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  • Title: Cholinesterase activity and exposure time to acetylcholine as factors influencing the muscarinic inhibition of [3H]-noradrenaline overflow from guinea-pig isolated atria.
    Author: Fuder H, Muscholl E, Wolf K.
    Journal: Br J Pharmacol; 1985 Dec; 86(4):905-14. PubMed ID: 2866805.
    Abstract:
    Guinea-pig isolated atria were incubated and loaded with [3H]-noradrenaline. The release of 3H and of [3H]-noradrenaline was induced by field stimulation (6-9 trains of 150 pulses at 5 Hz). The stimulation-evoked overflows of 3H and of [3H]-noradrenaline were determined. In the absence of an inhibitor of acetylcholinesterase, acetylcholine (12 min preincubation before nerve stimulation, up to 10 microM) failed to inhibit the evoked [3H]-noradrenaline overflow. In the presence of atropine, an increase by acetylcholine of evoked release was observed in the same atria. In contrast, the selective muscarinic agonist methacholine significantly decreased the evoked overflow. The inhibition was antagonized by atropine. Methacholine did not enhance release in the presence of atropine. When present for only 2 min, acetylcholine 10 microM inhibited the evoked overflow and no facilitation of release was observed in the presence of atropine. In the presence of physostigmine, acetylcholine (12 min preincubation, 1 and 10 microM) inhibited evoked [3H]-noradrenaline overflow, but the overflow was increased by acetylcholine 10 microM in the presence of atropine. In the presence of cocaine, corticosterone, phentolamine, propranolol and hexamethonium together, acetylcholine 1 microM inhibited the evoked [3H]-noradrenaline overflow. The inhibition was significantly enhanced in the presence of physostigmine. It decreased with preincubation time of the agonist, despite the presence of physostigmine and constant replacement by new drug. Neither inhibition nor facilitation of evoked release was observed in the presence of atropine. It is concluded that a muscarinic inhibition by acetylcholine (upon prolonged exposure time) may be masked by a concomitant facilitation of release and/or desensitization of the muscarinic inhibitory mechanism. Furthermore, degradation by acetylcholinesterase contributes in part to the ineffectiveness of acetylcholine as a presynaptic inhibitor. When a distortion of the overflow/release ratio was excluded, adrenergic and nicotinic effects were prevented, and acetylcholinesterase was inhibited, the fading of muscarinic inhibition by acetylcholine may have been exclusively due to a slow and moderate desensitization of the presynaptic muscarinic mechanism.
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