| ObjectivesCyclooxygenase-2(COX-2) is constitutively expressed in the kidney and involved in regulating many renal physiologic and pathophysiologic functions. Some clinical trials indicated that COX-2 selective inhibitors(coxibs) still retained renal side-effect just as those seen with NSAIDs,such as hypertension and edema, but the underlying mechanisms are not clear.SHR is the most widely studied animal model of essential hypertension.The present study was designed to investigate the effect of COX-2 inhibition on water-sodium metabolism and blood pressure regulation and to screen the high risk factors of side effects in patients taking coxibs.Methods8-weeks-old,male SHR and its control WKY,rats were randomly divided into low-salt groups(SHR coxib+LS,WKY coxib+LS) and high-salt groups(SHR coxib+HS,WKY coxib+HS),5 in each group.All rats were fed with low-salt diet (containing 0.04%NaCl) and celecoxib(25 mg/kg per day) since the beginning of the study.From day 6 to day 8,low-salt groups did not change their diet,but high-salt groups were fed with high-salt diet(containing 8%NaCl).Total food intake was calculated every day.The systolic blood pressure(SBP) was determined by automatic sphygmomanometer at the tail artery.The urine volume(UV), urinary sodium excretion(UNa) as well as serum sodium levels were also measured.Urinary and plasma of aldosterone were detected by radioimmunity. Protein expression of COX-1 and COX-2 was assessed by immunohistochemistry and Western blot.ResultsCelecoxib treatment for 5 days or different salt intake did not affect SBP of WKY compared with its baseline level.SBP of SHR in two groups was significantly higher than that of WKY groups.After taking celecoxib for 5 days, SBP of SHR groups was significantly increased compared with their baseline level, but there was no obvious difference between low-salt group and high-salt group(SBP SHR coxib+LS 3.31±1.20mmHg,SHR coxib+HS 3.15±1.7mmHg). High-salt intake produced more significant enhancement of SBP in SHR than in SHR coxib+LS group and WKY coxib+HS group.Serum sodium concentration was significantly higher in SHR coxib+HS group than that of WKY groups after feeding high-salt diet for 3 days(SHR coxib+HS 158.20±9.44mmol/L,WKY coxib+HS 143.75±9.00mmol/L,P＜0.05),but no difference was observed between SHR and WKY groups fed with low-salt diet(SHR coxib+LS 144.75±8.54mmol/L, WKY coxib+LS 137.25±7.41 mmol/L,P＞0.05).UV and UNa of WKY and SHR were significantly increased after high-salt intake compared with those at baseline and treatment of celecoxib for 5 days,but there was no difference between the two high-salt groups.Radioimmunoassay showed that high-salt diet induced markedly decreased of plasma aldosterone in WKY rats(WKY coxib+HS 1.10±0.31ng/ml, WKY coxib+HS 0.64±0.09ng/ml,P＜0.05).However,plasma aldosterone of SHR had no response to change of dietary salt intake(SHR coxib+LS 0.61±0.05ng/ml, SHR coxib+HS 0.74±0.16ng/ml,P＞0.05).Immunohistochemistry analysis showed that COX-1 was distributed in renal glomeruli and collecting ducts,and did not affected by different salt intake.COX-2 was mainly localized in the cells of macula desna,adjacent cortical thick ascending limb of Henle(cTALH) and medullary interstitial cells.Using Western method,we foud that the level of COX-2 increased enormously in the cortex of WKY fed with low-salt diet,while medullary COX-2 expression was significantly induced in WKY after high-salt intake.To contrast, COX-2 protein levels of SHR in either cortex or medulla had no significant difference between groups fed with low-salt diet or high-salt diet.ConclusionsThe SBP of SHR was increased after administration of celecoxib for 5 days, and that was more significantly increased after high-salt intake.In addition,there was a deficiency of renal COX-2 regulation in SHR treated with coxib and salt loading.These results suggested that COX-2 was involved in water-sodium metabolism and blood pressure regulation of SHR.Coxibs should be used with caution in the setting of hypertension.
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