INTERACTION OF THE RENIN-ANGIOTENSIN SYSTEM, BRADYKININ AND SYMPATHETIC-NERVES WITH CHOLINERGIC TRANSMISSION IN THE RAT ISOLATED TRACHEA

1 The present study was undertaken to investigate the interaction of t he renin - angiotensin system (RAS), bradykinin and the sympathetic ne rvous system with cholinergic transmission in the rat airways. Experim ents were performed on epithelium-intact and epithelium-denuded prepar ations of rat isolated trachea which had been incubated with [H-3]-cho line to incorporate [H-3]-acetylcholine into the cholinergic transmitt er stores. Tracheal preparations were subjected to electrical field st imulation (trains of 1 ms pulses, 5 Hz, 15 V) and the stimulation-indu ced (S-I) efflux taken as an index of transmitter acetylcholine releas e. 2 In both epithelium-intact and epithelium-denuded tracheal prepara tions, the alpha(2)-adrenoceptor agonist UK14304 (0.1 and 1 mu M) inhi bited the S-I efflux, in a concentration-dependent manner. The inhibit ion of S-I efflux produced by UK14304 (1 mu M) was antagonized by the selective alpha(2)-adrenoceptor antagonist idazoxan (0.3 mu M). Idazox an (0.3 mu M) alone had no effect on the S-I efflux. 3 Angiotensin II (0.1 and 1 mu M) was without effect on the S-I efflux in either epithe lium-intact or epithelium-denuded tracheal preparations. When angioten sin-converting enzyme was inhibited by perindoprilat (10 mu M), angiot ensin II (1 mu M) was also without effect on the S-I efflux. Similarly , in the presence of idazoxan (0.3 mu M), to block prejunctional alpha (2)-adrenoceptors, angiotensin II (0.1 and 1 mu M) did not alter the S -I efflux. When added alone, perindoprilat (10 mu M) did not alter the S-I efflux. 4 In epithelium-denuded preparations, bradykinin (0.01-1 mu M) inhibited the S-I efflux. In epithelium-intact preparations, the re was also a tendency for bradykinin (0.1 and 1 mu M) to inhibit the S-I efflux but this was not statistically significant. However, when a ngiotensin-converting enzyme and neutral endopeptidase were inhibited by perindoprilat (10 mu M) and phosphoramidon (1 mu M), respectively, bradykinin (1 mu M) significantly inhibited the S-I efflux in epitheli um-intact preparations as well as in epithelium-denuded preparations. The inhibition of the S-I efflux produced by bradykinin, in the combin ed presence of perindoprilat (10 mu M) and phosphoramidon (1 mu M), wa s unaffected by the additional presence of the cyclo-oxygenase inhibit or indomethacin (10 mu M) and/or the nitric oxide synthase inhibitor N -G-nitro-L-arginine (100 mu M), in either epithelium-intact or epithel ium-denuded preparations. 5 In conclusion, the findings of the present study suggest that airway parasympathetic nerves are endowed with alp ha(2)-adrenoceptors which subserve inhibition of transmitter acetylcho line release. Under the present conditions, however, transmitter acety lcholine release is not subject to transneuronal modulation by noradre naline released from adjacent sympathetic nerves in the airways. Moreo ver, angiotensin II and perindoprilat do not appear to modulate acetyl choline release from parasympathetic nerves of the airways. In contras t, bradykinin inhibits acetylcholine release from airway parasympathet ic nerves but this action of bradykinin is limited by the activity of epithelial angiotensin-converting enzyme and/or neutral endopeptidase. The inhibitory action of bradykinin on cholinergic transmission in th e airways does not appear to involve the liberation of prostaglandins or nitric oxide.