Bradykinin-evoked sensitization of neuropeptide release from afferent neurons in the guinea-pig lung

Abstract

1. It has been shown that bradykinin (BK) causes sensitization of airway sensory neurons and an enhancement of the cough reflex in guinea-pigs. In the present study, the guineapig isolated perfused lung was used to investigate the possible enhancement by BK of histamine-evoked neuropeptide release from peripheral terminals of primary afferent neurons, and to determine the contribution of cyclooxygenase products of arachidonate metabolism to this effect.

2. The lung was perfused with oxygenated physiological salt solution containing peptidase inhibitors (thiorphan, bestatin and captopril, 1 μM each). BK and histamine were added to the perfusate for 10 and 5 min, respectively.

3. BK alone (0.1 μM) evoked the release of 10.35±2.4 fmol immunoreactive calcitonin gene-related peptide (CGRP), histamine alone (100 μM) evoked the release of 12.7±1.6 fmol CGRP. Stimulation with 100 μM histamine in the presence of 0.1 μM BK (added 5 min before histamine and present during histamine) evoked the release of 67.1±5.3 fmol CGRP.

4. Prostaglandin (PG) release was stimulated by BK (418±71 pmol 15-keto-13,14-dihydro-PGF_2α and 345±59 pmol 6-keto-PGF_1α), and, to a lesser extent, by histamine (36.1±7.4 pmol 15-keto-13,14-dihydro-PGF_2α, and 24.6±3.9 pmol 6-keto-PGF_1α). Prostaglandin release induced by histamine in the presence of BK was not significantly higher than with BK alone.

5. Indomethacin (5 μM) as well as the bradykinin B₂ receptor antagonist HOE140 (icatibant, 1 μM) inhibited prostaglandin release following stimulation with histamine in combination with BK. CGRP release evoked by histamine in combination with BK was attenuated by indomethacin and HOE140 to 22.1±7.8 fmol and 16.4±3.8 fmol, respectively, significantly less than the value obtained in control experiments (67.1±5.3 fmol).

6. The results suggest that BK-induced stimulation of prostaglandin synthesis results in facilitation of histamine–evoked release of pro-inflammatory neuropeptides from afferent neurons, a mechanism that probably becomes relevant during inflammation, and that can be blocked by a bradykinin B₂ receptor antagonist.

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