Effects of the orally active non-peptide bradykinin B2 receptor antagonist, FR173657, on plasma extravasation in guinea pig airways

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Abstract

We investigated the effect of the orally active non-peptide bradykinin B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-di-chloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methy-laminocarbonylmethyl] acrylamide), on plasma extravasation mediated by activation of sensory nerves in guinea pig airways. Plasma extravasation was assessed by the photometric measurement of the extravasated Evans blue after formamide extraction. We found that the increase in Evans blue dye extravasation evoked by an aerosol of bradykinin (0.1 mM, 2 min) in the presence of phosphoramidon (2.5 mg/kg, i.v.) was abolished completely by FR173657 (20 mg/kg, p.o.) in the trachea and main bronchi. In sensitized guinea pigs pretreated with phosphoramidon, FR173657 (20 mg/kg, p.o.) inhibited plasma extravasation evoked by ovalbumin aerosol (5%, 2 min) by 77±14.2% in the trachea and 65±11.2% in the main bronchi. FR173657 (20 mg/kg, p.o.) did not affect the plasma extravasation caused by aerosolised capsaicin. These findings suggest that FR173657 is an orally active, promising anti-inflammatory agent for kinin-dependent inflammation following antigen challenge.

Introduction

Bradykinin, a nonapeptide produced by kallikrein, is a powerful proinflammatory autacoid (Regoli and Barabé, 1980). Bradykinin may cause inflammation by a direct action on bradykinin receptors, on effector cells, or via indirect mechanisms. For instance, part of the inflammatory response produced by locally applied bradykinin in certain tissues, such as the airways, is due to stimulation of the release of neuropeptides, including tachykinins, from peripheral endings of primary sensory neurons (Saria et al., 1988; Geppetti et al., 1988). There is growing evidence that endogenously released bradykinin also causes inflammation via sensory neuropeptide release (Bertrand and Geppetti, 1996; Lu et al., 1997). These and other findings from human studies have suggested the hypothesis that inflammatory responses induced by bradykinin may play a role in airway diseases such as asthma (Church and Levi-Schaffer, 1997).

Two subtypes of bradykinin receptors (B1 and B2 receptors) have been identified by pharmacological analysis and molecular cloning (Regoli and Barabé, 1980; Hess et al., 1992; Menke et al., 1994). Bradykinin B2 receptors mediate most of the biological action of the kinins in the airway (Bhoola et al., 1992). HOE140 (d-Arg-[Hyp3,Thi5,d-Tic7,Oic8]bradykinin) is a highly potent and long-acting bradykinin B2 receptor antagonist that has been widely used to inhibit bradykinin-induced inflammatory responses both in vitro and in vivo (Wirth et al., 1991). For instance, HOE140 blocks bradykinin-induced plasma extravasation in the guinea pig trachea and reduces that evoked by aerosolized antigen challenge in sensitized guinea pigs (Bertrand et al., 1993a). However, this antagonist is a peptide analog with limited therapeutic use because of its poor oral bioavailability. Especially when the antagonists are used as treatment for a chronic disease, oral activity is a prerequisite.

Recently, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-di-chloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methy-laminocarbonylmethyl] acrylamide), an orally active non-peptide bradykinin B2 receptor antagonist has been developed (Asano et al., 1997). Oral administration of FR173657 inhibits bradykinin-induced bronchoconstriction in guinea pigs in vivo (Griesbacher et al., 1997). However, no information is available regarding the ability of FR173657 to inhibit microvascular leakage induced by bradykinin in the airways. The aim of the present study was two-fold. Firstly, we tested whether FR173657 modulates bradykinin-induced plasma extravasation. Secondly, we examined whether FR173657 inhibits antigen-induced plasma extravasation in sensitized guinea pig airways.

Section snippets

Animals

Male Hartley guinea pigs (Japan SLC) weighing 300–500 g at the time of housing, were used in this study. They were kept under constant temperature and humidity, and were deprived of food overnight before the experiments.

Sensitisation procedure

The animals were sensitised according to a protocol described previously (Dunn et al., 1988; Yoshihara et al., 1995) that consisted of injection of 70 mg ovalbumin (Grade V) in 1.5 ml 0.9% NaCl intraperitoneally twice with a 1-week interval between injections. The animals were

Effect of FR173657 on bradykinin-induced plasma extravasation

The extravasation of Evans blue dye in the trachea and main bronchi of guinea pig after exposure to aerosolised vehicle of bradykinin and in the presence of phosphoramidon (2.5 mg/kg, i.v.) was 44.8±3.5 ng/mg (n=5, Fig. 1a) and 32.3±2.2 ng/mg (n=5, Fig. 1b), respectively. Injection of the vehicle for bradykinin (0.9% NaCl) did not affect baseline plasma extravasation (data not shown). Inhalation of 0.1 mM bradykinin for 2 min in the presence of phosphoramidon (2.5 mg/kg, i.v.) increased the

Discussion

The pathophysiological role of kinins in various models of inflammatory diseases has been determined with various methods including the use of receptor antagonists. In this respect, one of the most successful compounds has been the potent and selective antagonist, HOE140 which binds with high affinity to bradykinin B2 receptors. For instance, HOE140 was shown to inhibit antigen-induced bronchoconstriction and plasma extravasation in sensitized guinea pigs (Bertrand et al., 1993b; Bertrand and

Acknowledgements

We thank Dr. P. Geppetti for fruitful discussion.

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