COCAINE AND TRACHEAL EPITHELIAL FUNCTION - EFFECTS ON SHORT-CIRCUIT CURRENT AND NEUROTRANSMITTER RECEPTORS

After snorting crystalline cocaine, the nasal and airway mucosa will be exposed to high concentrations of this drug. We have examined the actions of mucosal and serosal cocaine application on the basal short circuit current (I(sc)) and the changes in I(sc) (DELTA-I(sc)) induced by acetylcholine (ACh) and isoproterenol (ISO) across swine tracheal epithelium. Cocaine displacement of muscarinic receptor and beta adrenoceptor radioligands was also examined. Cocaine at low, < 1 mM, concentrations induced basal I(sc) to increase in some tissues by 9 to 10-mu-A In some preparations it induced only a decrease in basal I(sc). The maximal decrease was 15 to 20-mu-A in these preparations. In all tissues 14 mM cocaine decreased basal I(sc). The IC50 for the cocaine inhibition of I(sc) was 3 +/- 0.9 mM after mucosal application. Mucosal cocaine (3 mM) did not affect the actions of mucosal amiloride, an epithelial sodium channel blocker (IC50 = 0.6 +/- .1-mu-M, control; 1.5 +/- 0.3-mu-M, in the presence of 3 mM cocaine) or serosal tetraethylammonium, a potassium channel blocker. However, cocaine altered the response of the tissue to ACh and ISO. Cocaine (14 mM) applied mucosally reduced the maximal DELTA-I(sc) induced by ACh (serosal) to 34 +/- 14% of control. By contrast, serosal cocaine (3 mM) caused a parallel shift to the right in the concentration-response relationships for ACh- and ISO-induced increases in I(sc) (EC50 increased by approximately 6.3 and approximately 2.5 times, respectively) but did not reduce the maximal response. Cocaine displaced radioligands for muscarinic receptors ([H-3]N-methylscopolamine, [H-3] N-methylatropine) and beta-adrenoceptors ([H-3]dihydroalprenolol) from isolated epithelial cells with K(i) of 600 to 700-mu-M and 180-mu-M, respectively. Therefore, cocaine competitively inhibits neurotransmitter receptor interaction when applied serosally, and noncompetitively inhibits ACh-induced increases when applied mucosally. Thus, intranasal application of cocaine will have effects on the basal function and autonomic stimulation of mucosa.