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Mechanisms Underlying Lipopolysaccharide-Induced Kinin B₁ Receptor Up-Regulation in the Pig Iris Sphincter in Vitro

Department of Pharmacology, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil

Kinin B₁ receptors are known to be highly induced after inflammatory stimuli in several biological systems. We report that incubation of pig iris sphincter with lipopolysaccharide from Escherichia coli caused a marked and time-related up-regulation of B₁, accompanied by a reduction of B₂ receptor-mediated contractile responses. The up-regulation of B₁ receptors by lipopolysaccharide stimulation was decreased by the inhibitors of protein synthesis, cycloheximide and actinomycin D, and by dexamethasone and the nuclear factor-B (NF-B) inhibitor pyrrolidinedithiocarbamate (PDTC). In addition, lipopolysaccharide-induced up-regulation of B₁ receptors in the pig iris sphincter was significantly reduced by the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and to a lesser extent by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) blocker 2'-amino-3'-methoxyflavone (PD98059). Molecular biology experiments demonstrated that in vitro incubation with lipopolysaccharide resulted in a time-dependent and remarkable activation of NF-B and of p38 and ERK1/2 mitogen-activated protein (MAP) kinases, in pig iris sphincter preparations. While attempting to verify how MAP kinases are part of the B₁ receptor-activated signaling transduction pathways, we observed that PD98059 was able to markedly reduce the contraction induced by B₁ receptor activation in lipopolysaccharide-pretreated pig iris sphincter muscle but that this response was only partially decreased by SB203580. Our results extend the previous evidence on the mechanisms underlying the B₁ receptor upregulation processes and demonstrate for the first time how this takes place in an ocular tissue, the pig iris sphincter. It is therefore possible to define B₁ receptors as therapeutic targets for the treatment of infectious and inflammatory alterations of the eye.

Address correspondence to: Dr. J. B. Calixto, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco D, CCB, Postal Box 476, CEP 88049-900, Florianópolis, SC, Brazil. E-mail: calixto{at}farmaco.ufsc.br

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