1. Miniature end‐plate potentials (min.e.p.p.s) were recorded intracellularly from frog neuromuscular junctions. 2. The ‘phasic’ release of transmitter which is directly related to nerve impulses was suppressed by withdrawal of Ca from the external medium plus addition of Mg. 3. Under these conditions, min.e.p.p.s continued to be discharged even when EGTA was added, although in this case min.e.p.p. frequency appeared to decrease to about half the rate in normal Ringer. 4. Tetanic stimulation of the nerve approximately doubled the rate of min.e.p.p.s even in Ca‐free solutions with EGTA added. 5. The tetanic increase in frequency was greater without EGTA and greater still with some Ca added. Therefore, it is concluded that the tetanic rise in min.e.p.p. frequency can occur even in the absence of the immediate ‘phasic’ release of transmitter normally induced by nerve impulses; and that the magnitude of the increase is related to Ca concentration. A possible relation between ‘phasic’ and ‘residual’ effects of nerve impulses is described.

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Failure of muscular contraction during repetitive stimulation of motor nerves has been attributed to transmission block of neuromuscular junctions rather than to inexcitability of nerves or muscles (Waller, 1885; Wedensky, 1884, 1891). Such neuromuscular 'fatigue' is known to occur during prolonged stimulation at frequencies above 40/sec (Rosenblueth, 1950). Rapid stimulation and resultant failure, however, may be unrelated to natural activity because motor nerve fibres discharge during brief reflexes for only fractions of a minute at rates approximating 50/sec. During sustained contractions motor units discharge at rates between 5 and 25/sec (Adrian & Bronk, 1929). At these frequencies some form of presynaptic block may occur: repetitive stiniulation of muscles perfused with Locke's solution at 5-15/sec for several minutes leads to neuromuscular failure and cessation of transmitter release (Dale, Feldberg & Vogt, 1936). This result has been attributed to depletion of acetylcholine (ACh) content of motor nerve terminals (Rosenblueth, Lissak & Lanari, 1939), but failure may have been due to anoxia since muscles perfused with blood maintain their ability to contract (Emmelin & MacIntosh, 1956). Although depletion of ACh content is unlikely, evidence for reduction of ACh release per volley has been produced by del Castillo & Katz (1954b) for frog nerve-muscle preparations stimulated at 2-5/sec. It was suggested that this might forestall exhaustion of ACh content (del Castillo & Katz, 1956).The present experiments were designed to test if ACh release is similarly depressed during stimulation of mammalian nerve-muscle preparations at the moderate rates occurring during natural contractions. It will be shown that stimulation at rates up to 20/sec may cause reduction of ACh release per volley, but that this peripheral event is probably not a major rate limiting factor. A preliminary report of some of the findings has already appeared (Thies, 1960). REDUCED QUANTUM CONTENT 299 METHODS Preparations. Guinea-pigs' serratus muscles were irrigated with physiological saline solution in a 6 ml. Perspex bath; nerves were supported in an adjacent pool of paraffin oil and connected to the muscle bath through a slot filled with petroleum jelly (Brooks, 1956). Physiological saline solutions were warmed to 40°C or left at room temperature (23-25°C) and equilibrated with 95 % 02 and 5 % C02 in 21. reservoirs. Solutions flowed through the bath at 200-300 ml./hr; a thermistor indicated that warmed solutions were at 33380 C while in the bath.Irrigating solutions and drugs. Muscles were irrigated with a modified Krebs's solution whose composition (except where otherwise stated) was (mM): Na+ 143-4, K+ 5-6, Ca2+ 158, Mg2+ 1-0, HCO3-23-8, Cl-130-8 and glucose 5-5 (cf. Creese, Scholes & Taylor, 1958). The solution contained the high bicarbonate concentration, but the phosphate and sulphate of Krebs & Henseleit (1932) were omitted. In many experiments the concentrations of both calcium and magnesium ions were increased four to five ti...

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