Nitric oxide‐dependent relaxation induced by M1 muscarinic receptor activation in the rat small intestine

The aim of the present study was to investigate whether muscarinic M1 receptor activation induces intestinal relaxation via nerve-dependent nitric oxide formation. Mechanical activity in longitudinal segments of rat jejunum was recorded isotonically in organ baths. The muscarinic M1 receptor agonist 4-[[[(3-Chlorophenyl)amino]carbonyl]oxy]-N,N,N,-trimethyl-2-butyn-1-amonium chloride (McN-A-343, 10−7–10−4 M) induced a concentration-dependent relaxation of rat jejunum. Relaxations induced by McN-A-343 (10−5 M) were inhibited by the M1 receptor antagonist telenzepine (10−8 M), and enhanced by the M3 receptor antagonist para-fluoro-hexahydrosiladifenidol (p-F-HHSiD; 3×10−7 M). The inhibitory responses induced by McN-A-343 were abolished by the nitric oxide synthase inhibitors Nω-nitro-L-arginine (L-NOARG; 10−4 M) and Nω-monomethyl-L-arginine (L-NMMA; 3×10−5 M), the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ; 10−5 M), and by tetrodotoxin (TTX; 3×10−7 M). Guanethidine or hexamethonium did not affect inhibitory responses induced by McN-A-343. In conclusion, McN-A-343 induces nerve-dependent, nitrergic relaxations in rat jejunum, via activation of muscarinic M1 receptors. Hence, selective muscarinic M1 receptor agonists or antagonists might offer possibilities for pharmacological manipulation of the NO system. British Journal of Pharmacology (1999) 127, 309–313; doi:10.1038/sj.bjp.0702529