Prejunctional nicotinic receptors involved in facilitation of stimulation-evoked noradrenaline release from the vas deferens of the guinea-pig

Abstract

In guinea-pig prostatic vas deferens loaded with [3H]-noradrenaline ([3H]-NA), nicotinic receptor agonists, nicotine and dimethylphenylpiperazinium (DMPP) enhanced the resting and facilitated the stimulation-evoked release of [3H]-NA in a concentration-dependent fashion. The effect of nicotine on both contraction of vas deferens and release of NA in response to field stimulation was stereospecific in favour of the naturally occurring (-)-enantiomer. Prolonged (15 min) exposure to (-)-nicotine resulted in a cessation of the facilitatory effect on NA release and on responses of the vas deferens to field stimulation. 2 The rank order of agonist potency in facilitating NA release was DMPP = (-)-nicotine greater than (+)-nicotine. Cytisine had no agonistic activity. The dissociation constants (KD) of antagonists were 9.3 +/- 0.6 and 31.4 +/- 2.4 microM for (+)-tubocurarine and hexamethonium, respectively, when (-)-nicotine was used as agonist. alpha-Bungarotoxin had no antagonistic activity. These findings suggest that nicotinic receptors located on noradrenergic axon terminals are different from those located postsynaptically in striated muscle or ganglia but seem similar to those present on cholinergic axon terminals at the neuromuscular junction. 3. Cotinine, the breakdown product of nicotine failed to have any agonistic activity indicating that nicotine itself is responsible for the effects observed on axon terminals. 4 Stimulation of presynaptic muscarinic receptors by oxotremorine prevented the nicotine-induced facilitation of [3H]-NA release, indicating the presence of both inhibitory muscarinic and facilitatory nicotinic receptors on noradrenergic axon terminals.