Summary
Dose-response curves for (−)-noradrenaline, (−)-adrenaline and (−)-phenylephrine were determined on isolated nictitating membranes after pretreatment with reserpine (to impair vesicular retention of the amines), with pargyline (to block monoamine oxidase, MAO), or with both. Sensitivity was found to be increased by reserpine < pargyline < combined pretreatment. In addition, pretreatment with pargyline increased the slope of dose-response curves as well as the time required for the development of steady-state responses. The degree of supersensitivity to (−)-phenylephrine induced by the combined pretreatment was nearly as great as that produced by denervation. For (−)-noradrenaline and (−)-adrenaline it was smaller than that seen after denervation. Evidence is presented in favour of the view that desensitization to (−)-noradrenaline develops during prolonged exposures to this amine. The pretreatments had no effect on the sensitivity of the denervated membrane to the three amines.
The results are in agreement with the view that any impairment of the intraneuronal mechanisms of inactivation (vesicular retention and MAO) leads to supersensitivity by causing a decrease in the neuronal net uptake of the amines. This type of supersensitivity differs from that seen after denervation in that responses take a very long time to reach a steady state. It is suggested that the time course of the responses reflects a slowly developing exhaustion of the capacity of the nerve endings to inactivate the amines after their uptake. This type of supersensitivity should occur in all organs which have a dense and intimate adrenergic innervation.
The slowly increasing response seen after block of MAO has its counterpart in a very slow relaxation which is seen after an initial phase of quick relaxation. The evidence of this and other studies indicates that a slow efflux of noradrenaline from the neuronal cytoplasm is responsible for the second phase of slow relaxation. Apparently, relaxation can be slowed not only by a decrease in rate of inactivation of the amine but also by an escape of the amine from the neuronal cytoplasm.
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This study was supported partly by Research Grant NB-07131 from the National Institutes of Health, US Public Health Service, and partly by the Deutsche Forschungsgemeinschaft.
With the technical assistance of Miss Roneen D. Hobbs.
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Trendelenbubg, U. Supersensitivity of the isolated nictitating membrane of the cat to sympathomimetic amines after impairment of the intraneuronal mechanisms of inactivation. Naunyn-Schmiedebergs Arch. Pharmak. 271, 29–58 (1971). https://doi.org/10.1007/BF01002172
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DOI: https://doi.org/10.1007/BF01002172