Effects of adrenergic agonists and adenosine on cholinergic neurotransmission in human tracheal smooth muscle

Abstract

There is only limited information available on the prejunctional regulation of acetylcholine (ACh) release from cholinergic nerves in human airway smooth muscle. Stimulation of cholinergic nerves in fresh postmortem tracheal muscle strips with electrical field stimulation (EFS) causes reproducible contractions. We have studied the effect on contractile responses of: 1) The alpha 2-adrenoceptor agonist effect of noradrenaline (NA, 0.1-30 microM) and clonidine (10 nM-30 microM), in the presence of 1 microM propranolol and prazosin +/- idazoxan (0.1 microM); 2) The beta-adrenoceptor agonist effect of fenoterol (FEN) and isoprenaline (ISO, 1 nM-30 microM) +/- ICI 118,551 (10 nM), comparing EFS responses to comparable responses to exogenous ACh; 3) The A1 and A2 adenosine receptor agonists effects of L-PIA and NECA (1 nM-10 microM). NA caused a concentration-dependent depression of the cholinergic frequency-response curve. However responses at 5 Hz were not modified by the addition of idazoxan. Similarly clonidine did not reduce contractile responses. The concentrations of isoprenaline (56 nM) and fenoterol (165 nM) required to inhibit EFS (5 Hz) by 50% (IC50) were significantly less than those required to inhibit closely matched ACh responses to a comparable degree (ISO = 117 and FEN = 304 nM), and the maximum inhibition of EFS was greater. Following isoprenaline and the beta 2-antagonist ICI 118,551 the IC50's for EFS and ACh were not different. NECA and PIA had no effect on cholinergic EFS. We conclude that a prejunctional beta 2 receptor may be present on cholinergic nerves in post-mortem tracheal smooth muscle but no evidence for alpha 2-adrenoceptor or adenosine-receptor regulation was obtained.