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.
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
Carly
C
LaCroix
Jessica
J
Freeling
Alese
A
Giles
Jürgen
J
Wess
Yi-Fan
YF
Li
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