Changes in paw oedema triggered via bradykinin B1 and B2 receptors in streptozotocin-diabetic rats

https://doi.org/10.1016/S0014-2999(01)00883-4Get rights and content

Abstract

The present study investigated hind paw oedema mediated by bradykinin B1 and B2 receptors in streptozotocin-diabetic rats. Paw oedema induced by intraplantar (i.pl.) injection of bradykinin or the selective bradykinin B2 receptor agonist, Tyrosine8-bradykinin ([Tyr8]bradykinin) (both 3 nmol/paw), was significantly reduced at 4 weeks after streptozotocin treatment (34±8% and 40±7%). At 6 weeks after streptozotocin, when paw oedema caused by substance P or prostaglandin E2 (both 10 nmol/paw) was unchanged, inhibition of bradykinin B2 receptor-mediated oedema was maximal (66±6% and 72±2%, for bradykinin and [Tyr8]bradykinin, respectively). The selective bradykinin B1 receptor agonist, [des-Arg9]bradykinin (100 nmol/paw), induced only slight paw oedema in non-diabetic controls. Responses to [des-Arg9]bradykinin were markedly enhanced 8 weeks after streptozotocin (from 0.09±0.01 to 0.38±0.05 ml), less so at 10 weeks (0.22±0.03 ml), and returning to basal values at 12 weeks (0.11±0.03 ml). Treatment with insulin protamine zinc (1–3 U/day/7 weeks, s.c.) did not reverse the inhibition of responses to [Tyr8]bradykinin or the potentiation of responses to [des-Arg9]bradykinin seen at 8 weeks. Thus, streptozotocin-induced diabetes induces long-lasting alterations in oedematogenic responsiveness to kinins in the rat, characterized by marked reduction of oedema involving activation of bradykinin B2 receptors, associated with enhancement of bradykinin B1 receptor-mediated oedema.

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.

References (46)

  • M.T.R Subbiah et al.

    Altered synthesis of prostaglandins in platelet and aorta from spontaneously diabetic Wistar rats

    Biochem. Med.

    (1980)
  • C Tschöpe et al.

    Myocardial expression of rat bradykinin receptors and two tissue kallikrein genes in experimental diabetes

    Immunopharmacology

    (1999)
  • K.D Bhoola et al.

    Bioregulation of kinins: kallikreins, kininogens and kininases

    Pharmacol. Rev.

    (1992)
  • M.M Campos et al.

    Involvement of B1 and B2 receptors in bradykinin-induced rat paw oedema

    Br. J. Pharmacol.

    (1995)
  • M.M Campos et al.

    Expression of B1 receptors mediating paw oedema and formalin induced-nociception: modulation by glucocorticoids

    Can. J. Physiol. Pharmacol.

    (1995)
  • M.M Campos et al.

    Up-regulation of B1 mediating des-Arg9-bradykinin-induced rat paw oedema by systemic treatment with bacterial endotoxin

    Br. J. Pharmacol.

    (1996)
  • M.M Campos et al.

    The role of B1 and B2 receptors in oedema formation after long-term treatment with Mycobacterium bovis bacillus Calmette-Guérin (BCG)

    Br. J. Pharmacol.

    (1997)
  • S Cellek et al.

    Selective nitrergic neurodegeneration in diabetes mellitus—a nitric oxide-dependent phenomenon

    Br. J. Pharmacol.

    (1999)
  • N.N Chan et al.

    Nitric oxide and vascular responses in type I diabetes

    Diabetologia

    (2000)
  • F Cloutier et al.

    Pharmacological chracterization of the cardiovascular responses elicited by kinin B1 and B2-receptor agonists in the spinal cord of streptozotocin-diabetic rats

    Br. J. Pharmacol.

    (2000)
  • C.R Corrêa et al.

    Evidence for participation of B1 and B2 kinin receptors in formalin-induced nociceptive response in the mouse

    Br. J. Pharmacol.

    (1993)
  • C Courteix et al.

    Daily insulin treatment relieves long-term hyperalgesia in streptozotocin diabetic rats

    NeuroReport

    (1996)
  • D Eggerix et al.

    Molecular cloning, functional expression and pharmacological characterization of human bradykinin B2 receptor gene

    Biochem. Biophys. Res. Commun.

    (1992)
  • Cited by (0)

    View full text