Decamethonium both opens and blocks endplate channels.

Abstract

Miniature endplate currents, endplate current fluctuations ("membrane noise"), and voltage-jump current relaxations were studied in voltage-clamped frog muscle fibers during decamethonium action. All three types of experiments revealed two kinetic processes controlling the opening of endplate channels, one that reflects agonist action and another that reflects local anesthetic-like blocking activity. The kinetic constants for these two steps were evaluated from measurements of the fast and slow time constants as a function of decamethonium concentration. At -130 mV membrane potential and 130, the mean open time of decamethonium-activated channels is 2.8 msec. The forward and backward rate constants for channel blocking are -1.7 X 107 M l sec. and 103 sec-1. ITe voltage dependencies of the channel lifetime and of the blocking equilibrium are similar to those seen with pure agonists and local anesthetics, respectively. The transmitter at the nerve-muscle synapse of vertebrate skeletal muscle, acetylcholine (AcCho), acts by combining with postjunctional receptors and inducing the opening of discrete ion channels (1-3).A number of other quaternary ammonium compounds mimic this action of acetylcholine, although for some of them the maximum effect is quite feeble. Compounds that produce only small maximum potential or conductance changes are termed partial agonists. It has been generally supposed that these agonists are partial because they are relatively ineffective in triggering the conformational change of the receptor necessary for channel opening, either because the rate constants for this conformational change are such that the resting state is favored (4)

The channel‐blocking action of methonium compounds on rat submandibular ganglion cells

“…The value for decamethonium binding to the fast channel, 1.58 x 107 M-1s-I at -80 mV, is similar to the estimate by Adams & Sakmann (1978) of its rate of binding to ACh-operated channels at the frog neuromuscular junction measured at -130 mV (1.71 x 107 M-'s-1). A plot of the rates of association to the two kinds of channel against the chain length of the methonium drugs (Figure 4) shows some variation but no obvious pattern in the structure-activity relationship.…”

“…The third component was slower, and was further slowed by hyperpolarisation (see Figure 2); it was taken to represent unblocking of open channels as the drug dissociates (Adams, 1976;Adams & Sakmann, 1978). The presence of this slow component introduces more uncertainty into the estimates of the association rate constants, partly because of the problem of resolving the three exponential components, and partly because we cannot be sure that kis small enough to justify the use of equations (1) and (2).…”

Agmatine acts as an antagonist of neuronal nicotinic receptors

“…This possibility seems more plausible since the chemically similar compound, decamethonium, appears to travel through the muscle nicotinic receptor channel (Creese & Maclagan 1970). In addition, decamethonium has been shown to block the muscle nicotinic receptor channel at high concentrations (Adams & Sakmann, 1978). Hexamethonium is believed to act by blocking neuronal nicotinic receptor channels at effective doses (Ascher et al, 1979).…”

Conductance and kinetic properties of single nicotinic acetylcholine receptor channels in rat sympathetic neurones.

“…Gaps briefer than 200 ,us were left unfitted in each case, as they are difficult to distinguish at high agonist concentrations and should be relatively independent of agonist concentration. (Adams & Sakmann, 1978;Sine & Steinbach, 1984; Ogden Marshall, Ogden & Colquhoun, 1990). Another method that we used to quantify the channel block by DMPP was to measure the number of blockages per unit open time at different agonist concentrations (Ogden & Colquhoun, 1985).…”