Abstract
The present study was performed to: (a) evaluate the effects of kinin B1 (Sar[D-Phe8]-des-Arg9-BK; 10 nmol/kg) and B2 (bradykinin (BK); 10 nmol/kg) receptor agonists on plasma extravasation in selected rat tissues; (b) determine the contribution of a lipopolysaccharide (LPS) (100 microg/kg) to the effects triggered by B1 and B2 agonists; and (c) characterize the selectivity of B1 ([Leu8]desArg9-BK; 10 nmol/kg) and B2 (HOE 140; 10 nmol/kg) antagonists as inhibitors of this kinin-induced phenomenon. B1 and B2 agonists were shown to increase plasma extravasation in the duodenum, ileum and also in the urinary bladder of the rat. LPS pretreatment enhanced the plasma extravasation mediated only by the B1 agonist in the duodenum, ileum, trachea, main and segmentar bronchi. These effects were prevented by the B1. but not the B2 antagonist. In normal rats, the B2 antagonist inhibited the effect of B2 agonist in all the tissues analyzed. However, in LPS-treated rats, the B2 antagonist was ineffective in the urinary bladder. These results indicate that kinins induce plasma extravasation in selected rat tissues through activation of B1 and B2 receptors, and that LPS selectively enhances the kinin effect on the B1 receptor in the duodenum, ileum, trachea and main and segmentar bronchi, and may increase B1 receptor expression in these tissues.
Highlights
Kinins are powerful pro-inflammatory peptides that are released from their precursors, the kininogens, by proteolytic cleavage of specific and non-specific kininogenases.[1]
In the first series of experiments, we studied the effects of a kinin B2 receptor agonist on plasma extravasation in control and LPS-treated rats (Fig. 1)
Previous injection with the B2 antagonist in LPS-treated rats significantly reduced the plasma extravasation induced by BK in the duodenum (31%), ileum (22%), trachea (32%), and main (33%) and segmentar bronchi (29%), but not in the urinary bladder.As expected, the B1 antagonist ([Leu8]desArg9BK; 10 nmol/kg) had no effect on plasma extravasation induced by BK in LPS-treated rats
Summary
Kinins are powerful pro-inflammatory peptides that are released from their precursors, the kininogens, by proteolytic cleavage of specific and non-specific kininogenases.[1] Pharmacological actions of kinins are mediated by B1 and B2 receptors, the distribution of which has been studied through the use of specific and selective antagonists,[2,3,4] and the analysis of protein expression levels.[5]. The kinin B2 receptor is constitutively expressed in several different cell types and tissues, and most of the actions of kinins are mediated by this receptor.[6,7,8] In contrast, B1 receptors are rarely expressed constitutively but, rather, their expression is induced by experimental interventions such as exposure of tissue in vivo or in vitro to bacterial lipopolysaccharides (LPS), interleukin-1b or to ultraviolet irradiation.[6]. These results were observed only when we used the B1 agonist, Sar[D-Phe8]-desArg9-BK, which is resistant to metabolism by angiotensin-converting enzyme, neutral endopeptidase and aminopeptidases. 9
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