Antagonism by tricyclic antidepressants of the muscarinic receptors located on the adrenergic nerve endings in rabbit heart atrium

GT Somogyi and JM Perel

Western Psychiatric Institute and Clinic, University of Pittsburgh, Pennsylvania.

Strips of right atrial tissue obtained from male New Zealand rabbits were incubated in Krebs' buffer containing 10 mu Ci/ml of [3H]norepinephrine at 37 degrees C. After washing for 90 min with Krebs' solution containing 10 microM cocaine and 1 microM yohimbine, 2- min effluents were collected for 96 min. The preparations were stimulated 4 times for 3 min, S1, S2, S3 and S4 (field stimulation: 2 Hz, 1 msec, 60 V), and the tritium content of the samples was measured by scintillation spectrometry. S1 served as a control and at S2-4 oxotremorine dose-response curves were taken expressing the dose- related inhibition of the evoked release of [3H]norepinephrine as percentage of the control. Atropine shifted the dose-response curve to the right in a parallel fashion but the antagonism was noncompetitive in as much as the equilibrium constant was smaller at lower concentrations than at higher one (2.3 and 5.8 nM, respectively). The tricyclic antidepressants also displaced the dose-response curve to the right in a parallel fashion but their inhibitory effects were two orders of magnitude lower and the maximal inhibitory effect was reached at around 5 microM also proving the noncompetitive nature of the antagonism. These results are in good correlation with isolated muscarinic receptor binding studies as well as with the cardiac side- effects of tricyclic antidepressants experienced in the course of clinical administration.

Volume 251, Issue 3, pp. 922-928, 12/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics