ω‐Conotoxin GVIA‐resistant neurotransmitter release from postganglionic sympathetic nerves in the guinea‐pig vas deferens and its modulation by presynaptic receptors

Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea‐pig isolated vas deferens. Recently, a component of action potential‐evoked release which is insensitive to high concentrations of the selective N‐type calcium channel blocker ω‐conotoxin GVIA termed ‘residual release’ has been described. Under these conditions, release of the neurotransmitter ATP evoked by trains of low frequency stimuli is abolished, but at higher frequencies a substantial component of release is revealed. ‘Residual release’ was studied with trains of 5 or 10 stimuli at stimulation frequencies of 10, 20 and 50 Hz. The α2‐adrenoceptor agonist clonidine (30–100 nM) inhibited ‘residual release’, the degree of inhibition being most marked at the beginning of a train. The α2‐adrenoceptor antagonist yohimbine (1 μM) induced a marked increase in ‘residual release’ which was dependent on both the frequency of stimulation and the number of stimuli in a train. Prostaglandin E2 (30 nM) and neuropeptide Y (100 nM) caused a rapid inhibition of ‘residual release’ at all stimulation frequencies examined. 4‐Aminopyridine (100 μM) induced a powerful potential of ‘residual release’ and could reverse the inhibition of ω‐conotoxin GVIA. ‘Residual release’ was modulated through presynaptic α2‐adrenoceptors suggesting that (i) residual release of ATP is subject to α‐autoinhibition through the co‐release of noradrenaline, (ii) noradrenaline release can be triggered by calcium channels other than the N‐type and (iii) when presynaptic receptors are activated, inhibition of transmitter release can occur by mechanisms other than modulation of calcium‐entry through N‐type calcium channels in postganglionic sympathetic nerves. Prostaglandin E2 and neuropeptide Y also modulated neurotransmitter release. British Journal of Pharmacology (1998) 123, 167–172; doi:10.1038/sj.bjp.0701577