Effects of guanidine on transmitter release and neuronal excitability.

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Abstract
1. Guanidine hydrochloride (CH5N3‐HCl) was applied to frog neuromuscular junctions blocked by reduced external Ca2+, or increased external Mg2+ concentration, or by both. Guanidine produced a dose‐dependent increase in the average number of quanta released by presynaptic action potentials, the threshold dose being 0‐1‐0‐2 mM. No post‐synaptic effects were observed. 2. Guanidine also increased the excitability of the motor nerve fibres, as evidenced by multiple firing to single electrical stimuli and finally by spontaneous action potentials. These effects were studied in greater detail in giant axons (Müller axons) in the spinal cord of lamprey. Exposure to guanidine produced in these axons a progressive increase in excitability, manifested by repetitive firing to a single electrical stimulus, spontaneous membrane potential oscillations and spontaneous bursts of action potentials. Guanidine had no effect on the resting potential. 3. The effect of guanidine on the excitability of Müller axons was mimicked in every detail simply by reducing the divalent cation concentration of the bathing solution. 4. Guanidine also produced dose‐dependent increases in the duration of action potentials in Müller axons. This effect always preceded in time the appearance of the excitability effects and was not mimicked by reducing the divalent cation concentration. It is suggested that the broadening of the action potential is separate from the excitability effects and may reflect a decrease of delayed rectification. 5. Guanidine (0‐3 mM) increased the frequency of miniature end‐plate potentials (min. e.p.p.) in solutions containing 2‐11 mM‐K+ in such a way as to shift the relationship between min. e.p.p. frequency and extracellular K+ toward lower values of K+. This effect was interpreted to mean that guanidine produced a depolarization of the nerve terminal which summed with the depolarization produced by a given concentration of K+. The calculated depolarization produced by 0‐3 mM guanidine was 5‐7 mV. 6. The effects of guanidine on evoked transmitter release, excitability, and min. e.p.p. frequency are consistent with a hypothesis which states that guanidine binds at or near fixed negative changes on the outside of nerve membrane and reduces the screening effect of divalent cations.