A comparison in rabbit isolated hearts of the dysrhythmogenic potential of amitriptyline, maprotiline and mianserin in relation to their ability to block noradrenaline uptake.

1. In isolated hearts of rabbits, perfusion with (-)-noradrenaline (0.0059 to 5.9 micronM) resulted in chronotropic and inotropic responses and a shortening of the interval between peak atrial and peak ventricular tensions (the A-V contraction interval). No dysrhythmias developed but at higher concentrations (590 micronM) 2 out of 7 hearts developed dysrhythmias (extrasystoles). 2. Perfusion with the antidepressants amitriptyline or maprotiline (4.8 micronM) or mianserin (28.8 micronM) reduced ventricular force, did not change heart rate and only amitriptyline reduced atrial force and lengthened the A-V contraction interval. At 4.8 micronM mianserin produced only a marginal shortening of the A-V contraction interval. 3. At these concentrations no dysrhythmias developed but at higher concentrations (amitriptyline 8 micronM, maprotiline 8 micronM, mianserin 60 micronM) all the agents produced dysrhythmias involving an interference with atrio-ventricular synchronization. 4. In the presence of mianserin (4.8 micronM) perfusion with noradrenaline (0.0059 to 5.9 micronM) shortened the A-V contraction interval and did not produce dysrhythmias. In the presence of amitriptyline or maprotiline (4.8 micronM) or mianserin (28.8 micronM) the A-V contraction interval generally lengthened and most hearts developed dysrhythmias (usually involving interference with atrio-ventricular synchronization). 5. [3H]-(-)-Noradrenaline uptake in perfused rabbit hearts and in mouse isolated atria or vasa deferentia was inhibited by the antidepressants to a similar extent, amitriptyline being marginally most potent (molar potency taken as 1.0), maprotiline being less potent (1.5) and mianserin least potent (2.0)). 6. It is concluded that of these three antidepressants, mianserin is least cardiotoxic in this preparation and that the ability of these antidepressants to predispose to noradrenaline-induced dysrhythmias is not related to blockade of noradrenaline uptake.