Muscarinic receptor subtypes controlling the cationic current in guinea-pig ileal smooth muscle
Article first published online: 5 FEB 2009
1997 British Pharmacological Society
British Journal of Pharmacology
Volume 122, Issue 5, pages 885–893, November 1997
How to Cite
Zholos, A. V. and Bolton, T. B. (1997), Muscarinic receptor subtypes controlling the cationic current in guinea-pig ileal smooth muscle. British Journal of Pharmacology, 122: 885–893. doi: 10.1038/sj.bjp.0701438
- Issue published online: 5 FEB 2009
- Article first published online: 5 FEB 2009
- (Received December 13, 1996, Revised June 20, 1997, Accepted July 15, 1997)
- Gastrointestinal smooth muscle;
- M2 and M3 muscarinic receptors;
- cationic current;
- muscarinic antagonists
- 1The effects of muscarinic antagonists on cationic current evoked by activating muscarinic receptors with the stable agonist carbachol were studied by use of patch-clamp recording techniques in guinea-pig single ileal smooth muscle cells.
- 2Ascending concentrations of carbachol (3–300 μM) activated the cationic conductance in a concentration-dependent manner with conductance at a maximally effective carbachol concentration (Gmax) of 27.4±1.4 nS and a mean −log EC50 of 5.12±0.03 (mean±s.e.mean) (n=114).
- 3Muscarinic antagonists with higher affinity for the M2 receptor, methoctramine, himbacine and tripitramine, produced a parallel shift of the carbachol concentration-effect curve to the right in a concentration-dependent manner with pA2 values of 8.1, 8.0 and 9.1, respectively.
- 4All M3 selective muscarinic antagonists tested, 4-DAMP, p-F-HHSiD and zamifenacin, reduced the maximal response in a concentration-dependent and non-competitive manner. This effect could be observed even at concentrations which did not produce any increase in the EC50 for carbachol. At higher concentrations M3 antagonists shifted the agonist curve to the right, increasing the EC50, and depressed the maximum conductance response. Atropine, a non-selective antagonist, produced both reduction in Gmax (M3 effect) and significant increase in the EC50 (M2 effect) in the same concentration range.
- 5The depression of the conductance by 4-DAMP, zamifenacin and atropine could not be explained by channel block as cationic current evoked by adding GTPγS to the pipette (without application of carbachol) was unaffected.
- 6The results support the hypothesis that carbachol activates M2 muscarinic receptors so initiating the opening of cationic channels which cause depolarization; this effect is potentiated by an unknown mechanism when carbachol activates M3 receptors. As an increasing fraction of M3 receptors are blocked by an antagonist, the effects on cationic current of an increasing proportion of activated M2 receptors are disabled.
British Journal of Pharmacology (1997) 122, 885–893; doi:10.1038/sj.bjp.0701438