Differential Effects of Selective Cyclooxygenase-2 Inhibitors on Endothelial Function in Salt-Induced Hypertension

Abstract

Background— In view of the ongoing controversy about potential differences in cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors (coxibs), we compared the effects of 2 different coxibs and a traditional NSAID on endothelial dysfunction, a well-established surrogate of cardiovascular disease, in salt-induced hypertension. Methods and Results— Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed a high-sodium diet (4% NaCl) for 56 days. From days 35 to 56, diclofenac (6 mg · kg −1 · d −1 ; DS-diclofenac), rofecoxib (2 mg · kg −1 · d −1 ; DS-rofecoxib), celecoxib (25 mg · kg −1 · d −1 ; DS-celecoxib) or placebo (DS-placebo) was added to the chow. Blood pressure increased with sodium diet in the DS groups, which was more pronounced after diclofenac and rofecoxib treatment ( P <0.005 versus DS-placebo) but was slightly decreased by celecoxib ( P <0.001 versus DS-placebo). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (10 −10 -10 −5 mol/L) in aortic rings of untreated hypertensive rats ( P <0.005 versus DR-placebo). Relaxation to acetylcholine improved after celecoxib ( P <0.005 versus DS-placebo and DS-rofecoxib) but remained unchanged after rofecoxib and diclofenac treatment. Vasoconstriction after nitric oxide synthase inhibition, indicating basal NO release, with N ω -nitro- l -arginine methyl ester (10 −4 mol/L) was blunted in DS rats ( P <0.05 versus DR-placebo), normalized by celecoxib, but not affected by rofecoxib or diclofenac. Indicators of oxidative stress, 8-isoprostane levels, were elevated in untreated DS rats on 4% NaCl (6.55±0.58 versus 3.65±1.05 ng/mL, P <0.05) and normalized by celecoxib only (4.29±0.58 ng/mL). Conclusions— 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-induced hypertension.