Abstract

Although the M₂ 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 M₁ mAChR on heart function was investigated using M₁ knockout (M₁-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 M₁-KO mice. Injection of the putative M₁-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 M₁-KO mice. The stimulatory effect of McN-A-343 in WT mice was blocked by pretreatment with propranolol, indicating that stimulation of the M₁ mAChRs on sympathetic postganglionic neurons evoked release of catecholamines. Intravenous injection of ACh in both WT and M₁-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 M₁ mAChR in cardiac tissue from WT mice. The carbachol-induced increase of phospholipase C activity in cardiac tissues was not different between WT and M₁-KO mice. These results demonstrate that 1) activation of M₁ mAChR subtype on sympathetic postganglionic cells results in catecholamine-mediated cardiac stimulation, 2) M₁ mAChR is not expressed in mouse heart, and 3) administration of ACh to mice induces arrhythmia.