A hypothesis to explain the presynaptic effects of adrenoceptor antagonists.

The hypothesis of negative feedback regulation of transmitter release was examined in a range of tissues obtained from three species. Tissues were transmurally stimulated with 100 pulses at 2 Hz with pulse durations from 50 microseconds to 5,000 microseconds, and the efflux of [3H]-noradrenaline determined. The stimulation-induced efflux of tritium increased with increasing pulse duration, but yohimbine, a prototypal alpha 2-antagonist had an effect which was consistently contrary to expectations for a negative feedback system. Enhancement of efflux by the antagonist, supposedly correlated directly with the extent of ongoing auto-inhibition, became smaller rather than larger as the stimulation-induced efflux rose with increases in pulse duration, with all other parameters of stimulation maintained constant. Similar findings were obtained in rat spleen with the haloalkylamine antagonist, phenoxybenzamine. It is concluded that the presynaptic effects of adrenoceptor antagonists do not involve a negative feedback function nor do they relate, in any detectable way, to the extracellular concentration of transmitter. The effects on stimulation-induced tritium efflux of yohimbine, phenoxybenzamine and enlargment of the pulse duration, in a variety of tissues, support the previously described hypothesis of a common action to enhance efflux. The antagonists increased efflux to approximately the same value between 50 and 1,000 microseconds pulse durations and that value was equivalent to that obtained in each given tissue with pulses of 1,000-2,000 microseconds in the absence of the antagonist. Tetraethylammonium, an inhibitor of stimulation-induced potassium efflux from nerves had an effect on transmitter efflux in rat spleen essentially like that of the adrenoceptor antagonists. These findings provide further support for an alternative to the hypothesis of negative feedback. Yohimbine and other presynaptic antagonists may prolong the period of potassium efflux from nerve varicosities, and by this means prolong depolarization and the associated period of transmitter release, rather than act by disrupting an ongoing system sensing and responding to fluctuations in extracellular transmitter levels.