Endplate channel block by guanidine derivatives.

Abstract

The effects of the n-alkyl derivatives of guanidine on the frog neuromuscular junction were studied using the two-microelectrode voltage clamp and other eleetrophysiological techniques. Methyl-, ethyl-, and propylguanidine stimulated the nerve-evoked release of transmitter. However, amyland octylguanidine had no apparent presynaptic action. All of the derivatives blocked the postsynaptic response to acetylcholine, the potency sequence being octyl-> amyl-> propyl-, methyl-> ethylguanidine. Methyl-and octylguanidine did not protect the receptor from a-bungarotoxin block, suggesting that these compounds do not bind to the receptor but probably block the ionic channel. Methyl-, ethyl-, and propylguanidine shortened inward endplate currents but prolonged outward currents. Amylguanidine prolonged both inward and outward endplate currents, and the currents became biphasic at negative membrane potentials. Octylguanidine increased the rate of decay of endplate currents at all potentials. All of the derivatives blocked inward endplate currents more markedly than outward currents, resulting in a highly nonlinear current-voltage relation. Methyl-, ethyl-, and propylguanidine reversed the voltage dependence of endplate current decay, while amyl-and octylguanidine reduced the voltage dependence of endplate current decay. Octylguanidine appears to block the ionic channel in both the open and the closed state. The block of the open channel follows pseudo-first-order kinetics with a forward rate constant of 4-6 • 107 M -1 s-1.

The interaction between hexamethonium and tubocurarine on the rat neuromuscular junction

“…piperocaine, quinacrine, histrionicotoxin) on the endplate (see Albuquerque et al, 1974;Adler et al, 1979;Tiedt et al, 1979;Adams & Feltz, 1980 a,b; Farley et al, 1981), for which the most usual explanation is binding to closed ionic channels, thus affecting the amplitude but not the time course of endplate currents. In summary, we suggest that the Tc reversal seen with C6 at the mammalian endplate results from (a) a competitive interaction at the receptors as postulated by Ginsborg & Stephenson (1974) and (b) a weak anticholinesterase effect.…”

Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog.

“…amplitude (Pennefather & Quastel, 1980;Farley, Yeh, Watanabe & Narahashi, 1981;Vogel, Yeh & Narahashi, 1983). If a series of structurally related compounds were all found to produce prolonged changes in channel kinetics with a longer chain congener independently producing additional transient effects characteristic of open-channel block, then the view that the biphasic decay reflects persistent changes in channel kinetics would be rendered unlikely for that drug.…”

The charge carried by single‐channel currents of rat cultured muscle cells in the presence of local anaesthetics.

“…A wealth ofexperimental data regarding the effects on nerve and muscle membrane of local anaesthetics and related drugs has been interpreted by a mechanism of channel blockade (Adams, 1976;Hille, 1977;Ruff, 1977Ruff, , 1982Ascher, Marty & Neild, 1978;Neher & Steinbach, 1978;Colquhoun & Sheridan, 1981;Farley, Yeh, Watanabe & Narahashi, 1981;Gage & Hamill, 1981). More specifically, a model where ionic channels can be blocked only after they have opened, and where channels can close only after unblocking, has been found satisfactory in many cases.…”