Differential effects of selective cyclooxygenase-2 inhibitors on endothelial function in salt-induced hypertension.
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.


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 x kg(-1) x d(-1); DS-diclofenac), rofecoxib (2 mg x kg(-1) x d(-1); DS-rofecoxib), celecoxib (25 mg x kg(-1) x 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(omega)-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.
Cardiology, Cardiovascular Center, University Hospital Zürich, the Institute of Physiology, University of Zürich-Irchel, Germany.
Matthias
M
Hermann
Giovanni
G
Camici
Aisha
A
Fratton
David
D
Hurlimann
Felix C
FC
Tanner
Jens P
JP
Hellermann
Martin
M
Fiedler
Joachim
J
Thiery
Michel
M
Neidhart
Renate E
RE
Gay
Steffen
S
Gay
Thomas F
TF
Lüscher
Frank
F
Ruschitzka
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004008:Diclofenac / Q000494:pharmacology / Q000627:therapeutic use; D015237:Dinoprost / Q000031:analogs & derivatives*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D028441:F2-Isoprostanes / Q000096:biosynthesis; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D007375:Interleukin-1 / Q000097:blood; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D051381:Rats; D020303:Rats, Inbred Dahl; D012449:Safety; D017673:Sodium Chloride, Dietary / Q000633:toxicity*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D007375:Interleukin-1; D007527:Isoenzymes; D007783:Lactones; D011720:Pyrazoles; D017673:Sodium Chloride, Dietary; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D004008:Diclofenac; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester