Restoration of the chronotropic effect of tyramine on rat atria after reserpine

1 The restoration by various sympathomimetic amines of the chronotropic response to tyramine was studied on the isolated atria of rats pretreated with reserpine. The atria were exposed to the “restorative” sympathomimetic amine for 10 min, washed over a period of 1 hr and then tested with 10 μ m tyramine. The effect of noradrenaline, dopamine and norphenylephrine before and after inhibition of monoamine oxidase by 0.5 m m iproniazid were compared with their α‐methyl and N‐alkyl analogues in their ability to restore the chronotropic response to tyramine. 2 Noradrenaline and adrenaline restored the chronotropic response to tyramine, the degree of restoration depending on the concentration of the restorative amine used. Noradrenaline after iproniazid and α‐methylnoradrenaline were equipotent and were about 1,000 times more active than noradrenaline where monoamine oxidase was not inhibited. Dopamine, epinine, norphenylephrine, phenylephrine, octopamine, synephrine and isoprenaline in the absence of monoamine oxidase inhibition had no effect. Dopamine after iproniazid and α‐methyldopamine were equipotent and were about 1/10 as active as α‐methylnoradrenaline. Norphenylephrine after iproniazid and metaraminol were equipotent and were about 1/500 as active as α‐methylnoradrenaline. Octopamine after iproniazid was even less active. The N‐methylated analogues were about 1/10 as active as their nor‐compounds but the N‐isopropyl analogue, isoprenaline, was devoid of activity. 3 Dopamine after iproniazid and α‐methyldopamine were inactive if a dopamine‐β‐hydroxylase inhibitor, disulphiram or sodium diethyldithio‐carbamate, was present. 4 It is concluded that, in atria of reserpinized rats, ( a ) protection from monoamine oxidase increases; ( b ) N‐substitution decreases; and ( c ) hydroxyl groups at the β‐carbon and ring positions 3 and 4 increase the capabilities of a sympathomimetic amine to restore the chronotropic response to tyramine.