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Inhibition by endothelin‐1 of cholinergic nerve‐mediated acetylcholine release and contraction in sheep isolated trachea
Author(s) -
Henry Peter J.,
Shen Albert,
Mitchelson Fred,
Goldie Roy G.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15465.x
Subject(s) - endocrinology , contraction (grammar) , hexamethonium , medicine , acetylcholine , atropine , agonist , tetrodotoxin , cholinergic , muscle contraction , endothelin receptor , chemistry , endothelin 3 , muscarinic acetylcholine receptor , endothelins , stimulation , endothelin 1 , receptor , biology
1 The relative roles of ET A and ET B receptor activation on cholinergic nerve‐mediated contraction and acetylcholine (ACh) release were examined in sheep isolated tracheal smooth muscle. 2 Electrical field stimulation (EFS; 90 V, 0.5 ms duration, 1 Hz, 10 s train) applied to sheep isolated tracheal smooth muscle strips induced monophasic contractile responses that were abolished by either 1 μ m tetrodotoxin or 0.1 μ m atropine, but were insensitive to 10 μ m hexamethonium and 100 μ m L‐NAME. Thus, EFS‐induced contractions resulted from the spasmogenic actions of ACh released from parasympathetic, postganglionic nerves. 3 As expected, sheep isolated tracheal smooth muscle preparations did not contract in response to the ET B receptor‐selective agonist, sarafotoxin S6c (0.1–100 nM). However, sarafotoxin S6c caused a concentration‐dependent and transient inhibition of EFS‐induced contractions. The inhibitory effect induced by a maximally effective concentration of sarafotoxin S6c (10 nM; 72.1 ± 5.7%, n = 6) was abolished in the presence of the ET B receptor‐selective antagonist BQ‐788 (1 μ m ). Contractile responses to exogenously administered ACh (10 nM‐0.3 mM) were not inhibited by sarafotoxin S6c (1 or 10 nM; n = 7). 4 In contrast to sarafotoxin S6c, endothelin‐1 induced marked contractions in sheep isolated tracheal smooth muscle. These contractions were inhibited by BQ‐123, consistent with an ET A receptor‐mediated response. In the presence of BQ‐123 (3 μ m ), endothelin‐1 produced a concentration‐dependent inhibition of EFS‐induced contractions (30 nM endothelin‐1, 68.9 ± 10.2% inhibition, n = 5). These responses were inhibited by 1 μ m BQ‐788, indicative of an ET B receptor‐mediated process. Endothelin‐1 was about 3 fold less potent than sarafotoxin S6c. 5 EFS (90 V, 0.5 ms duration, 1 Hz, 15 min train) induced the release of endogenous ACh (1.94 ± 0.28 pmol mg −1 tissue, n = 12), as assayed by h.p.l.c. with electrochemical detection. EFS‐induced release of ACh was inhibited to a similar extent by 100 nM endothelin‐1 (47 ± 4%, n = 9) and 10 nM sarafotoxin S6c (46 ± 9%, n = 3). These effects of endothelin‐1 on ACh release were inhibited by 1 μ m BQ‐788 alone ( n = 4), by BQ‐788 in the presence of 3 μ m BQ‐123 ( n = 4), but not by 3 μ m BQ‐123 alone ( n = 5). 6 In summary, sheep isolated tracheal smooth muscle contains two anatomically and functionally distinct endothelin receptor populations. ET A receptors located on airway smooth muscle mediate contraction, whereas ET B receptors appear to exist on cholinergic nerves that innervate tracheal smooth muscle cells and mediate inhibition of ACh release. The inhibitory effect of ET B receptor stimulation on cholinergic neurotransmission is in stark contrast to the enhancing effects hitherto described in the airways.