Receptor signaling mechanisms underlying muscarinic agonist‐evoked contraction in guinea‐pig ileal longitudinal smooth muscle

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Abstract
In guinea‐pig ileal longitudinal muscle, muscarinic partial agonists, 4‐(N‐[3‐chlorophenyl]‐carbomoyloxy)‐2‐butynyl‐trimethylammonium (McN‐A343) and pilocarpine, each produced parallel increases in tension and cytosolic Ca2+ concentration ([Ca2+]c) with a higher EC50 than that of the full agonist carbachol. The maximum response of [Ca2+]c or tension was not much different among the three agonists. The Ca2+ channel blocker nicardipine markedly inhibited the effects of all three agonists The contractile response to any agonist was antagonized in a competitive manner by M2 receptor selective antagonists (N,N′‐bis[6‐[[(2‐methoyphenyl)methyl]amino]hexyl]‐1,8‐octanediamine tetrahydrochloride and 11‐[[2‐[(diethlamino)methyl]‐1‐piperidinyl]acetyl]‐5,11‐dihydro‐6H‐pyrido[2,3‐b][1,4] benzodiazepine‐6‐one), and the apparent order of M2 antagonist sensitivity was McN‐A343>pilocarpine>carbachol. M3 receptor selective antagonists, 1,1‐dimethyl‐4‐diphenylacetoxypiperidinium iodide and darifenacin, both severely depressed the maximum response for McN‐A343, while darifenacin had a similar action in the case of pilocarpine. Both M3 antagonists behaved in a competitive manner in the case of the carbachol response. McN‐A343 failed to release Ca2+ from the intracellular stores, and the Ca2+‐releasing action of pilocarpine was very weak compared with that of carbachol. All three agonists were capable of increasing Ca2+ sensitivity of the contractile proteins. McN‐A343 rarely produced membrane depolarization, but always accelerated electrical spike discharge. Pilocarpine effect was more often accompanied by membrane depolarization, as was usually seen using carbachol. The results suggest that muscarinic agonist‐evoked contractions result primarily from the integration of Ca2+ entry associated with the increased spike discharge and myofilaments Ca2+ sensitization, and that Ca2+ store release may contribute to the contraction indirectly via potentiation of the electrical membrane responses. They may also support the idea that an interaction of M2 and M3 receptors plays a crucial role in mediating the contraction response. British Journal of Pharmacology (2003) 139, 337–350. doi:10.1038/sj.bjp.0705267

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