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
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.