P-576: Differential effects of selective cyclooxygenase-2 inhibitors on endothelial function in salt-induced hypertension

Hermann, Matthias ; Camici, Giovanni ; Tanner, Felix C. ; Thiery, Joachim ; Gay, Steffen ; Luscher, Thomas F. ; Ruschitzka, Frank

In: American Journal of Hypertension, 2004, vol. 17, no. S1, p. 243A-243A

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    In view of the ongoing controversy of potential differences in cardiovascular safety of selective COX-2 inhibitors (coxibs), we compared the effects of two different coxibs and a traditional NSAID on endothelial dysfunction, a well established surrogate of cardiovascular disease, in salt-induced hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (4% NaCl) for 56 days. From days 35 to 56, diclofenac (6 mg/kg/d; DS-diclofenac), rofecoxib (2 mg/kg/d; DS-rofecoxib), celecoxib (25 mg/kg/d; DS-celecoxib) or placebo (DS-placebo) were added to the chow. Vascular reactivity of isolated aortic rings was assessed by isometric tension recording. Blood pressure increased with high sodium diet in the DS-groups which was more pronounced after diclofenac and rofecoxib treatment (p<0.005 vs DS-placebo), but slightly blunted by celecoxib (p<0.001 vs DS-placebo). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (ACh, 10−10−10−5 mol/L) in untreated hypertensive rats (p<0.0001 vs DR-placebo). Relaxation to ACh improved after celecoxib (p<0.005 vs DS-placebo and DS-rofecoxib), but remained unchanged after rofecoxib and diclofenac treatment. Vasoconstriction after NOS inhibition with Nω-Nitro-L-Arginine Methyl Ester (10-4 mol/L) was blunted in DS rats (p<0.05 vs DR-placebo), normalized by celecoxib, but not affected by rofecoxib or diclofenac. Protein expression of eNOS was decreased in DS rats with a trend for increased eNOS levels in the DS-celecoxib group (97.8±25.6 vs 54.8±2.8 %, p=0.088 vs DS-placebo). Indicators of oxidative stress, 8-isoprostane levels, were elevated in untreated DS rats on 4% NaCl (6.55±0.58 vs 3.65±1.05 ng/ml, p<0.05) and normalized by celecoxib only (4.29±0.58 ng/ml), while SOD protein expression was decreased in DS rats and not affected by any treatment. Plasma levels of prostaglandines did not change during high sodium diet or any treatment. These data show that celecoxib, but not rofecoxib or diclofenac, improves endothelial dysfunction and reduces oxidative stress, thus pointing to differential effects of coxibs in salt-sensitive hypertension. Am J Hypertens (2004) 17, 243A-243A; doi: 10.1016/j.amjhyper.2004.03.650