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.
"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. "
[Show abstract][Hide abstract] ABSTRACT: To examine the participation of endogenous cyclooxygenase (COX) in the mnemonic effect of NC-1900, an arginine-vasopressin fragment analog, the latencies of mice in the step-through passive avoidance (PA) task were determined following the administration of COX inhibitors and/or NC-1900 (1 ng/kg). When administered immediately after the acquisition trial (Acq) in the PA task, indomethacin (20 mg/kg), a nonspecific COX inhibitor, and NS-398 (10 and 20 mg/kg), a specific COX-2 inhibitor, but not piroxicam (10 and 20 mg/kg), a specific COX-1 inhibitor, decreased the latency on the retention trial (Ret). The mnemonic effect of 1 ng/kg NC-1900 on the Ret in the PA task was also inhibited by the administration of either indomethacin (20 mg/kg) or NS-398 (20 mg/kg) but not by piroxicam. However, when 20 mg/kg indomethacin and NS-398 were administered 3 h after the Acq, the increase in Ret latency induced by NC-1900 was not inhibited. These results suggested that the action of NC-1900 on the early stage of memory formation in the PA task may be modulated by endogenous COX-2 but not by COX-1.
Methods and Findings in Experimental and Clinical Pharmacology 07/2007; 29(5):315-20. DOI:10.1358/mf.2007.29.5.1117559 · 0.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endotoxic shock is a systemic inflammatory response that is associated with an increase in nitric oxide production and a decrease in the formation of 20-hydroxyeicosatetraenoic acid (20-HETE), which may contribute to the fall in blood pressure and vascular reactivity. The present study examined the effects of a synthetic analogue of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-HEDGE), on the fall in blood pressure and vascular responsiveness to vasoscontrictors and acetylcholine in rats treated with endotoxin. The MAP fell by 31 mmHg, and the heart rate rose by 90 beats/min in male Wistar rats treated with endotoxin (10 mg/kg, intraperitoneally). The fall in MAP was associated with a decrease in the vasoconstrictor response to norepinephrine in isolated aorta and superior mesenteric artery and increased levels of nitrite in the serum, kidney, heart, and vascular tissues. The effects of endotoxin were prevented by 5,14-HEDGE (30 mg/kg, s.c.) given 1 h after injection of endotoxin. Furthermore, a competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (30 mg/kg, s.c.), prevented the beneficial effects of 5,14-HEDGE on MAP and vascular tone in rats treated with endotoxin. These data are consistent with the view that a fall in the production of 20-HETE contributes to the fall in MAP and vascular reactivity in rats treated with endotoxin, and that 5,14-HEDGE has a beneficial effect.
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