Biphasic effect of tricyclic antidepressants on the release of norepinephrine from the adrenergic nerves of the rabbit heart.
The release of norepinephrine (NE) from the right atrium of the rabbit heart was used as a model to investigate biphasic effects due to tricyclic antidepressants, similar to those clinically observed in the treatment of depression and known as "therapeutic window". Strips of the atrium were loaded with 3H-NE, and then superfused by Krebs solution. The basal release and the electrical stimulation evoked release of 3H-NE were measured in the presence and absence of four clinically used tricyclic antidepressants: imipramine, amitriptyline, desipramine and nortriptyline. In addition, guanethidine, an adrenergic neuron blocker, was also studied. At lower concentrations (0.5-10 microM) tricyclic antidepressants increased, whereas higher concentrations (50-100 microM), inhibited the evoked release of NE. This inhibition was not prevented by the alpha2 adrenoceptor antagonist yohimbine, excluding the possibility of alpha 2 adrenoceptor-mediated inhibition of NE release. In higher concentrations the tricyclic antidepressants increased the basal release of NE in a Ca-independent way. Secondary amine derivatives were more potent inhibitors of the evoked release, and enhance the resting basal release of NE to a greater extent than the tertiary ones. Similarly, guanethidine (1-50 microM) also decreased the evoked release and increased the basal release of NE in a concentration dependent manner. Yohimbine failed to counteract the inhibition caused by guanethidine and the increment of the basal release was Ca-independent. It is concluded that the effect of tricyclic antidepressants in potentiating the release of NE is masked by their adrenergic neuron blocking properties, i.e. they inhibit the release of NE.(ABSTRACT TRUNCATED AT 250 WORDS)
Somogyi
G T
GT
Department of Psychiatry, University of Pittsburgh, PA 15213.
Perel
J M
JM
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006145:Guanethidine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010477:Perfusion; D011817:Rabbits; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D015016:Yohimbine / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D015016:Yohimbine; D002118:Calcium; D009638:Norepinephrine; D006145:Guanethidine