Short- and long-latency muscarinic inhibition of noradrenaline release from rabbit atria induced by vagal stimulation.

1. The influence of the time interval between vagal and sympathetic nerve stimuli on the magnitude of muscarinic inhibition of noradrenaline release was studied in the isolated perfused rabbit atria preparation. The transmitter stores were labelled with [14C]choline and [3H]noradrenaline. 2. The right cardiac postganglionic sympathetic nerves were stimulated at 3 Hz for 3 min three times at intervals of 10 min. The [3H]noradrenaline outflow evoked by the second stimulation equalled the averaged means of the log values of amine outflows evoked by the first and third stimulations. 3. During the second sympathetic stimulation the right vagus nerve was stimulated (3 Hz, 3 min) in such a way that the impulses preceded the sympathetic stimuli by a fixed time interval varying within the range 0.3-283 ms. Outflow of [3H]noradrenaline was then compared with the individual 'expected value' calculated from the first and the third nerve stimulations. 4. [3H]Noradrenaline outflow was significantly decreased when the sympathetic impulses were delayed for between 3 and 10 ms or between 200 and 283 ms with respect to the vagus impulses. No significant inhibition of [3H]noradrenaline outflow occurred with delay times between 0.3 and 1.7 or 30 and 167 ms. Acetylcholine release was unaffected by varying the impulse delay time. 5. Atropine (1-300 nM) decreased and eventually abolished vagally mediated inhibition of [3H]noradrenaline outflow at both the 3 and 233 ms impulse delay periods and the evoked outflow of [14C]choline and [14C]acetylcholine was then approximately doubled. No enhancement of [3H]noradrenaline outflow was observed at an intermediate impulse delay time (100 ms) in the presence of atropine. 6. In the presence of (+)-tubocurarine (10 microM) [3H]noradrenaline outflow was unaffected by vagal stimulation at either the short or the long impulse delay time whereas that of [14C]choline and [14C]acetylcholine dropped to 3.4% (short) and 4.6% (long) of the control values. 7. Allowing for estimated conduction times in the vagal and sympathetic nerve pathways, the initial peak of muscarinic inhibition of noradrenaline release corresponds with excitation of the terminal cholinergic fibres occurring 20 ms before their adrenergic counterparts. A 'silent period' follows and then a second phase of muscarinic presynaptic inhibition occurs, peaking 250 ms after excitation of the cholinergic nerve terminals and levelling off completely within 100 ms. 8. It is concluded that both inhibitory peak responses are caused by a single volley of acetylcholine that affects two separate populations of muscarinic receptors.(ABSTRACT TRUNCATED AT 400 WORDS)