The effect of physostigmine on the vagally induced muscarinic inhibition of noradrenaline release from the isolated perfused rabbit atria

Abstract

1. Presynaptic cholinergic-adrenergic interactions were studied on isolated perfused rabbit atria with the extrinsic right vagus and sympathetic innervation intact. The transmitter stores were labelled with 14C-choline and 3H-noradrenaline. The radioactive compounds were separated on columns and determined by scintillation spectrometry. The stimulation-evoked overflow of both transmitters was calcium-dependent and abolished by tetrodotoxin. 2. Methacholine caused a concentration-dependent decrease of atrial tension development and 3H-noradrenaline overflow evoked by 3 Hz sympathetic stimulation. Vagus nerve stimulation (1-20 Hz), although nearly abolishing tension development at 20 Hz, decreased evoked 3H-noradrenaline overflow by not more than 18%. 3. Physostigmine decreased atrial cholinesterase activity by 80% and increased the fraction of stimulation-evoked unhydrolyzed 14C-acetylcholine in the persufates from 58 to 86%. However, the inhibition by vagus stimulation (1-10 Hz) of evoked 3H-noradrenaline overflow was smaller than in the absence of the drug. This was closely related to a decrease in acetylcholine overflow. Yet for a give fractional rate of acetylcholine release the muscarinic inhibition of noradrenaline overflow still did not exceed that observed in the absence of physostigmine. 4. It is concluded that the vagally induced control of noradrenaline release occurs at discrete sites rather than in a diffuse pattern at multiple terminal axon sites as is the case after exogenous muscarinic agonists.