Low-affinity M(2) receptor binding state mediates mouse atrial bradycardia: comparative effects of carbamylcholine and the M(1) receptor agonists sabcomeline and xanomeline

• Published in: The Journal of pharmacology and experimental therapeutics 2001-03, Vol.296 (3), p.818
• Main Authors: Stengel, P W, Cohen, M L
• Format: Article
• Language: English
• Subjects: Animals; Atropine - pharmacology; Bradycardia - chemically induced; Bradycardia - physiopathology; Carbachol - adverse effects; Carbachol - antagonists & inhibitors; Carbachol - pharmacology; Drug Interactions; Heart - drug effects; Heart - physiopathology; Heart Rate - drug effects; Imines - pharmacology; In Vitro Techniques; Mice; Muscarinic Agonists - pharmacology; Pyridines - pharmacology; Quinuclidines - pharmacology; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptors, Muscarinic - metabolism; Receptors, Muscarinic - physiology; Thiadiazoles - pharmacology
• ISSN: 0022-3565

Carbamylcholine, a nonselective muscarinic receptor agonist, and sabcomeline and xanomeline, functional M(1) receptor-selective agonists with high M(2) receptor affinities, were used to explore the relationship of the M(2) receptor affinity of these agonists to mouse atrial bradycardia and to understand the relationship of the high and low M(2) receptor affinity states to carbamylcholine-induced mouse atrial bradycardia. All three agonists produced bradycardia with sabcomeline (pEC(50) = 6.7) more potent than either carbamylcholine (pEC(50) = 5.9) or xanomeline (pEC(50) = 5.1). Sabcomeline and carbamylcholine produced a rapid, concentration-related bradycardia, which was antagonized by atropine with pK(B) values of 8.6 and 8.9, respectively. In addition, sabcomeline antagonized carbamylcholine-induced bradycardia (pK(B) = 7.48), indicating that sabcomeline was a partial agonist at M(2) receptors. In contrast, xanomeline (up to 10(-5) M), did not antagonize carbamylcholine-induced bradycardia, and atropine (3.0 x 10(-8) M) did not antagonize xanomeline-induced bradycardia, suggesting that xanomeline-induced bradycardia was not mediated by M(2) receptors. Analysis of receptor occupancy curves indicated that bradycardia resulted from the interaction of carbamylcholine with the low- rather than high-affinity state of the M(2) receptor and that sabcomeline was a partial agonist at M(2) receptors in mouse atria. In contrast, similar analysis for xanomeline using the receptor affinity of xanomeline at M(2) receptors (1.8 x 10(-8) M) was not consistent with classical receptor theory. These data document that 1) the low-affinity state of the M(2) receptor is responsible for muscarinic-induced atrial bradycardia, 2) sabcomeline was an M(2) receptor partial agonist, and 3) xanomeline-induced bradycardia was not mediated by activation of M(2) muscarinic receptors.