Inhibition of extracellular signal-regulated kinase (ERK1/2) activity reverses endotoxin-induced hypotension via decreased nitric oxide production in rats.
Overproduction of reactive oxygen and nitrogen species leads to oxidative stress and decreased total antioxidant capacity, which is responsible for high mortality from several inflammatory diseases such as endotoxic shock. Among reactive nitrogen species, nitric oxide (NO) produced by inducible NO synthase (iNOS) during endotoxemia is the major cause of vascular hyporeactivity, hypotension and multiple organ failure. This study was conducted to determine if mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK1/2) contributes to endotoxin-induced hypotension as well as vascular inflammation and oxidative stress via NO production. In conscious male Wistar rats, injection of endotoxin (10 mg kg(-1), i.p.) caused a decrease in mean arterial pressure (MAP) for 4h and increased levels of nitrite in serum, aorta and mesenteric artery. These effects of endotoxin were prevented by selective inhibition of ERK1/2 phosphorylation by MAPK kinase (MEK1/2) with U0126 (5 mg kg(-1), i.p.; 1h after endotoxin). Endotoxin also caused an increase in protein levels of phosphorylated ERK1/2 in aorta which was abolished by U0126. Selective inhibition of iNOS with phenylene-1,3-bis[ethane-2-isothiourea] dihydrobromide (1,3-PBIT) (10 mg kg(-1), i.p.; 1h after endotoxin) did not change the endotoxin-induced increase in ERK1/2 activity. Myeloperoxidase activity was increased in aorta and decreased in mesenteric artery by endotoxin, which was reversed by U0126. Endotoxin-induced decrease in one of the products of lipid peroxidation, malonedialdehyde (MDA) was prevented by U0126 in mesenteric artery; however, U0126 caused a further decrease in the levels of MDA in aorta. These data suggest that increased phosphorylation of ERK1/2 by MEK1/2 contributes to the endotoxin-induced hypotension via NO production rat aorta and mesenteric artery. It is likely that ERK1/2 mediates the effect of endotoxin on MPO activity in a different degree in the tissues suggesting possible involvement of any mediator and/or mechanism which also causes neutrophil infiltration during inflammatory response at least in mesenteric artery. Moreover, ERK1/2 seems to be involved in the endotoxin-induced increase in total antioxidant capacity in mesenteric artery.
Tunctan
B
B
Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, Mersin 33169, Turkey. btunctan@yahoo.com
Korkmaz
B
B
Dogruer
Z N
ZN
Tamer
L
L
Atik
U
U
Buharalioglu
C K
CK
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D002070:Butadienes; D004731:Endotoxins; D004791:Enzyme Inhibitors; D009570:Nitriles; D009573:Nitrites; D047428:Protein Kinase Inhibitors; C118852:S,S'-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea; C113580:U 0126; D009569:Nitric Oxide; D008315:Malondialdehyde; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013890:Thiourea