacin and the ACE inhibitor lisinopril. Am J Nephrol 10: 94–97, 1990
    OpenUrlCrossRefPubMed
  105. ↵
    Wang JL, Cheng HF, Zhang MZ, McKanna JA, Harris RC: Selective increase of cyclooxygenase-2 expression in a model of renal ablation. Am J Physiol 275: F613–F622, 1998
    OpenUrlPubMed
  106. ↵
    Sanchez PL, Salgado LM, Ferreri NR, Escalante B: Effect of cyclooxygenase-2 inhibition on renal function after renal ablation. Hypertension 34: 848–853, 1999
    OpenUrlAbstract/FREE Full Text
  107. ↵
    Horiba N, Kumano E, Watanabe T, Shinkura H, Sugimoto T, Inoue M: Subtotal nephrectomy stimulates cyclooxygenase 2 expression and prostacyclin synthesis in the rat remnant kidney. Nephron 91: 134–141, 2002
    OpenUrlCrossRefPubMed
  108. ↵
    Komers R, Lindsley JN, Oyama TT, Schutzer WE, Reed JF, Mader SL, Anderson S: Immunohistochemical and functional correlations of renal cyclooxygenase-2 in experimental diabetes. J Clin Invest 107: 889–898, 2001
    OpenUrlPubMed
  109. ↵
    Cheng HF, Wang CJ, Moeckel GW, Zhang MZ, McKanna JA, Harris RC: Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension. Kidney Int 62: 929–939, 2002
    OpenUrlCrossRefPubMed
  110. ↵
    Wilke WL, Persson AE: Captopril and tubuloglomerular feedback in remnant kidneys of prehypertensive rats. J Am Soc Nephrol 3: 73–79, 1992
    OpenUrlAbstract
  111. ↵
    Seney FD Jr, Wright FS: Dietary protein suppresses feedback control of glomerular filtration in rats. J Clin Invest 75: 558–568, 1985
    OpenUrlPubMed
  112. ↵
    Seney FD Jr, Persson EG, Wright FS: Modification of tubuloglomerular feedback signal by dietary protein. Am J Physiol 252: F83–F90, 1987
    OpenUrlPubMed
  113. ↵
    Murray BM, Brown GP: Effect of protein intake on the autoregulation of renal blood flow. Am J Physiol 258: F168–F174, 1990
    OpenUrlPubMed
  114. ↵
    Pelayo JC, Westcott JY: Impaired autoregulation of glomerular capillary hydrostatic pressure in the rat remnant nephron. J Clin Invest 88: 101–105, 1991
    OpenUrlCrossRefPubMed
  115. ↵
    Vallon V, Kirschenmann D, Wead LM, Lortie MJ, Satriano J, Blantz RC, Thomson SC: Effect of chronic salt loading on kidney function in early and established diabetes mellitus in rats. J Lab Clin Med 130: 76–82, 1997
    OpenUrlCrossRefPubMed
  116. ↵
    Thomson SC, Deng A, Bao D, Satriano J, Blantz RC, Vallon V: Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 107: 217–224, 2001
    OpenUrlCrossRefPubMed
  117. ↵
    Ichihara A, Imig JD, Inscho EW, Navar LG: Cyclooxygenase-2 participates in tubular flow-dependent afferent arteriolar tone: Interaction with neuronal NOS. Am J Physiol 275: F605–F612, 1998
    OpenUrlPubMed
  118. ↵
    Ichihara A, Imig JD, Navar LG: Cyclooxygenase-2 modulates afferent arteriolar responses to increases in pressure. Hypertension 34: 843–847, 1999
    OpenUrlAbstract/FREE Full Text
  119. ↵
    Fujihara CK, Antunes GR, Mattar AL, Andreoli N, Malheiros DM, Noronha IL, Zatz R: Cyclooxygenase-2 (COX-2) inhibition limits abnormal COX-2 expression and progressive injury in the remnant kidney. Kidney Int 64: 2172–2181, 2003
    OpenUrlCrossRefPubMed
  120. ↵
    Kong WX, Ma J, Gu Y, Yang HC, Zuo YQ, Lin SY: [Renal protective effects of specific cyclooxygenase-2 inhibitor in rats with subtotal renal ablation]. Zhonghua Nei Ke Za Zhi 42: 186–190, 2003
    OpenUrlPubMed
  121. ↵
    Chang I, Harris RC: Are all COX-2 inhibitors created equal? Hypertension 45: 178–180, 2005
    OpenUrlFREE Full Text
  122. ↵
    Miyataka M, Rich KA, Ingram M, Yamamoto T, Bing RJ: Nitric oxide, anti-inflammatory drugs on renal prostaglandins and cyclooxygenase-2. Hypertension 39: 785–789, 2002
    OpenUrlAbstract/FREE Full Text
  123. ↵
    Celotti F, Laufer S: Anti-inflammatory drugs: New multitarget compounds to face an old problem. The dual inhibition concept. Pharmacol Res 43: 429–436, 2001
    OpenUrlCrossRefPubMed
  124. ↵
    Celotti F, Durand T: The metabolic effects of inhibitors of 5-lipoxygenase and of cyclooxygenase 1 and 2 are an advancement in the efficacy and safety of anti-inflammatory therapy. Prostaglandins Other Lipid Mediat 71: 147–162, 2003
    OpenUrlCrossRefPubMed
  125. ↵
    Alvaro-Gracia JM: Licofelone—Clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis. Rheumatology (Oxford) 43[Suppl 1]: i21–i25, 2004
    OpenUrlCrossRef
  126. ↵
    Negus P, Tannen RL, Dunn MJ: Indomethacin potentiates the vasoconstrictor actions of angiotensin II in normal man. Prostaglandins 12: 175–180, 1976
    OpenUrlCrossRefPubMed
  127. ↵
    FitzGerald GA, Patrono C: The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 345: 433–442, 2001
    OpenUrlCrossRefPubMed
  128. ↵
    Banks RA, Beilin LJ: The effects of meclofenamate, captopril and phentolamine on organ blood flow in the conscious rabbit. Clin Sci (Lond) 61: 97–105, 1981
    OpenUrlPubMed
  129. Henrion D, Dechaux E, Dowell FJ, Maclour J, Samuel JL, Levy BI, Michel JB: Alteration of flow-induced dilatation in mesenteric resistance arteries of L-NAME treated rats and its partial association with induction of cyclo-oxygenase-2. Br J Pharmacol 121: 83–90, 1997
    OpenUrlCrossRefPubMed
  130. ↵
    Bagi Z, Erdei N, Toth A, Li W, Hintze TH, Koller A, Kaley G: Type 2 diabetic mice have increased arteriolar tone and blood pressure: Enhanced release of COX-2-derived constrictor prostaglandins. Arterioscler Thromb Vasc Biol 25: 1610–1616, 2005
    OpenUrlAbstract/FREE Full Text
  131. ↵
    Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR, Garcia-Cardena G: Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci 902: 230–239; discussion 239–240, 2000
    OpenUrl
  132. ↵
    McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA: Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 96: 272–277, 1999
    OpenUrlAbstract/FREE Full Text
  133. ↵
    Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med 351: 1709–1711, 2004
    OpenUrlCrossRefPubMed
  134. ↵
    Bea F, Blessing E, Bennett BJ, Kuo CC, Campbell LA, Kreuzer J, Rosenfeld ME: Chronic inhibition of cyclooxygenase-2 does not alter plaque composition in a mouse model of advanced unstable atherosclerosis. Cardiovasc Res 60: 198–204, 2003
    OpenUrlAbstract/FREE Full Text
  135. Burleigh ME, Babaev VR, Yancey PG, Major AS, McCaleb JL, Oates JA, Morrow JD, Fazio S, Linton MF: Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice. J Mol Cell Cardiol 39: 443–452, 2005
    OpenUrlCrossRefPubMed
  136. Belton OA, Duffy A, Toomey S, Fitzgerald DJ: Cyclooxygenase isoforms and platelet vessel wall interactions in the apolipoprotein E knockout mouse model of atherosclerosis. Circulation 108: 3017–3023, 2003
    OpenUrlAbstract/FREE Full Text
  137. Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF: Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation 105: 1816–1823, 2002
    OpenUrlAbstract/FREE Full Text
  138. ↵
    Pratico D, Tillmann C, Zhang ZB, Li H, FitzGerald GA: Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc Natl Acad Sci U S A 98: 3358–3363, 2001
    OpenUrlAbstract/FREE Full Text
  139. ↵
    Egan KM, Wang M, Fries S, Lucitt MB, Zukas AM, Pure E, Lawson JA, FitzGerald GA: Cyclooxygenases, thromboxane, and atherosclerosis: Plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation 111: 334–342, 2005
    OpenUrlAbstract/FREE Full Text
  140. ↵
    Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352: 1685–1695, 2005
    OpenUrlCrossRefPubMed
  141. Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ: Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 102: 840–845, 2000
    OpenUrlAbstract/FREE Full Text
  142. ↵
    Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P: Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 155: 1281–1291, 1999
    OpenUrlCrossRefPubMed
  143. ↵
    Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343: 1520–1528, 2000
    OpenUrlCrossRefPubMed
  144. ↵
    Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286: 954–959, 2001
    OpenUrlCrossRefPubMed
  145. ↵
    Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, Gertz BJ: Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 104: 2280–2288, 2001
    OpenUrlAbstract/FREE Full Text
  146. ↵
    Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352: 1092–1102, 2005
    OpenUrlCrossRefPubMed
  147. ↵
    Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352: 1071–1080, 2005
    OpenUrlCrossRefPubMed
  148. ↵
    Konstantinopoulos PA, Lehmann DF: The cardiovascular toxicity of selective and nonselective cyclooxygenase inhibitors: Comparisons, contrasts, and aspirin confounding. J Clin Pharmacol 45: 742–750, 2005
    OpenUrlCrossRefPubMed
  149. ↵
    Johnsen SP, Larsson H, Tarone RE, McLaughlin JK, Norgard B, Friis S, Sorensen HT: Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: A population-based case-control study. Arch Intern Med 165: 978–984, 2005
    OpenUrlCrossRefPubMed
  150. ↵
    Hippisley-Cox J, Coupland C: Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: Population based nested case-control analysis. BMJ 330: 1366, 2005
    OpenUrlAbstract/FREE Full Text
View Abstract
Back to top

In this issue

View Selected Citations (0)
Print
Download PDF
Article Alerts
Email Article
Citation Tools
Request Permissions
Update on Cyclooxygenase-2 Inhibitors
Raymond C. Harris, Matthew D. Breyer
CJASN Mar 2006, 1 (2) 236-245; DOI: 10.2215/CJN.00890805
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Recent Tweets about the Article