Effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on cardiovascular alterations in endotoxemia.
Prostanoids and cytokines are known to play a pivotal role in the mechanisms leading to endotoxin-induced cardiovascular failure. We investigated the effect of nimesulide (NIM), a selective cyclooxygenase-2 (COX-2) inhibitor, on the cardiovascular alterations occurring during endotoxemia, and on prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in endotoxemic rats. NIM significantly reduced endotoxin-induced elevation of plasma and myocardial levels of TNF-alpha, but not those of IL-1beta. Searching for the mechanism underlying the anti-TNF-alpha effect of NIM, it was found that the drug reduced nuclear factor kappa B activation through diminished nuclear levels of p-65 accompanied by a protective effect against the cardiovascular alterations and mortality seen during endotoxemia. In addition, the inhibitory effect of NIM on endotoxin-induced elevation in plasma and hypothalamic levels of PGE2 was noteworthy, and this may suggest that the large amounts of PGE2 observed during endotoxemia are mainly produced via COX-2.
Azab
Abed N
AN
Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Kobal
Sergio
S
Rubin
Mazal
M
Kaplanski
Jacob
J
D000818:Animals; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015150:Echocardiography, Doppler; D019446:Endotoxemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007375:Interleukin-1; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C012655:nimesulide