Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress

1 Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota; and 2 Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland Submitted 21 June 2007 ; accepted in final form 29 November 2007 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 M 2 muscarinic acetylcholine receptor (M 2 -AChR). In this study, we tested the hypothesis that lack of M 2 -AChR-mediated PSNS function may adversely impact cardiac ventricular function. Using M 2 -AChR knockout (KO) and wild-type (WT) mice, we found that the basal levels of heart rate and left ventricular function were similar in M 2 -AChR KO and WT mice. A bolus injection of isoproterenol (Iso) induced a greater increase in heart rate in M 2 -AChR KO mice than in WT mice. However, the responses of change in pressure over time (dP/d t ) to Iso were similar in the two groups. After chronic infusion with Iso for 1 wk, the baseline values of left ventricular function were increased to similar extents in M 2 -AChR KO and WT mice. However, the M 2 -AChR KO mice exhibited impaired ventricular function, indicated as attenuated dP/d t and increased end-diastolic pressure, during an increase in cardiac afterload induced by a bolus injection of phenylephrine. Furthermore, chronic Iso infusion significantly increased matrix metalloproteinase (MMP) activity in the heart in M 2 -AChR KO mice. In primary culture of mixed neonatal rat cardiac fibroblast and cardiomyocytes, cotreatment with muscarinic agonist bethanechol reversed phenylephrine-induced increase in MMP-9 activation. These data suggest that M 2 -AChR may mediate an inhibitory regulation on MMP function. The overall results from this study suggest that M 2 -AChR-mediated PSNS function may provide cardiac protection. Lack of this protective mechanism will increase the susceptibility of the heart to cardiac stresses. muscarinic; cardiac; contractility; matrix metalloproteinase; isoproterenol Address for reprint requests and other correspondence: Y.-F. Li, Division of Basic Biomedical Sciences, Sanford S