PT - JOURNAL ARTICLE AU - Takio Kitazawa AU - Koichi Asakawa AU - Tatsuro Nakamura AU - Hiroki Teraoka AU - Toshihiro Unno AU - Sei-ichi Komori AU - Masahisa Yamada AU - Jürgen Wess TI - M<sub>3</sub> Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice AID - 10.1124/jpet.109.153304 DP - 2009 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 487--493 VI - 330 IP - 2 4099 - http://jpet.aspetjournals.org/content/330/2/487.short 4100 - http://jpet.aspetjournals.org/content/330/2/487.full SO - J Pharmacol Exp Ther2009 Aug 01; 330 AB - The potential functional roles of M3 muscarinic receptors in mouse atria were examined by pharmacological and molecular biological techniques, using wild-type mice, muscarinic M2 or M3 receptor single knockout (M2KO, M3KO), and M2 and M3 muscarinic receptor double knockout mice (M2/M3KO). Real-time quantitative reverse transcriptase-polymerase chain reaction analysis showed that the M2 receptor mRNA was expressed predominantly in mouse atria but that the M1, M3, M4, and M5 receptor subtypes were also expressed at low levels. Carbachol (10 nM–30 μM) decreased the spontaneous beating frequency of right atria isolated from wild-type mice. Studies with subtype-preferring antagonists and atria from M2KO mice confirmed that this activity is mediated by the M2 receptor subtype. In left atria from wild-type mice, carbachol decreased the amplitude of electrical field stimulation-evoked contractions (negative inotropic action), but this inhibition was transient and was followed by a gradual increase in contraction amplitude (positive inotropic response). In atria from M3KO mice, the transient negative inotropic action of carbachol changed to a sustained negative inotropic action. In contrast, in atria from M2KO mice, carbachol showed only positive inotropic activity. In atria from M2/M3 double KO mice, carbachol was devoid of any inotropic activity. These observations, complemented by functional studies with subtype-preferring antagonists, convincingly demonstrate that atrial M3 muscarinic receptors mediate positive inotropic effects in mouse atria. Physiologically, this activity may serve to dampen the inhibitory effects of M2 receptor activation on atrial contractility. U.S. Government work not protected by U.S. copyright