Relationships between chronotropic effect, 1 3H noradrenaline uptake and tissue concentrations of desipramine, protriptyline and doxepin in rat isolated atria

The pharmacological effects of three tricyclic antidepressant agents (desipramine, protriptyline and doxepin) are evaluated in rat isolated atria in relation to their accumulation and efflux kinetics. The pharmacological effects studied are: inhibition of 1 ³H noradrenaline uptake, potentiation of 1 noradrenaline chronotropic response, and changes in spontaneous atrial rate. All drugs inhibit noradrenaline uptake and potentiate noradrenaline chronotropic response (desipramine ∞ protriptyline > doxepin). Desipramine and protriptyline, at concentrations of 10 ^-7-10 ^-6 M stimulate the spontaneous rate; higher concentrations (>10 ^-6 M) depress it. Doxepin has only a negative chronotropic effect. When the drugs are removed from the incubation medium, the depressing effect starts to disappear immediately for doxepin and desipramine and after 20 min for protriptyline. On the contrary the stimulating effect persists after repeatedly washing the preparations. Desipramine, protriptyline and doxepin extensively accumulate in the myocardial tissue (desipramine ≥ protriptyline > doxepin). In the efflux studies doxepin is washed out more rapidly than desipramine and protriptyline. Although the kinetics of uptake and efflux of the three compounds are not sufficient to interpret their different pharmacological activities in isolated atria, they give useful information on the persistence of the sympathomimetic effect and the rapid disappearing of the negative chronotropic effect after washing.