Reversal of β-Agonist-Induced Refractoriness in Skin by Tetracaine and Mepacrine

Abstract

We previously reported that in skin slices stimulated by a beta-adrenergic agonist, the intracellular cyclic AMP level increased transiently. The level returned to a low steady state in 20-30 min and further stimulation by the agonist did not increase the cyclic AMP level. This state of "refractoriness" was found to be specific to the initial stimulator, i.e., histamine but not epinephrine could restimulate the cyclic AMP system after an initial exposure to epinephrine (Biochim Biophys Acta 497:428-436, 1977). We now report that incubation of skin with mepacrine or tetracaine after beta-adrenergic stimulation caused partial recovery from the refractoriness. Neither the simultaneous incubation of skin with epinephrine plus mepacrine (or tetracaine) nor preincubation of skin with mepacrine (or tetracaine) before the beta-adrenergic stimulation prevented the development of the refractoriness. Mepacrine inhibited the skin adenylate cyclase catalytic (or the complex of GTP-regulatory protein and catalytic) unit. The available data suggest that mepacrine and tetracaine interacted with the agonist-receptor complex at the cell membrane.