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A simple quantitative method for measuring in vivo antagonist potencies at M2 and M3 muscarinic receptors using the pithed rat assay
Author(s) -
Armstrong Scott,
Briones Sergio,
Richardson Carrie,
Horger Brian,
Hegde Sharath
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1160-c
Subject(s) - in vivo , muscarinic acetylcholine receptor , potency , chemistry , pharmacology , receptor , muscarinic acetylcholine receptor m1 , pirenzepine , antagonist , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m3 , endocrinology , medicine , in vitro , biology , biochemistry , microbiology and biotechnology
Muscarinic receptor antagonists form the mainstay of the therapeutic options for the management of urinary incontinence. Both M 2 and M 3 muscarinic receptors are involved in mediating smooth muscle contractility although the relative functional contribution of each subtype, especially in the disease state is unclear. Since the potency and selectivity of compounds for a given receptor in an in vivo setting can be dissimilar to that observed in an in vitro system, we developed an in vivo assay to determine the absolute potency and selectivity of muscarinic receptor antagonists at M 2 and M 3 receptors using the pithed rat. Methacholine (MCh)‐induced bradycardia and depressor responses were used as surrogate functional endpoints for M 2 and M 3 receptor activation, respectively. Two dose‐response curves to MCh were constructed in each animal. The antagonists (tolterodine, oxybutynin, Ro‐320‐6206, or darifenacin) or vehicle were infused intravenously before the second MCh curve. The in vivo potency (DR 10 ; dose producing a 10‐fold shift in the MCh curve) and selectivity data are summarized in the table below; the values are consistent with reported in vitro affinities and selectivities of these compounds. The pithed rat assay offers a novel method for characterizing the in vivo M 2 /M 3 potencies and selectivities of muscarinic antagonists.