Published Online
on November 3, 2003

A more recent version of this article appeared on November 11, 2003

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Submitted on August 4, 2003
Revised on September 19, 2003
Accepted on September 22, 2003

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

Matthias Hermann MD, Giovanni Camici BSc, Aisha Fratton BSc, David Hurlimann MD, Felix C. Tanner MD, Jens P. Hellermann MD, MSc, Martin Fiedler MD, Joachim Thiery MD, Michel Neidhart PhD, Renate E. Gay MD, Steffen Gay MD, Thomas F. Lüscher MD, and Frank Ruschitzka MD^*

From Cardiology, Cardiovascular Center, University Hospital Zürich, the Institute of Physiology, University of Zürich-Irchel (M.H., G.C., A.F., F.C.T., J.P.H., T.F.L., F.R.), and the Center for Experimental Rheumatology, University Hospital Zürich, Switzerland (M.N., R.G., S.G.); and the Institute of Clinical Chemistry, University of Leipzig, Germany (M.F., J.T.).

^* To whom correspondence should be addressed. E-mail: frank.ruschitzka{at}usz.ch.

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-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.

Key words: endothelium • drugs, antiinflammatory • hypertension • nitric oxide • stress

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