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A muscarinic receptor subtype modulates vagally stimulated bronchial contraction
J W Bloom1, C Baumgartener-Folkerts, J D Palmer
1Division of Respiratory Sciences (Westend Laboratories), University of Arizona College of Medicine, Tucson 85724.
Abstract:
An in vitro preparation was developed to study vagus nerve-stimulated (preganglionic) and field-stimulated (post-ganglionic) contraction of the rabbit main stem bronchus and to compare the inhibitory effects of muscarinic antagonists on that contraction. The maximal contractile responses (20 V, 0.5 ms, 64 Hz) for either field or vagal stimulation were completely abolished by atropine (60 nM). Hexamethonium (0.1 mM) abolished the response to vagal stimulation but did not affect the field-stimulated response. To compare the effectiveness of atropine and pirenzepine as antagonists at the nerve-smooth muscle junction, inhibition studies of field-stimulated contractions were performed. Pirenzepine was 102- to 178-fold less potent than atropine when compared at the inhibitory concentration of antagonist that produced 25, 50, and 75% inhibition (IC25, IC50, and IC75, respectively), indicating that the muscarinic receptor at the nerve-smooth muscle junction is a muscarinic receptor with low affinity for pirenzepine (M2 subtype). Atropine had similar inhibitory effects on vagal- and field-stimulated contractions. In contrast, pirenzepine was more potent in inhibiting vagally stimulated contraction than field-stimulated contraction, especially at the IC25 where pirenzepine was only 8- to 22-fold less potent than atropine in inhibiting vagally stimulated contraction. These data suggest that an M1 subtype of muscarinic receptor modulates excitatory neurotransmission through bronchial parasympathetic ganglia.
Insights
Researchers studied rabbit bronchial smooth muscle contractions stimulated by vagus nerves and electrical fields. Atropine blocked both, while pirenzepine selectively inhibited vagally stimulated contractions, suggesting M1 muscarinic receptors modulate parasympathetic ganglia.
Area of Science:
- Pharmacology
- Neuroscience
- Respiratory Physiology
Background:
- The vagus nerve plays a crucial role in regulating airway smooth muscle tone.
- Muscarinic receptors are key mediators of parasympathetic neurotransmission in the airways.
- Understanding muscarinic receptor subtypes involved in airway control is essential for developing targeted therapies.
Purpose of the Study:
- To investigate the role of different muscarinic acetylcholine receptor (mAChR) subtypes in modulating vagal and field stimulation-induced contractions of the rabbit main stem bronchus.
- To compare the potency of atropine and pirenzepine as antagonists at the nerve-smooth muscle junction and within parasympathetic ganglia.
- To elucidate the specific muscarinic receptor subtypes involved in preganglionic and postganglionic neurotransmission in the airways.
Main Methods:
- Development of an in vitro rabbit main stem bronchus preparation.
- Stimulation of vagus nerve (preganglionic) and field stimulation (post-ganglionic) to induce smooth muscle contraction.
- Pharmacological characterization using muscarinic antagonists: atropine and pirenzepine.
- Dose-response inhibition studies to determine antagonist potency (IC25, IC50, IC75) at the nerve-smooth muscle junction and within ganglia.
Main Results:
- Atropine (60 nM) completely abolished maximal contractile responses to both vagal and field stimulation.
- Hexamethonium (0.1 mM) abolished vagal stimulation-induced contractions but did not affect field-stimulated responses, indicating ganglionic involvement in vagal transmission.
- Pirenzepine was significantly less potent (102- to 178-fold) than atropine at inhibiting field-stimulated contractions, suggesting M2 receptor predominance at the nerve-smooth muscle junction.
- Pirenzepine demonstrated greater potency in inhibiting vagally stimulated contractions compared to field-stimulated contractions, particularly at lower inhibition levels (IC25).
Conclusions:
- The muscarinic receptor at the airway smooth muscle junction is primarily of the M2 subtype, exhibiting low affinity for pirenzepine.
- An M1 subtype of muscarinic receptor likely modulates excitatory neurotransmission through bronchial parasympathetic ganglia.
- These findings highlight the differential roles of muscarinic receptor subtypes in regulating airway smooth muscle function via pre- and post-ganglionic pathways.