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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H810    most recent 00724.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by LaCroix, C. Articles by Li, Y.-F. Search for Related Content PubMed PubMed Citation Articles by LaCroix, C. Articles by Li, Y.-F.

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

¹Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota; and ²Molecular 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 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 (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 change in pressure over time (dP/dt) 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 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. 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, cotreatment with muscarinic agonist bethanechol reversed phenylephrine-induced increase in MMP-9 activation. These data suggest that M₂-AChR may mediate an inhibitory regulation on MMP function. 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.

muscarinic; cardiac; contractility; matrix metalloproteinase; isoproterenol