Summary 1. Indirect and direct twitch (0.1-Hz) stimulation of the rat phrenic nerve-diaphragm disclosed that the inhibitory effect of HgCl
2, 3.7 × 10
–5
M, on the neuromuscular transmission and in the muscle cell, was accelerated by 10-sec periods of 50-Hz tetanic stimulation every 10 min. This activity-dependent enhancement suggested an inhibitory mechanism of HgCl
2 related to the development of fatigue, like membrane depolarization or decreased excitability, decreased availability of transmitter, or interference with the factors controlling excitation-secretion coupling of the nerve terminal, i.e. (Ca
2+)
0 or (Ca
2+)
i, and excitation-contraction coupling in the muscle cell, i.e., (Ca
2+)
i.2. During both indirect and direct stimulation, HgCl
2-induced inhibition was enhanced markedly by pretreatment with caffeine, which releases Ca
2+ from endoplasmic and sarcoplasmic reticulum in the nerve terminal and muscle cell, respectively. This caffeine-induced enhancement was completely antagonized by dantrolene, which inhibits the caffeine-induced release. However, dantrolene alone did not antagonize the HgCl
2-induced inhibition.3. Since caffeine depletes the intracellular Ca
2+ stores of the smooth endoplasmic reticulum, HgCl
2 probably inhibits by binding to SH groups of transport proteins conveying the messenger function of (Ca
2+)
i. In the muscle cell this leads to inhibition of contraction. In the nerve terminal, an additional enhancement of the HgCl
2-induced inhibition, by inhibiting reuptake of choline by TEA and tetanic stimulation, suggested that HgCl
2 inhibited a (Ca
2+)
i signal necessary for this limiting factor in resynthesis of acetylcholine.4. The (Ca
2+)
0 signal necessary for stimulus-induced release of acetylcholine was not affected by HgCl
2. Hyperpolarization in K
+-free solution antagonized the inhibitory effect of HgCl
2 at indirect stimulation, and Ca
2+-free solution enhanced the inhibitory effect at direct stimulation. K
+ depolarization, membrane electric field increase with high Ca
2+, membrane stabilization with lidocaine, and half-threshold stimulation, did not change the inhibitory effect of HgCl CH
3HgCl, 1.85 × 10
–5
M, disclosed a synergistic interaction with caffeine during direct, but not during indirect, stimulation.
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