Inhibition of neuronal M-2 muscarinic receptor function in the lungs by extracellular nitric oxide

Citation
L. Golkar et al., Inhibition of neuronal M-2 muscarinic receptor function in the lungs by extracellular nitric oxide, BR J PHARM, 131(2), 2000, pp. 312-318
Citations number
34
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN journal
00071188 → ACNP
Volume
131
Issue
2
Year of publication
2000
Pages
312 - 318
Database
ISI
SICI code
0007-1188(200009)131:2<312:IONMMR>2.0.ZU;2-2
Abstract
1 These experiments were carried out to test whether neuronal M-2, muscarin ic receptor function in the lungs is affected by nitric oxide (NO) and whet her the source of the NO is epithelial or neuronal. 2 In pathogen free, anaesthetized guinea-pigs, the muscarinic agonist piloc arpine inhibited vagally induced bronchoconstriction demonstrating function al neuronal M-2 muscarinic receptors. In the presence of the NO donor, 3-mo rpholino-sydnonimine (SIN-1), pilocarpine no longer inhibited vagally induc ed bronchoconstriction. In contrast, inhibiting endogenous NO with N-G-mono methyl-L-arginine methyl ester (L-NMMA) did not affect the ability of piloc arpine to decrease vagally induced bronchoconstriction. 3 In isolated tracheas, pilocarpine inhibited contractions induced by elect rical field stimulation demonstrating that neuronal M-2 muscarinic receptor s function in vitro. As in the anaesthetized guinea-pigs, SIN-1 shifted the pilocarpine dose response curve to the right, demonstrating decreased neur onal M-2 receptor function. However, in vitro, L-NMMA shifted the pilocarpi ne dose response curve to the left, demonstrating that endogenous NO was in hibiting the ability of the M-2 receptors to decrease acetylcholine (ACh) r elease. 4 Both haemoglobin (Hb), which scavenges NO, and epithelial removal also sh ifted the pilocarpine dose response curve to the left, demonstrating that t he NO inhibiting neuronal M-2 receptor function was extracellular and proba bly of epithelial origin. 5 In conclusion, extracellular NO appears to inhibit the ability of the M-2 receptors to decrease ACh release from the parasympathetic nerves in the l ungs in vivo and in vivo in pathogen free guinea-pigs. However, while the n euronal M-2 receptors will respond to NO (from SIN-1) in vivo, there does n ot appear to be an endogenous source of NO since L-NMMA had no effect in vi ve.