Submitted on June 21, 2007
Accepted on November 29, 2007
Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress
Carly LaCroix1, Jessica Freeling1, Alese Giles1, Jurgen Wess2, and Yi-Fan Li1*
1 Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota School of Medicine, Vermillion, South Dakota, United States
2 Molecular Signaling Section, Laboratory of Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, United States; United States
* To whom correspondence should be addressed. E-mail: yli01{at}usd.edu.
Suppressed parasympathetic nervous system (PSNS) function has been found in a variety of cardiovascular diseases such as hypertension, heart failure and diabetes. However, whether impaired PSNS function plays a significant role in ventricular dysfunction remains to be investigated. Cardiac regulation by the PSNS is primarily mediated by the M2 muscarinic acetylcholine receptor (M2-AchR). In this study, we tested the hypothesis that lack of M2-AchR mediated PSNS function may adversely impact cardiac ventricular function. Using M2-AchR knockout (M2-AchR KO) and wild type (WT) mice, we found that the basal levels of heart rate and left ventricular function were similar in M2-AchR KO and WT mice. A bolus injection of Isoproterenol (Iso) induced a greater increase in heart rate in M2-AchR KO mice than in WT mice. However, the responses of dP/dt to Iso were similar in the two groups. After chronic infusion with Iso for one week, the baseline values of left ventricular function were increased to similar extents in M2-AchR KO and WT mice. However, the M2-AchR KO mice exhibited impaired ventricular function, indicated as attenuated dP/dt and increased end diastolic pressure, during an increase in cardiac afterload induced by a bolus injection of phenylephrine (PE). Furthermore, chronic Iso infusion significantly increased matrix metalloproteinase (MMP) activity in the heart in M2-AchR KO mice. In primary culture of mixed neonatal rat cardiac fibroblast and cardiomyocytes, co-treatment with muscarinic agonist bethanechol (Beth) reversed PE-induced increase in MMP9 activation. These data suggest that M2-AChR may mediate an inhibitory regulation on MMP function to prevent MMP over activation. The overall results from this study suggest that M2-AchR mediated PSNS function may provide cardiac protection. Lack of this protective mechanism will increase the susceptibility of the heart to cardiac stresses.
