Nitric oxide‐dependent relaxation induced by M 1 muscarinic receptor activation in the rat small intestine

The aim of the present study was to investigate whether muscarinic M 1 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 M 1 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 M 1 receptor antagonist telenzepine (10 −8   M ), and enhanced by the M 3 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 N ω ‐nitro‐ L ‐arginine ( L ‐NOARG; 10 −4   M ) and N ω ‐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 M 1 receptors. Hence, selective muscarinic M 1 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