Cocaine and tracheal epithelial function: effects on short circuit current and neurotransmitter receptors
Farley, J.M.; Adderholt, J.G.; Dwyer, T.M.
Journal of Pharmacology and Experimental Therapeutics 259(1): 241-247
1991
ISSN/ISBN: 0022-3565 PMID: 1656021 Document Number: 387343
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 (Isc) and the changes in Isc (.DELTA.Isc) 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 Isc to increase in some tissues by 9 to 10 .mu.A in some preparations it induced only a decrease in basal Isc. The maximal decrease was 15 to 20 .mu.A in these preparations. In all tissues 14 mM cocaine decreased basal Isc. The IC50 for the cocaine inhibition of Isc 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.Isc 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 Isc (EC50 increased by .apprx. 6.3 and .apprx. 2.5 times, respectively) but did not reduce the maximal response. Cocaine displaced radioligands for muscarinic receptor s([3H]N-methylscopolamine, (3H]N-methylatropine) and beta adrenoceptors ([3H]dihydroalprenolol) from isolated epithelial cells with Ki 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.