Changes in paw oedema triggered via bradykinin B1 and B2 receptors in streptozotocin-diabetic rats
Introduction
Generated in plasma and peripheral tissues, especially in response to tissue trauma or infection, bradykinin and other related endogenous kinins are a group of peptides, which not only participate in blood pressure control, but exert important actions in inflammation and pain (for review see: Regoli and Barabé, 1980, Bhoola et al., 1992, Marceau and Bachvarov, 1998, Calixto et al., 2000). Indeed, kinins seem to be implicated in several physiopathologies including asthma, allergy, rheumatoid arthritis, endotoxic shock and acute pancreatitis (for review see: Calixto et al., 2000).
Most actions of kinins are mediated by activation of two specific G protein-coupled transmembrane receptors, denoted as B1 and B2. Both bradykinin receptor types have been well characterized at the pharmacological, genetic and structural levels Regoli and Barabé, 1980, Eggerix et al., 1992, Hess et al., 1994, McEachern et al., 1991, Pesquero et al., 1996, Marceau and Bachvarov, 1998. The bradykinin B2 receptors are expressed largely in a constitutive fashion, and seem to underlie most of the physiological responses to kinins and mediate several early (acute phase) inflammatory events (Marceau and Bachvarov, 1998). The bradykinin B1 receptors, on the other hand, are not normally present in non-traumatised tissues, but may be upregulated under some special conditions, particularly related to chronic inflammatory processes and activation of the cytokine network (Marceau et al., 1998). More recently, the roles of both bradykinin B1 and B2 receptors have also begun to be probed by means of gene knockout technology. In this regard, pronounced changes in responsiveness to nociceptive and pro-inflammatory stimuli have been detected in mice lacking bradykinin B1 (Pesquero et al., 2000) or B2 receptors (Boyce et al., 1996).
Diabetes, a disease currently affecting over 120 million people worldwide (Seidell, 2000), is caused either by insulin deficiency due to pancreatic β-cell dysfunction or destruction, or by failure of target organs to respond to this hormone. The diabetic condition is associated with multiple changes of vascular structures, as well as interference with production of vasoactive substances Fortes et al., 1983, Morrish et al., 1991, Giannattasio et al., 1999. Onset of diabetes seems to be related to functional alterations of the endothelium, an action which contributes directly to the progress and complexity of the disease Hopfner and Gopalakrishnan, 1999, Chan et al., 2000. Several lines of evidence have suggested the involvement of the kallikrein–kinin system in the pathogenesis of diabetes Garcia Leme et al., 1973, Wang et al., 1998, Cloutier and Couture, 2000. Indeed, different symptoms of diabetes in mice can be offset by treatment with antagonists of bradykinin B1 and B2 receptors (Zuccollo et al., 1996). Streptozotocin, a nitrosamine that produces insulitis and selective destruction of pancreatic β-cells, has been widely employed to induce insulin-dependent (type I) diabetes in rats and mice. This model of experimental diabetes has been of paramount importance regarding current knowledge about this disease (for review see: Chan et al., 2000).
In the present study, we investigated the time-related influence of streptozotocin-induced type I diabetes on the rat paw oedema formation, induced by selective bradykinin B1 and B2 receptors agonists.
Section snippets
Rat paw oedema
The procedures used were similar to those described previously (Campos and Calixto, 1995). Experiments were performed with non-fasted male Wistar rats (160–180 g; n=308) housed at 22±2°C with a 12/12 h light–dark cycle (lights on at 06:00). Under light anesthesia with 2,2,2 tribromoethanol (0.12 g/kg), the animals received a 0.1 ml intraplantar (i.pl.) injection, into the right hind paw, of bradykinin (3 nmol/paw), [Tyr8]bradykinin (3 nmol/paw) or [des-Arg9]bradykinin (100 nmol/paw) in
Results
The treatment of animals with streptozotocin produced, within 1 week, a sustained increase in blood glucose levels, associated with a severe decrease in body weight (see Table 1). As described previously Campos and Calixto, 1995, Campos et al., 1995, the i.pl. injection of bradykinin or the selective bradykinin B2 receptor agonist [Tyr8]bradykinin (each at 3 nmol/paw) produced a marked increase in rat hind paw volume, with peak responses of 0.44±0.04 and 0.40±0.01 ml, respectively, 20 min after
Discussion
We now investigated the time-related alterations in oedematogenic responsiveness of the hind paw of streptozotocin-induced diabetic rats to stimulation of bradykinin B1 and B2 receptors. The results reveal substantial and distinct changes in oedema triggered by bradykinin B1 and B2 receptors in this experimental model of type I diabetes.
Our results demonstrate that the treatment of animals with streptozotocin results in a marked decrease of the paw oedema responses mediated by bradykinin B2
Acknowledgements
This work was supported by grants from CNPq, CAPES, FINEP, PRONEX and by Vitae Foundation (Brazil). M.M. Campos, D.A. Cabrini and A.H.M. Cardozo are PhD Pharmacology students, and they thank CNPq and CAPES for financial support.
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