Desensitization of the adrenergic neurons of the isolated rabbit ear artery to nicotinic agonists.

At 37 degrees C the vasoconstrictor response of the isolated, perfused rabbit ear artery to an infusion of nicotine or acetylcholine (ACh) was transient--rising rapidly to a peak and then fading completely within a minute or two. After complete fade of the response during continued infusion of either nicotine or ACh (in the presence of atropine), the vasoconstrictor responses to stimulation of periarterial adrenergic neurons or to infused norepinephrine (NE) were not diminished. The fade of response was attributed to desensitization of nicotinic receptors at the adrenergic nerve terminals on which nicotine and ACh act to release NE. On washout of either nicotinic agonist after development of desensitization, recovery of sensitivity was essentially complete within several minutes, provided that neither excessively high concentrations nor excessively long periods of infusion had been used. The rate of desensitization to nicotine of ACh increased with concentration of the agonist. On infusion of high concentrations (200 mug/ml) of either, the time required for full desensitization was estimated to be less than 5 seconds. Cross-desensitization was demonstrated for nicotine, ACh and tetramethylammonium. Considerable desensitization occurred even on infusion of nicotine (1 mug/ml) slightly below that required to give a threshold vasoconstrictor response. Moreover, full desensitization without any preceding vasoconstrictor response could be obtained if the concentration of infused nicotine was gradually increased from an initial subthreshold to a final very high suprathreshold level over a 20- to 30-minute period. Both the rate and degree of desensitization to nicotine decreased as the temperature was decreased from 37 degrees to 27 degrees C. The present results are consistent with the concept that the nicotinic receptor (or receptor mechanism) at the adrenergic nerve terminal, after being activated as a result of combination with the agonist, can undergo a transformation to an inactive or desensitized state. It is proposed that under conditions where desensitization to the agonist develops in the absence of any vasoconstrictor response, the fraction of receptors in the activated state at any instant in time during the development is too small to trigger the release of NE.