Involvement of calcium/calmodulin-dependent protein kinase II to endotoxin-induced vascular hyporeactivity in rat superior mesenteric artery

Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33169 Mersin, Turkey.
Pharmacological Research (Impact Factor: 4.41). 10/2006; 54(3):208-18. DOI: 10.1016/j.phrs.2006.05.001
Source: PubMed


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.

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    • "release and PGE 2 production by the up-regulation of cPLA 2 and COX-2 via Ca 2+ /PKC/MAPKs (Lee et al., 2009). Ozveren et al. demonstrated that involvement of calcium/CaMKII in endotoxin-induced COX-2 expression (Ozveren et al., 2006). Indeed, we found that in A549 cells, ATP␥S-induced COX-2 expression and PGE 2 generation were reduced via inhibition of PI-PLC, PC-PLC, and Ca 2+ /CaMKII. "
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