Atypical presynaptic alpha-adrenoceptor modulation of neurally-mediated cholinergic responses in guinea-pig tracheal smooth muscle

Cholinergic excitatory nerves in guinea-pig trachea are subject to inhibitory control by presynaptic alpha 2-adrenoceptors. Recently, the nature of these receptors has come into question insofar as the presynaptic inhibitory effects of the alpha 2-adrenoceptor agonist, clonidine, in the guinea-pig trachea have been shown to be antagonized by the alpha 2-adrenoceptor antagonist, yohimbine, as well as the alpha 1-adrenoceptor antagonist, prazosin. This inhibitory action of prazosin had not been described previously in the airways and may relate to the use of norepinephrine rather than clonidine as the alpha-adrenoceptor agonist in earlier studies. The present study evaluates the susceptibility of norepinephrine-induced inhibition of neurally-mediated cholinergic excitatory responses to antagonism by prazosin and yohimbine under conditions identical to those which showed clonidine to be sensitive to these antagonists. In tissues pretreated with guanethidine, propranolol and indomethacin, norepinephrine (1 microM) induced a 37-fold rightward shift of the frequency-response curve for neurally-mediated cholinergic contractions which was reversed partially by pretreatment of tissues with yohimbine. Norepinephrine also caused a concentration-dependent inhibition of cholinergic 'twitch' responses induced by intermittent (1 Hz) nerve stimulation. This action of norepinephrine was antagonized in a concentration-dependent manner by yohimbine but was unaffected by prazosin. These results indicate that in guinea-pig trachea the presynaptic inhibitory actions of norepinephrine on cholinergic nerves are mediated via classical alpha 2-adrenoceptors, i.e. receptors that can be blocked by yohimbine but not by prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)