Mechanisms underlying the modulatory action of platelet activating factor (PAF) on the upregulation of kinin B1 receptors in the rat paw

The present study evaluated the ability of the administration of platelet activating factor (PAF) to induce the upregulation of B1 receptors in the rat paw. Local treatment with PAF resulted in a time‐dependent increase of oedema formation induced by the B1 receptor agonist des‐Arg9‐BK (des‐Arg9‐bradykinin), but not by the B2 receptor agonist tyrosine8‐bradykinin. Functional upregulation of B1 receptors was accompanied by a prominent increase of B1 receptor mRNA expression in the rat paw. In PAF‐treated paws, des‐Arg9‐BK‐induced oedema formation was significantly inhibited by the B1 receptor antagonists des‐Arg9‐[Leu8]‐BK and R‐715. The effects of PAF pretreatment were receptor operated, as assessed by the effects of the PAF receptor antagonist WEB2086 or by desensitisation of PAF receptors. The protein synthesis inhibitor cycloheximide, the anti‐inflammatory steroid dexamethasone or the nuclear factor (NF‐κB) blockers pyrrolidine‐dithiocarbamate (PDTC) and Nα‐tosyl‐L‐chloromethylketone significantly blocked the functional upregulation of B1 receptors. The selectin inhibitor fucoidin, an anti‐CD18 antibody or an anti‐rat neutrophil antiserum, also significantly prevented des‐Arg9‐BK‐induced paw oedema in rats pretreated with PAF. Intradermal injection of PAF induced a 25‐fold increase of myeloperoxidase activity in the rat paw, a response that was significantly inhibited by fucoidin, anti‐CD‐18, anti‐rat neutrophil antiserum or PDTC. Local treatment with PAF also resulted in a marked increase of NF‐κB activation, an effect largely prevented by PDTC or by the anti‐rat neutrophil antiserum. Collectively, the present results indicate that the induction of B1 receptors following treatment with the chemotatic mediator PAF is dependent on the recruitment of neutrophils, an event that is under the control of adhesion molecules, protein synthesis and NF‐κB activation. These findings provide new insights into the role played by cell migration and chemotatic factors on B1 receptor upregulation in vivo. British Journal of Pharmacology (2003) 139, 973–981. doi:10.1038/sj.bjp.0705314