Large doses of nicotine produce a prolonged blockade of ganglionic nicotinic receptors. Unlike the blockade of ganglionic transmission produced by most ganglionic blocking agents, that is, a nondepolarizing competitive antagonism, the blockade produced by nicotine consists of two phases. Phase 1 can be described as persistent depolarization of the ganglion cell. The initial application of nicotine to the ganglion cells depolarizes the cell, which initiates an action potential. After a few seconds, however, this discharge stops and transmission is blocked. At this time, antidromic stimuli fail to induce an action potential. In fact, during this phase, the ganglia fail to respond to the administration of any ganglionic stimulant, regardless of the type of receptor it activates. The main reason for the loss of electrical or receptor-mediated excitability during a period of maintained depolarization is that the voltage-sensitive sodium channel is inactivated and no longer opens in response to a brief depolarizing stimulus. During the latter part of phase 1, all ganglionic stimulants that are not nicotinic, such as histamine, angiotensin, bradykinin, and serotonin, become effective.
Phase 1 is followed by a postdepolarization phase (phase 2) during which only the actions of nicotinic receptor agonists are blocked. This phase takes place after nicotine has acted for several minutes. At this time, the cell partially repolarizes, and its electrical excitability returns. The main factor responsible for phase 2 block appears to be desensitization of the receptor to ACh, which causes transmission failure.
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