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Muscarinic receptor subtypes controlling the cationic current in guinea‐pig ileal smooth muscle
Author(s) -
Zholos Alexander V.,
Bolton Thomas B.
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701438
Subject(s) - carbachol , muscarinic acetylcholine receptor , methoctramine , chemistry , medicine , endocrinology , agonist , schild regression , muscarine , muscarinic antagonist , pirenzepine , patch clamp , atropine , biophysics , receptor , biology , biochemistry
1 The 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. 2 Ascending concentrations of carbachol (3–300 μ M ) activated the cationic conductance in a concentration‐dependent manner with conductance at a maximally effective carbachol concentration ( G max ) of 27.4±1.4 nS and a mean −log EC 50 of 5.12±0.03 (mean±s.e.mean) ( n =114). 3 Muscarinic antagonists with higher affinity for the M 2 receptor, methoctramine, himbacine and tripitramine, produced a parallel shift of the carbachol concentration‐effect curve to the right in a concentration‐dependent manner with pA 2 values of 8.1, 8.0 and 9.1, respectively. 4 All M 3 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 EC 50 for carbachol. At higher concentrations M 3 antagonists shifted the agonist curve to the right, increasing the EC 50 , and depressed the maximum conductance response. Atropine, a non‐selective antagonist, produced both reduction in G max (M 3 effect) and significant increase in the EC 50 (M 2 effect) in the same concentration range. 5 The 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. 6 The results support the hypothesis that carbachol activates M 2 muscarinic receptors so initiating the opening of cationic channels which cause depolarization; this effect is potentiated by an unknown mechanism when carbachol activates M 3 receptors. As an increasing fraction of M 3 receptors are blocked by an antagonist, the effects on cationic current of an increasing proportion of activated M 2 receptors are disabled.British Journal of Pharmacology (1997) 122 , 885–893; doi: 10.1038/sj.bjp.0701438