Ketamine and ditran block end-plate ion conductance and [³H]phencyclidine binding to electric organ membrane

Alterations by ketamine (10-100 μM) and ditran (50-100 μM) of end-plate currents were studies using transected cutaneous pectoris muscles. Both drugs reduced peak current and shortened the time constant for end-plate current decay (τ). Ketamine was more effective at pH 5.3 than at 7.4 or 9.1. Recovery from blockade was asymmetrical in that τ recovered more quickly than did peak current when the drugs were removed from the bath. By contrast, 4-aminopyridine antagonized the depression of peak current by ketamine, but not the reduction of τ. Both ketamine and ditran disrupted the voltage dependence of τ. The binding to microsacs prepared from electric organs of [³H]phencyclidine ([³H]PCP) was blocked by ketamine and ditran. In microsacs treated with carbachol, the IC₅₀ for ketamine block of [³H]PCP binding was 6.6 x 10^-6 M. For ditran, the IC₅₀ for block of [³H]PCP binding in the presence of carbachol was 1.7 x 10^-6 M. The binding of [α-¹²⁵I]bungarotoxin to the microsacs or to the cultured chick myotubes was reduced only slightly by ketamine. Because ketamine has no effect on transmitter release and little effect on [α-¹²⁵I]bungarotoxin binding, it is concluded that, like PCP, ketamine and ditran block open channels in the end-plate. In addition, the asymmetrical recovery of end-plate current parameters suggests that ketamine may block closed channels. The recovery from block of closed channels (caused by either a direct action on closed channels or a very slow channel unblocking rate) proceeds more slowly than does the block of open channels.