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/dtmax (LV dP/dtmax), 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/dtmax, 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.
Footnotes
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This work was supported by National Institutes of Health Grants HL44948, HL58676, and NS26920. S.N.H. is a recipient of an American Heart Association Northwest Affiliate postdoctoral fellowship.
- Abbreviations:
- ACh
- acetylcholine
- mAChR
- muscarinic acetylcholine receptor
- PLC
- phospholipase C
- McN-A-343
- 4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium
- M1-KO
- M1 mAChR knockout
- MBP
- mean blood pressure
- LV dP/dtmax
- maximum left ventricular dP/dt
- DLVP
- developed left ventricular pressure
- HR
- heart rate
- bpm
- beats per minute
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- QNB
- quinuclidinyl benzilate
- WT
- wild-type
- ANOVA
- analysis of variance
- HET
- heterozygote
- Received September 25, 2001.
- Accepted December 18, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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