Effects of Selective Cyclooxygenase-2 Inhibition on Vascular Responses and Thrombosis in Canine Coronary Arteries

Hennan, James K.; Huang, Jinbao; Barrett, Terrance D.; Driscoll, Edward M.; Willens, David E; Park, Andrew M.; Crofford, Leslie J.; Lucchesi, Benedict R.

doi:10.1161/hc3301.092790

Cited by 157 publications

(109 citation statements)

References 25 publications

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“…COX2 is constitutively expressed in several locations in the kidney, including the loop of Henle, renal arterioles, and the macula densa, and undergoes inducible expression during inflammation (25,26). Intrarenal COX2 expression is important in the context of diabetes because its expression is augmented in the renal cortex of rats with streptozotocin-induced diabetes, largely due to the effect of hyperglycemia (9,27).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

et al. 2008

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OBJECTIVE-Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR).RESEARCH DESIGN AND METHODS-Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR Ն135 ml/min per 1.73 m 2 ), and 12 subjects exhibited normofiltration (GFR Ͻ135 ml/min per 1.73 m 2 ).RESULTS-Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 Ϯ 5 to 139 Ϯ 5 ml/min per 1.73 m 2 ) but increased GFR in the normofiltration group (118 Ϯ 5 to 138 Ϯ 5 ml/min per 1.73 m 2 ). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR.CONCLUSIONS-In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states. Diabetes 57: 688-695, 2008 A lterations in renal hemodynamic function are prevalent in diabetes (1,2) and include increased intraglomerular capillary pressure and hyperfiltration (3-5). Because blockade of the renin angiotensin system (RAS) does not completely normalize hyperfiltration (6), it is clear that other factors are operative in the renal microcirculation in diabetes.Animal studies have examined the role of vasodilatation (7) in the pathogenesis of hyperfiltration. Early work focused on the role of cyclooxygenase (COX)-derived prostanoids, which exert a variety of functions in the kidney, including important vasodilatory effects; however, studies initially used nonspecific COX1/COX2 inhibitors (8). With the discovery of the COX2 isoform and selective COX2 inhibitors, experimental models of diabetes revealed that COX2 expression is increased in the macula densa in this condition and is associated with enhanced production of vasodilatory prostaglandins, RAS activation, and renal hyperfiltration (9). Moreover, in streptozotocininduced diabetic rat models with a renal hyperfiltration phenotype, hyperglycemia-associated prostaglandin production and hyperfiltration were blunted using COX2 inhibition (9). Given the association between renal hyperfiltration, intraglomerular hypertension, and nephropathy related to diabetes (7,10,11), the elucidation of COX2-mediated renal hemodynamic function changes in dia...

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Section: Discussionmentioning

confidence: 99%

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

et al. 2008

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“…However, NSAIDs may induce gastrointestinal injury [4,5,35], renal failure [7,25,34], and inhibit platelet aggregation [15,17] by several mechanisms. These side effects are correlated with the length of administration and dose of medication.…”

Section: Discussionmentioning

confidence: 99%

“…These effects are in general mediated by the inhibition of inflammatory cyclooxygenase (COX-2). COX-2 is activated in injured tissue and produces prostaglandins (PGs) for hyperalgesia by sensitizing sensory nerve endings to various other mediators such as bradykinin, histamine and substance P. However, most NSAIDs also have various adverse effects including gastrointestinal irritation in dogs [4,5,35], renal disorders in dogs and rats [7,25,34], and inhibition of platelet aggregation in dogs [15,17] caused by the suppression of homeostatic cyclooxygenase (COX-1), which produces PGs for physiological roles within these tissues and cells [30]. Hepatotoxicity has also been reported after the administration of some NSAIDs in dogs [2,21,23].…”

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confidence: 99%

Effects of Long-Term Oral Administration of Ketoprofen in Clinically Healthy Beagle Dogs

Narita

Tomizawa

Sato

et al. 2005

The Journal of Veterinary Medical Science

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ABSTRACT. To investigate the adverse effects of long-term administration of ketoprofen in dogs, ketoprofen (1 mg/kg) was administered to five clinically healthy beagle dogs (ketoprofen group) and gelatin capsules (control group) were administered to four clinically healthy beagle dogs for 30 days. We monitored the dogs through periodic physical examination, blood analyses, endoscopic examinations, fecal occult blood tests, renal function tests, urinalysis, urinary enzyme indices and cuticle bleeding time analysis. The lesions in the stomach, especially in the pyloric antrum, and fecal occult blood progressively worsened in the ketoprofen group. However, the differences between the ketoprofen group and the control group were not statistically significant. One dog in the ketoprofen group temporarily exhibited a decrease in renal plasma flow and two dogs exhibited enzymuria. However, these changes did not persist and the other examinations showed no significant difference between premedication and postmedication in the ketoprofen group. Therefore, the adverse effects of long-term administration of ketoprofen observed in this study were not clinically important in healthy dogs. Nevertheless, further investigation of adverse renal effects from long-term administration of ketoprofen is necessary in the dogs with subclinical renal disease. KEY WORDS: adverse effect, canine, Ketoprofen, long-term administration.

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“…In two small trials with healthy human volunteers, the effects of aspirin were found not to be attenuated by celecoxib (15,16); however, in both trials, the volunteers were given a 324 mg daily dose of aspirin, which is four times the dose of 81 mg commonly considered to be "low-dose" aspirin. In a potentially related study, celecoxib did attenuate aspirin inhibition in a dog model of thrombosis (20).…”

mentioning

confidence: 91%

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

Rimon

Sidhu

Lauver

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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174

210

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Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A 2 formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.arachidonic acid | adrenic acid | nonsteroidal antiinflammatory drugs | platelet | prostaglandin

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Effects of Selective Cyclooxygenase-2 Inhibition on Vascular Responses and Thrombosis in Canine Coronary Arteries

Cited by 157 publications

References 25 publications

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

Effects of Long-Term Oral Administration of Ketoprofen in Clinically Healthy Beagle Dogs

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

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