Prejunctional muscarinic receptor modulation of noradrenaline release fromsympathetic neurones in rabbit aorta

The prejunctional muscarinic modulation of stimulation-evoked release of H- 3-noradrenaline from sympathetic neurones in rabbit aorta was examined. The role of transmitter uptake, alpha-adrenoceptor blockade, stimulation frequ ency and endothelium on the modulation was investigated. Rings of aorta wer e incubated with (-)-H-3-noradrenaline and subsequently subjected to electr ical-field stimulation. Fractional H-3-overflow was determined by liquid sc intillation counting. Acetylcholine (10(-8)-3x10(-6) M) added cumulatively, reduced the stimulation-evoked 3H-overflow up to 80%. The effect of acetyl choline was the same in intact and endothelium-free aorta. The inhibitory e ffect of acetylcholine was inversely related to the frequency of stimulatio n (1-10 Hz). The maximal inhibition (%) was 80 (1 Hz), 53 (3 Hz) and 14 (10 Hz). The inhibitory effect of acetylcholine (10(-6) M) and carbachol (10(- 5) M) reached a maximum 15 min. after addition and then remained almost con stant. Cocaine (3x10(-5) M) did not alter the effect of acetylcholine. Desi pramine (10(-6) M) and corticosterone (4x10(-5) M) attenuated the inhibitio n seen with low concentrations (10(-8)-10(-7) M) of acetylcholine. The acet ylcholine-induced inhibition was antagonized by desipramine. Cocaine plus c orticosterone attenuated the inhibition seen with high concentrations (10(- 6)-3 x 10(-6) M) of acetylcholine. Rauwolscine (10(-6) M) enhanced the maxi mal inhibitory effect of acetylcholine. We conclude that the inhibitory eff ect of acetylcholine on H-3-overflow from rabbit aorta preloaded with H-3-n oradrenaline is (1) inversely related to stimulation frequency; (2) indepen dent of endothelium; (3) unaffected by neuronal and extraneuronal transmitt er uptake; (4) that cocaine is not a prejunctional muscarinic antagonist; ( 5) that cocaine, but not desipramine, is suited as a neuronal uptake inhibi tor in studies of prejunctional muscarinic receptor subtypes; and (6) and t hat there is an inverse interaction between prejunctional alpha(2)-adrenoce ptors and muscarinic receptors.