Deficiency of M2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress.
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/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 M(2)-AChR KO and WT mice. However, the M(2)-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 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.
LaCroix
Carly
C
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
Freeling
Jessica
J
Giles
Alese
A
Wess
Jürgen
J
Li
Yi-Fan
YF
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D002908:Chronic Disease; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000502:physiology
D000318:Adrenergic beta-Agonists; D018721:Muscarinic Agonists; D043585:Receptor, Muscarinic M2; D019714:Tissue Inhibitor of Metalloproteinases; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D012313:RNA; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases; D007545:Isoproterenol