title: Involvement of calcium/calmodulin-dependent protein kinase II to endotoxin-induced vascular hyporeactivity in rat superior mesenteric artery.
abstract: Endotoxin causes impaired vascular contractility proposed to be mediated mainly by induction of inducible nitric oxide synthase (iNOS). Evidence suggests that calcium/calmodulin dependent protein kinase II (CaMKII) may lead to activation of cytosolic phospholipase A(2alpha) (cPLA(2alpha))/inducible cyclooxygenase (COX-2) pathway in response to endotoxin in vascular smooth muscle cells. This study was conducted to determine if CaMKII is involved in the endotoxin-induced vascular hyporeactivity by activating of iNOS and/or cPLA(2alpha)/COX-2 enzymes in rat isolated superior mesenteric artery with endothelium. Incubation with endotoxin (100 microg ml(-1)) for 4h caused vascular hyporeactivity to norepinephrine which was completely abolished by phenylene-1,3-bis[ethane-2-isothiourea] dihydrobromide (1,3-PBIT), a selective iNOS inhibitor, methyl arachidonyl fluorophosphonate (MAFP), a selective 85kDa cPLA(2alpha) inhibitor, DFU, a selective COX-2 inhibitor, and KN-93, a selective CaMKII inhibitor. Endotoxin-induced increase in tissue nitrite production was decreased by 1,3-PBIT and DFU, and further increased by MAFP. MAFP, DFU and KN-93 reversed the endotoxin-induced decrease in tissue 6-keto-PGF(1alpha). These data suggest that reversal of the endotoxin-induced vascular hyporeactivity by inhibition of CaMKII in rat superior mesenteric artery may be related to increased production of vasodilator arachidonic acid products by cPLA(2alpha)/COX-2 pathway rather than prostacyclin and nitric oxide.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169 Mersin, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Ozveren
authors.forename: B
authors.initials: B
authors.lastname: Korkmaz
authors.forename: C K
authors.initials: CK
authors.lastname: Buharalioglu
authors.forename: B
authors.initials: B
authors.lastname: Tunctan
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology*; D011464:Epoprostenol / Q000378:metabolism; D054513:Group IV Phospholipases A2; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004731:Endotoxins; D009573:Nitrites; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D009638:Norepinephrine