Desensitization of the cholinergic receptor at the sinoatrial cell of the kitten.

The hyperpolarizing effects of long periods of vagal stimulation were studied in kitten sinoatrial node-vagus nerve preparations. Verapamil (2.2 x 10(-6) M) was used to arrest spontaneous pacemaker activity, thus permitting uninterrupted observation of the time course of cholinergically mediated hyperpolarizations. With progressively longer vagal trains the hyperpolarization was not maintained but decreased, rapidly at first, and then more gradually despite continuous vagal stimulation. Similar decay of the cholinergic effect was also observed during continuous iontophoretic application of acetylcholine (ACh) or carbamylcholine (CCh). The results show that, for the most part, the decay of the hyperpolarizing response cannot be due to "fatigue" of nerve terminals, to a gradual reduction in the driving force for K+, or to hydrolysis of ACh by cholinesterase. These experiments demonstrate the development of desensitization of the cholinergic receptor at the sinoatrial cell membrane. The data fit the "cyclic reaction" model proposed by Katz and Thelsleff (J. Physiol. London 138:63-80, 1957) for the neuromuscular junction.