Inhibition of neuronal M(2) muscarinic receptor function in the lungs by extracellular nitric oxide.
1. These experiments were carried out to test whether neuronal M(2) muscarinic receptor function in the lungs is affected by nitric oxide (NO) and whether the source of the NO is epithelial or neuronal. 2. In pathogen free, anaesthetized guinea-pigs, the muscarinic agonist pilocarpine inhibited vagally induced bronchoconstriction demonstrating functional neuronal M(2) muscarinic receptors. In the presence of the NO donor, 3-morpholino-sydnonimine (SIN-1), pilocarpine no longer inhibited vagally induced bronchoconstriction. In contrast, inhibiting endogenous NO with N(G)-monomethyl-L-arginine methyl ester (L-NMMA) did not affect the ability of pilocarpine to decrease vagally induced bronchoconstriction. 3. In isolated tracheas, pilocarpine inhibited contractions induced by electrical field stimulation demonstrating that neuronal M(2) muscarinic receptors function in vitro. As in the anaesthetized guinea-pigs, SIN-1 shifted the pilocarpine dose response curve to the right, demonstrating decreased neuronal M(2) receptor function. However, in vitro, L-NMMA shifted the pilocarpine dose response curve to the left, demonstrating that endogenous NO was inhibiting the ability of the M(2) receptors to decrease acetylcholine (ACh) release. 4. Both haemoglobin (Hb), which scavenges NO, and epithelial removal also shifted the pilocarpine dose response curve to the left, demonstrating that the NO inhibiting neuronal M(2) receptor function was extracellular and probably 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 lungs in vivo and in vitro in pathogen free guinea-pigs. However, while the neuronal M(2) receptors will respond to NO (from SIN-1) in vivo, there does not appear to be an endogenous source of NO since L-NMMA had no effect in vivo.
Golkar
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Johns Hopkins University School of Public Health, 615 N Wolfe Street, Baltimore, Maryland, MD 21209, USA.
Yarkony
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Fryer
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D000704:Analysis of Variance; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005703:Gallamine Triethiodide / Q000494:pharmacology; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010862:Pilocarpine / Q000494:pharmacology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D005703:Gallamine Triethiodide