BRADYKININ-EVOKED SENSITIZATION OF NEUROPEPTIDE RELEASE FROM AFFERENTNEURONS IN THE GUINEA-PIG LUNG

1 It has been shown that bradykinin (BK) causes sensitization of airwa y sensory neurons and an enhancement of the cough reflex in guinea-pig s. In the present study, the guineapig isolated perfused lung was used to investigate the possible enhancement by BK of histamine-evoked neu ropeptide release from peripheral terminals of primary afferent neuron s, and to determine the contribution of cyclooxygenase products of ara chidonate metabolism to this effect. 2 The lung was perfused with oxyg enated physiological salt solution containing peptidase inhibitors (th iorphan, bestatin and captopril, 1 mu M each). BK and histamine were a dded to the perfusate for 10 and 5 min, respectively. 3 BK alone (0.1 mu M) evoked the release of 10.35 +/- 2.4 fmol immunoreactive calciton in gene-related peptide (CGRP), histamine alone (100 mu M) evoked the release of 12.7 +/- 1.6 fmol CGRP. Stimulation with 100 mu M histamine in the presence of 0.1 mu M BK (added 5 min before histamine and pres ent during histamine) evoked the release of 67.1 +/- 5.3 fmol CGRP. 4 Prostaglandin (PG) release was stimulated by BK (418 +/- 71 pmol 15-ke to-13,14-dihydro-PGF(2 alpha) and 345 +/- 59 pmol 6-keto-PGF(1 alpha)) , and, to a lesser extent, by histamine (36.1 +/- 7.4 pmol 15-keto-13, 14-dihydro-PG(2 alpha), and 24.6 +/- 3.9 pmol 6-keto-PGF(1 alpha)). Pr ostaglandin release induced by histamine in the presence of BK was not significantly higher than with BK alone. 5 Indomethacin (5 mu M) as w ell as the bradykinin B-2 receptor antagonist HOE140 (icatibant, 1 mu M) inhibited prostaglandin release following stimulation with histamin e in combination with BK. CGRP release evoked by histamine in combinat ion 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 resul ts suggest that BK-induced stimulation of prostaglandin synthesis resu lts in facilitation of histamine-evoked release of pro-inflammatory ne uropeptides from afferent neurons, a mechanism that probably becomes r elevant during inflammation, and that can be blocked by a bradykinin B -2 receptor antagonist.