title: Altered cardiovascular responses in mice lacking the M(1) muscarinic acetylcholine receptor.
abstract: Although the M(2) muscarinic acetylcholine receptor (mAChR) is the predominant functional mAChR subtype in the heart, some responses of the cardiovascular system to acetylcholine (ACh) may be mediated by other mAChR subtypes. The potential effect of M(1) mAChR on heart function was investigated using M(1) knockout (M(1)-KO) mice. In vivo cardiodynamic analysis showed that basal values of heart rate (HR), developed left ventricular pressure (DLVP), left ventricular dP/dt(max) (LV dP/dt(max)), and mean blood pressure (MBP) were similar between wild-type (WT) and M(1)-KO mice. Injection of the putative M(1)-selective agonist 4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium (McN-A-343) produced an increase in LV dP/dt(max), DLVP, HR, and MBP in WT mice but did not affect hemodynamic function in the M(1)-KO mice. The stimulatory effect of McN-A-343 in WT mice was blocked by pretreatment with propranolol, indicating that stimulation of the M(1) mAChRs on sympathetic postganglionic neurons evoked release of catecholamines. Intravenous injection of ACh in both WT and M(1)-KO mice caused atrioventricular conduction block, without a significant change in the frequency of atrial depolarization, or atrial fibrillation. Immunoprecipitation and reverse transcriptase-polymerase chain reaction failed to detect the expression of M(1) mAChR in cardiac tissue from WT mice. The carbachol-induced increase of phospholipase C activity in cardiac tissues was not different between WT and M(1)-KO mice. These results demonstrate that 1) activation of M(1) mAChR subtype on sympathetic postganglionic cells results in catecholamine-mediated cardiac stimulation, 2) M(1) mAChR is not expressed in mouse heart, and 3) administration of ACh to mice induces arrhythmia.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Sandrine N
authors.initials: SN
authors.lastname: Hardouin
authors.forename: Keith N
authors.initials: KN
authors.lastname: Richmond
authors.forename: Andrew
authors.initials: A
authors.lastname: Zimmerman
authors.forename: Susan E
authors.initials: SE
authors.lastname: Hamilton
authors.forename: Eric O
authors.initials: EO
authors.lastname: Feigl
authors.forename: Neil M
authors.initials: NM
authors.lastname: Nathanson
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015139:Blotting, Southern; D002217:Carbachol / Q000494:pharmacology; D005728:Ganglia, Sympathetic / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011233:Precipitin Tests; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D043643:Receptor, Muscarinic M1; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D014628:Vagotomy
chemical_list: D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010716:Phosphatidylinositols; D043643:Receptor, Muscarinic M1; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D012313:RNA; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D000109:Acetylcholine