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Prejunctional muscarinic inhibitory control of acetylcholine release in the human isolated detrusor: involvement of the M4 receptor subtype.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2000 Feb; Vol. 129 (3), pp. 493-500. - Publication Year :
- 2000
-
Abstract
- 1. Experiments were carried out in human detrusor strips to characterize muscarinic receptor subtypes involved in the prejunctional regulation of acetylcholine (ACh) release from cholinergic nerve terminals, and in the postjunctional smooth muscle contractile response. 2. In detrusor strips preincubated with [3H]-choline, electrical field stimulation (600 pulses) delivered in six trains at 10 Hz produced a tritium outflow and a contractile response. In the presence of 10 microM paraoxon (to prevent ACh degradation) the tritium outflow was characterized by HPLC analysis as [3H]-ACh (76%) and [3H]-choline (24%). 3. Electrically-evoked [3H]-ACh release was abolished by tetrodotoxin (TTX: 300 nM) and unaffected by hexamethonium (10 microM), indicating a postganglionic event. It was reduced by physostigmine (100 nM) and the muscarinic receptor agonist, muscarone (10 nM-1 microM), and enhanced by atropine (0.1-100 nM). These findings indicate the presence of a muscarinic negative feedback mechanism controlling ACh release. 4. The effects of various subtype-preferring muscarinic receptor antagonists were evaluated on [3H]-ACh release and muscle contraction. The rank potency (-log EC50) orders at pre- and postjunctional level were: atropine > or = 4-diphenyl-acetoxy-N-piperidine (4-DAMP) > mamba toxin 3 (MT-3) > tripitramine > para-fluorohexahydrosiladiphenidol (pF-HHSiD) > or = methoctramine > or = pirenzepine > tripinamide, and atropine > or = 4-DAMP > pF-HHSiD >> pirenzepine = tripitramine > tripinamide > methoctramine >> MT-3, respectively. 5. The comparison of pre- and post-junctional potencies and the relationship analysis with the affinity constants at human cloned muscarinic receptor subtypes indicates that the muscarinic autoreceptor inhibiting ACh release in human detrusor is an M4 receptor, while the receptor involved in muscular contraction belongs to the M3 subtype.
- Subjects :
- Adult
Aged
Aged, 80 and over
Autoreceptors drug effects
Choline metabolism
Electric Stimulation
Feedback physiology
Humans
In Vitro Techniques
Male
Middle Aged
Muscarine analogs & derivatives
Muscarine pharmacology
Muscle Contraction drug effects
Muscle, Smooth drug effects
Muscle, Smooth innervation
Neuromuscular Junction drug effects
Neuromuscular Junction metabolism
Receptor, Muscarinic M4
Receptors, Muscarinic drug effects
Urinary Bladder drug effects
Urinary Bladder innervation
Acetylcholine metabolism
Muscarinic Antagonists pharmacology
Muscle, Smooth metabolism
Receptors, Muscarinic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 129
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 10711347
- Full Text :
- https://doi.org/10.1038/sj.bjp.0703080