title: Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular failure.
abstract: The present study aimed to determine the relevance of cyclooxygenase-2 (COX-2)-derived prostanoids for the adverse effects of lipopolysaccharides (LPSs) on cardiovascular function. For this goal, male Sprague-Dawley rats received a single intravenous dose of LPS (10 mg/kg) and were treated with different cyclooxygenase inhibitors. Injection of LPS caused a marked decrease of systolic arterial pressure, from 128 to 79 mm Hg, and a concomitant increase of heart rate, from 380 to 530 minutes(-1). Both the decrease of systemic arterial pressure and the increase of heart rate induced by LPS were almost absent if the animals also received the COX-2 blocker rofecoxib (20 mg/kg), regardless whether the drug was given 1 hour before or 1 hour after LPS. Although plasma and organ levels of prostanoids were lowered by rofecoxib, the characteristic LPS-induced increases of NO synthase II and COX-2 gene expression, as well as of plasma and tissue nitrate/nitrite concentrations, were not affected by rofecoxib. Although rofecoxib treatment did also not change LPS-induced tissue cytokine concentrations, it markedly improved LPS-induced liver damage, as indicated by the decrease of transaminases. Moreover, the overall well-being of the LPS-injected animals improved on concomitant treatment with the COX-2 inhibitor. Taken together, our data suggest that COX-2-derived prostanoids are major mediators for the detrimental effects of LPS on cardiovascular and organ function.
authors.affiliation: Department of Pharmacology, University of Regensburg, Regensburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Höcherl
authors.forename: Franziska
authors.initials: F
authors.lastname: Dreher
authors.forename: Armin
authors.initials: A
authors.lastname: Kurtz
authors.forename: Michael
authors.initials: M
authors.lastname: Bucher
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D008565:Membrane Proteins; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones; D000637:Transaminases / Q000097:blood
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D007783:Lactones; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009566:Nitrates; D009573:Nitrites; D011453:Prostaglandins; D012333:RNA, Messenger; D013450:Sulfones; C116926:rofecoxib; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000637:Transaminases