Noradrenaline action on nerve terminal in the rat diaphragm.

1. The mechanism by which noradrenaline increases the release of transmitter from the nerve terminal was investigated in the rat diaphragm.2. Increase of the frequency of the miniature end-plate potential (m.e.p.p.) was exponential when plotted against the intensity of a constant current which depolarized the nerve terminal. Noradrenaline (5 x 10(-6) g/ml.) did not change the slope of the curve showing the relationship between the logarithm of the frequency of m.e.p.p.s and the depolarizing current (m.e.p.p.-current relationship), but simply shifted the curve along the axis of the current towards weaker intensities.3. End-plate potentials (e.p.p.s) were evoked by passing a brief depolarizing pulse to the nerve terminal in the presence of tetrodotoxin (1 x 10(-7) g/ml.). A sigmoidal relationship was obtained between the amplitude of e.p.p. and the intensity of the current pulse (e.p.p.-current intensity relationship). Noradrenaline (5 x 10(-6) g/ml.) shifted the e.p.p.-current intensity relationship along the axis of the current intensity to smaller values, without any change in the maximum amplitude of e.p.p.s.4. The frequency of m.e.p.p. was increased, as the [Ca](0) was raised from 0.01 to 7.5 mM. An increase in [Ca](0) beyond the normal concentration (2.5 mM) had no remarkable effect on the action of noradrenaline. However, when [Ca](0) was reduced, the action of noradrenaline became weaker.5. A kinetic model in which the transmitter release is modified by the binding of Ca with a specific site in the nerve terminal may explain the results. According to this model, noradrenaline did not change the dissociation constant of the reaction between Ca and the specific site (X), but increased the rate constant of the Ca complex (CaX) for releasing acetylcholine.6. The action of noradrenaline was potentiated when [Na](0) was reduced, and suppressed when [Mg](0) was increased. The results may be summarized: that noradrenaline augments the probability of release of transmitter quanta from the resting nerve terminals and that this action can be intensified by first raising the probability of release by some other means. Depolarization of the nerve terminals by current, increase of the external Ca concentration, decrease of Na and decrease of Mg are all effective in promoting the action of noradrenaline.