Caffeine-induced blockade of neuromuscular transmission and its reversal by dantrolene sodium.

Caffeine, 10(2) M, blocked the indirectly stimulated rat phrenic nerve-diaphragm preparation at 37 degrees C. Dantrolene, above 2.25 x 10(-7) M, reversed the blockade. Microelectrode recordings showed a gradual reduction of the end plate potential (EPP) amplitude following a period of facilitation. An increased frequency of miniature (EPPs was still recorded after complete EPP blockade. A presynaptic blockade of stimulus-secretion coupling caused by an effect upon Ca2+ balance is suggested. Caffeine may release and deplete Ca2+ from the smooth endoplasmic reticulum (SER) in the nerve terminals. This Ca2+ may be sequestered by the mitochondria. The blockade suggests that the SER may also supply Ca2+ to another intraterminal release site which is necessary for stimulus-secretion coupling. This site is unaffected by caffeine and dantrolene. The dantrolene reversal may result from inhibition of the caffeine-induced release from the same Ca2+ pool. The facilitatory effects of caffeine were not antagonized by dantrolene and may result from Ca2+ release from another pool.