The "in vivo" and "ex vivo" roles of cylcooxygenase-2, nuclear factor-kappaB and protein kinases pathways in the up-regulation of B1 receptor-mediated contraction of the rabbit aorta.
This study investigates some of the mechanisms involved in the up-regulation of the B1 receptor in the rabbit aorta. Pre-treatment of rabbit aorta with cyclooxygenase (COX) inhibitors 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsuphonyl) phenyl-2 (5H)-furanone (DFU), N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide (NS-398) or with indomethacin, but not with piroxicam, for 6 h, resulted in a significant inhibition of time-dependent contraction to the B1 selective agonist des-Arg9-Bradykinin (des-Arg9-BK), without affecting noradrenaline (NA) response. The kinase inhibitors bisindoylmaleimidine IX (RO 318220), staurosporine, genistein or tyrphostin B42 and the nuclear factor-kappaB (NF-kappaB) inhibitors pyrrolidinedithiocarbamate (PDTC), N(alpha)-p-tosyl-L-lysine chloro-methyl ketone (TLCK) or sulfasalazine, incubated for 6 h each, resulted in similar inhibition of des-Arg9-BK-induced contraction. When these inhibitors were pre-incubated for only 30 min, 6 h after setting up the preparations, sulfasalazine was the only drug tested that inhibited des-Arg9-BK-induced contraction, an effect which was reverted after the washing-out of the preparations. In preparations obtained from animals treated with lipopolysaccharide i.v. (LPS) 12 h prior, the up-regulation of B1 receptor in the aorta was markedly increased. The treatment of rabbits with PDTC, dexamethasone (Dexa), genistein or an association of subliminal doses of Dexa or with PDTC 12 h prior, which alone had no effect, all caused significant inhibition of des-Arg9-BK-induced contraction in the rabbit aorta. These results indicate that the time-dependent up-regulation of des-Arg9-BK-mediated contraction in the rabbit aorta involves the activation of protein kinase C, tyrosine kinase, through participation of COX-2 and the NF-kappaB transcription factor pathways.
Medeiros
R
R
Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina, Rua Ferreira Lima 82, 88015-420 Florianópolis, SC, Brazil.
Cabrini
D A
DA
Calixto
J B
JB
D000818:Animals; D001011:Aorta / Q000502:physiology*; D051546:Cyclooxygenase 2; D005260:Female; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000502:physiology*; D015854:Up-Regulation
D007527:Isoenzymes; D016328:NF-kappa B; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011494:Protein Kinases