Sensory receptor activation by mediators of defense reflexes in guinea-pig lungs

Abstract

Histamine and bradykinin are mediators released within the lungs during lung defense. Both pulmonary rapidly-adapting receptors (RARs) and afferent C-fibers have been suggested to initiate defense reflexes evoked by these mediators. However, it is not known whether the sensory endings are directly stimulated by these mediators rather than indirectly by mechanical changes. Therefore, pulmonary RARs and C-fibers were challenged with aerosols of histamine, bradykinin and capsaicin in anesthetized guinea pigs. During histamine challenge tracheal pressure (P_Tr) and RAR nerve activity (NA) increased concurrently. After isoproterenol administration to attenuate increases in P_Tr, histamine-induced increases in RAR NA were similarly attenuated. Results with bradykinin or capsaicin challenge were similar. Therefore activation of RARs by histamine, capsaicin and bradykinin was dependent upon changes in lung mechanics. C-fibers were activated by capsaicin or bradykinin prior to any changes in P_Tr. However, C-fibers were not affected by histamine challenge despite substantial increases in P_Tr. C-fibers are activated directly by either capsaicin or bradykinin but not by histamine.

Introduction

Activation of sensory receptors in the airways by exogenous and endogenous mediators initiates both central and local defense reflexes (Barnes et al., 1991). Defense reflexes increase airway smooth muscle tone and secretions as well as induce vasodilation and plasma exudation, particularly in asthma. Defense reflexes often are attributed to activation of RARs or the so called `irritant' receptors (Karlsson et al., 1988). Certain mediators released during mechanisms of lung defense are reported to directly activate RARs, these include histamine (Mills et al., 1969, Vidruk et al., 1977), which is released during mast cell degranulation and bradykinin (Hargreaves et al., 1993), which is formed during kallikrein activation.

Recent attention has focused on the role of sensory C-fibers in pulmonary defense reflexes. C-fibers not only evoke centrally- mediated reflexes, which influence pulmonary and cardiovascular function but also mediate the local or `axon' reflex in which neuropeptides are released (Saria et al., 1988). Neuropeptides released from C-fibers may include neurokinin A, substance P and calcitonin gene related peptide.

Whether both categories of sensory receptors mediate defense reflexes is unresolved. Moreover the specific endogenous and exogenous mediators that act directly on RARs or C-fibers has been controversial. Histamine was reported to directly activate RARs in cats and dogs (Mills et al., 1969, Vidruk et al., 1977) and C-fibers in dogs (Coleridge and Coleridge, 1977). On the other hand histamine was reported to act only indirectly on RARs in dogs, guinea pigs and rats (Coleridge and Coleridge, 1977, Bergren and Sampson, 1982, Bergren and Peterson, 1993) and to have no effect on C-fibers in guinea pigs in vitro (Fox et al., 1993). Both direct (Hargreaves et al., 1993) and indirect (Kaufman et al., 1980) activation of RARs by bradykinin has been reported. Bradykinin directly activates bronchial C-fibers in dogs (Kaufman et al., 1980) and guinea pig tracheal and main stem bronchi C-fibers in vitro (Fox et al., 1993). However, both histamine and bradykinin are reported to induce neuropeptide release from C-fibers via the `axon' reflex (Saria et al., 1988) which implies direct C-fiber activation.

The purpose of the present study was to determine whether mediators believed to induce defense reflexes, i.e. histamine, bradykinin and capsaicin, activate RARs and C-fibers, and if so whether the activation is direct or indirect. It is likely that only directly stimulated fibers actually initiate defense reflexes.