Storage and release of false transmitters after infusion of (+)- and (−)-α-methyldopamine

Summary Rabbits were given an infusion of 10 mg/kg (–)- or 30 mg/kg (+)--methyldopamine and killed after 135 min. The noradrenaline content of the heart was decreased to 26±5 and 34±2%, respectively, of the control value. After infusion of the (+)-isomer the missing noradrenaline was replaced by (–)--methylnoradrenaline. Electrical stimulation of the sympathetic nerves or infusion of acetylcholine plus atropine caused an output of noradrenaline and (–)--methylnoradrenaline from the isolated heart. The two amines were released in the same proportion as they were stored in the heart and the total output of both amines equalled the output of noradrenaline from control hearts. Nerve stimulation caused frequency-dependent increases in the rate and tension of cardiac contraction. There was no significant difference between the frequency-response curves obtained from untreated hearts and those treated with (+)--methyldopamine.After pretreatment with (–)--methyldopamine the noradrenaline lost from the heart was substituted by the infused amine;-methylnoradrenaline was not detected. Nerve stimulation or infusion of acetylcholine plus atropine caused an output of noradrenaline and (–)--methyldopamine at the same proportion as the amines were stored. Electrical stimulation of the sympathetic nerves caused an undiminished output of noradrenaline although the cardiac noradrenaline was decreased. It is suggested that the (–)--methyldopamine released during nerve stimulation interferes with the membranal re-uptake and therefore increases the overflow of the catecholamines. Pretreatment with (–)--methyldopamine shifted the frequencyresponse curves for rate and tension to the right.It concluded that treatment with (+)--methyldopamine failed to inhibit adrenergic transmission because the cardiostimulant activity of its metabolite, (–)--methylnoradrenaline, does not differ from that of noradrenaline, and the false transmitter released fully balances the decrease of noradrenaline output. In contrast, admixture of a large proportion of a weak cardiostimulant amine such as (–)--methyldopamine inhibits the actions of the physiological transmitter released by nerve stimulation probably by a postjunctional effect.This work was supported by the Deutsche Forsehungsgcmeinschaft. We wish to thank Dr. phil. et reed. Petra Netter (Institut für Medizinische Statistik und Dokumentation, Mainz) for her advice in the statistical analysis, and Dr. C. A. Stone (Merck, Sharpe and Dohme) for the donation of (–)- and (+)--methyldopamine. The technical assistance of Miss B. Hering and Miss H. Zappe is gratefully acknowledged.