QUANTITATIVE ASSESSMENT OF THE PRE-SYNAPTIC AND POSTSYNAPTIC ALPHA ADRENOCEPTOR ANTAGONIST POTENCY OF AMITRIPTYLINE
- 1 January 1982
- journal article
- research article
- Vol. 220 (2) , 299-304
Abstract
The pre- and postsynaptic .alpha.-adrenoceptor blocking affinity of amitriptyline [a tricyclic antidepressant] was determined in isolated tissues by Schild regression analysis. In the absence of uptake-1 blockade with cocaine, amitriptyline treatment (3 .times. 10-8-3 .times. 10-6 M) marginally affected norepinephrine [NE] concentration-response curves in the rat anococcygeus muscle, a result suggesting opposing pharmacological effects (uptake-1 blockade and .alpha.-blockade). After cocaine (3 .times. 10-5 M) treatment, amitriptyline (3 .times. 10-8-3 .times. 10-6 M) antagonized competitively concentration-response curves to NE, yielding a postsynaptic pKb of 7.51. A similar pKb was obtained when methoxamine was the agonist. Presynaptic .alpha.-blocking affinity was determined by using the field-stimulated rat vas deferens. Stimulus conditions were chosen which minimized the inhibition of twitch height by high concentrations of cocaine. Using these conditions (10 Hz, 200 ms duration at 100-s intervals), amitriptyline competitively antagonized clonidine inhibition of field-stimulated twitch contractions, yielding a pKb of 5.23. The presynaptic pKb was not changed in the presence of theophylline (10-4 M). Amitriptyline increased the release of [3H]NE from the field-stimulated rat anococcygeus muscle pretreated with cocaine. Although this effect primarily reflects .alpha. blockade, other biochemical and presynaptic mechanisms may be involved. Comparing the pre- and postsynaptic .alpha.-blocking affinities indicates that amitriptyline has 191 times greater affinity for post- than presynaptic .alpha.-adrenoceptors (i.e., .alpha.-1 .mchgt. .alpha.-2). The relevance of these observations to the mechanism of action and side effects of amitriptyline are discussed.This publication has 0 references indexed in Scilit: