Influence of amitriptyline, chlorpromazine, and imipramine on the activity of phosphohydrolases

We have studied the effects of the antidepressants amitriptyline and imipramine and the neuroleptic chlorpromazine on the enzymatic function of Ca²⁺-activating-Mg²⁺-dependent ATPase of sarcoplasmic reticulum (SR), Na⁺, K⁺-dependent ATPase of endoplasmic reticulum (ER), and phosphodiesterase of cyclic adenosine monophosphate (cAMP). It is shown that interference with the enzymatic function (decrease of [Ca²⁺]/[ATP]) or inhibition of active transport of calcium ions by Ca²⁺, Mg²⁺-ATPase of SR by the psychotropic drugs leads to impairment of Ca²⁺ transport into the SR vesicule, which increases the force of muscle contraction. This effect decreases with increasing concentrations of amitriptyline and imipramine and with decreasing concentration of chlorpromazine, which is evidence for different mechanisms of action of Ca²⁺, Mg²⁺-ATPase of SR. Amitriptyline was a noncompetitive reversible inhibitor of Ca²⁺, Mg²⁺-ATPase of SR with an ATP hydrolysis inhibition constant K_i = 1.8 × 10⁻⁴ M and an active calcium transport inhibition constant K_i = 0.7 × 10⁻⁴ M. The goal of the investigation was to study the molecular mechanisms of action of amitriptyline, imipramine, and chlorpromazine.