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Research ArticleCARDIOVASCULAR

Altered Cardiovascular Responses in Mice Lacking the M1 Muscarinic Acetylcholine Receptor

Sandrine N. Hardouin, Keith N. Richmond, Andrew Zimmerman, Susan E. Hamilton, Eric O. Feigl and Neil M. Nathanson
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 129-137; DOI: https://doi.org/10.1124/jpet.301.1.129
Sandrine N. Hardouin
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Keith N. Richmond
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Andrew Zimmerman
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Susan E. Hamilton
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Eric O. Feigl
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Neil M. Nathanson
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleCARDIOVASCULAR

Altered Cardiovascular Responses in Mice Lacking the M1 Muscarinic Acetylcholine Receptor

Sandrine N. Hardouin, Keith N. Richmond, Andrew Zimmerman, Susan E. Hamilton, Eric O. Feigl and Neil M. Nathanson
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 129-137; DOI: https://doi.org/10.1124/jpet.301.1.129

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Research ArticleCARDIOVASCULAR

Altered Cardiovascular Responses in Mice Lacking the M1 Muscarinic Acetylcholine Receptor

Sandrine N. Hardouin, Keith N. Richmond, Andrew Zimmerman, Susan E. Hamilton, Eric O. Feigl and Neil M. Nathanson
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 129-137; DOI: https://doi.org/10.1124/jpet.301.1.129
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