Degeneration of sympathetic nerves in vitro and development of smooth muscle supersensitivity to noradrenaline.

1. The sequence of events involved in degeneration of sympathetic nerve terminals has been studied in vitro in the expansor secundariorum muscle of the chicken.2. The muscle underwent a degeneration contraction due to abrupt release of noradrenaline stores from the nerves about 18 hr after isolation. The tension reached its peak within 6 hr at about 44% of the maximum tension developed to added noradrenaline.3. Responses to nerve stimulation were transiently potentiated by 35% on average just before the onset of the degeneration contraction and then failed abruptly.4. Degeneration release of noradrenaline was Ca(2+)-dependent. Development of the degeneration contraction was delayed by temporary withdrawal of Ca(2+) from the medium and was accelerated by a twofold increase in Ca(2+) concentration when applied at a critical period close to the onset.5. Neither continuous nerve stimulation nor alterations in the length of the nerve stump influenced the course of the degeneration contraction in vitro.6. When the muscle was left in situ after denervation, the degeneration contraction occurred between 2 and 3 days later depending on the length of the distal portion of nerve. Cutting the nerve supply 5 cm closer to the muscle in vivo hastened the loss of transmission and the onset of the degeneration contraction by 24-48 hr.7. Supersensitivity to noradrenaline occurred soon after the degeneration contraction but the full development of a sevenfold supersensitivity to noradrenaline, equivalent to that produced by cocaine, took up to 48 hr. No further increase in sensitivity to noradrenaline could be detected in vitro after chronic denervation in vivo for up to 30 days.8. It is concluded that the degeneration contraction and failure of transmission was precipitated by an abrupt increase in the Ca(2+) permeability of the axon causing discharge of transmitter from vesicles. This was probably the result of depletion of essential factors normally transported somatofugally in the axon at 1-2 mm/hr. The supersensitivity to noradrenaline that develops subsequently appears to be due to a loss of the uptake mechanism of the nerve terminals.