Omega-conotoxin GVIA-resistant neurotransmitter release from postganglionic sympathetic nerves in the guinea-pig vas deferens and its modulation by presynaptic receptors.

1 Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea-pig isolated vas deferens. 2 Recently, a component of action potential-evoked release which is insensitive to high concentrations of the selective N-type calcium channel blocker omega-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. 3 'Residual release' was studied with trains of 5 or 10 stimuli at stimulation frequencies of 10, 20 and 50 Hz. The alpha2-adrenoceptor agonist clonidine (30-100 nM) inhibited 'residual release', the degree of inhibition being most marked at the beginning of a train. 4 The alpha2-adrenoceptor antagonist yohimbine (1 microM) induced a marked increase in 'residual release' which was dependent on both the frequency of stimulation and the number of stimuli in a train. 5 Prostaglandin E2 (30 nM) and neuropeptide Y (100 nM) caused a rapid inhibition of 'residual release' at all stimulation frequencies examined. 6 4-Aminopyridine (100 microM) induced a powerful potential of 'residual release' and could reverse the inhibition of omega-conotoxin GVIA. 7 'Residual release' was modulated through presynaptic alpha2-adrenoceptors suggesting that (i) residual release of ATP is subject to alpha-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.