title: Prejunctional muscarinic receptor modulation of noradrenaline release from sympathetic neurones in rabbit aorta.
abstract: The prejunctional muscarinic modulation of stimulation-evoked release of 3H-noradrenaline from sympathetic neurones in rabbit aorta was examined. The role of transmitter uptake, alpha-adrenoceptor blockade, stimulation frequency and endothelium on the modulation was investigated. Rings of aorta were incubated with (-)-3H-noradrenaline and subsequently subjected to electrical-field stimulation. Fractional 3H-overflow was determined by liquid scintillation counting. Acetylcholine (10(-8)-3 x 10(-6) M) added cumulatively, reduced the stimulation-evoked 3H-overflow up to 80%. The effect of acetylcholine was the same in intact and endothelium-free aorta. The inhibitory effect of acetylcholine was inversely related to the frequency of stimulation (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 constant. Cocaine (3 x 10(-5) M) did not alter the effect of acetylcholine. Desipramine (10(-6) M) and corticosterone (4 x 10(-5) M) attenuated the inhibition seen with low concentrations (10(-8)-10(-7) M) of acetylcholine. The acetylcholine-induced inhibition was antagonized by desipramine. Cocaine plus corticosterone attenuated the inhibition seen with high concentrations (10(-6)-3 x 10(-6) M) of acetylcholine. Rauwolscine (10(-6) M) enhanced the maximal inhibitory effect of acetylcholine. We conclude that the inhibitory effect of acetylcholine on 3H-overflow from rabbit aorta preloaded with 3H-noradrenaline is (1) inversely related to stimulation frequency; (2) independent of endothelium; (3) unaffected by neuronal and extraneuronal transmitter uptake; (4) that cocaine is not a prejunctional muscarinic antagonist; (5) that cocaine, but not desipramine, is suited as a neuronal uptake inhibitor in studies of prejunctional muscarinic receptor subtypes; and (6) and that there is an inverse interaction between prejunctional alpha2-adrenoceptors and muscarinic receptors.
authors.affiliation: Department of Pharmacology, School of Medicine, Odense University, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Lomholt
authors.forename: O A
authors.initials: OA
authors.lastname: Nedergaard
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*
chemical_list: D011976:Receptors, Muscarinic; D017661:Receptors, Presynaptic; D002217:Carbachol; D003042:Cocaine; D000109:Acetylcholine; D003891:Desipramine; D003345:Corticosterone; D009638:Norepinephrine