Cardiac vagal control in a knock-in mouse model of dilated cardiomyopathy with a troponin mutation.
The aim of this study was to evaluate cardiac vagal nerve activity and identify the abnormality of cardiac vagal control in heart failure caused by dilated cardiomyopathy (DCM) using a knock-in mouse model with a ΔK210 mutation in the cardiac troponin T gene. The effects of electrical stimulation of the cervical vagal nerve at 5 and 10Hz (peripheral vagal control) and α2-adrennoceptor stimulation by intravenous medetomidine at 0.1mg/kg (central vagal control) were examined in wild-type (WT) mice and DCM mice. Microdialysis technique was applied to the left ventricular myocardium of anesthetized mice and myocardial interstitial acetylcholine (ACh) levels were measured by HPLC as an index of ACh release from cardiac vagal nerve endings. Electrical vagal nerve stimulation increased cardiac interval and myocardial interstitial ACh level in both WT and DCM mice, and these responses did not differ between WT and DCM mice. In contrast, intravenous medetomidine increased cardiac interval and myocardial interstitial ACh level in both WT and DCM mice, but the responses of cardiac interval and myocardial interstitial ACh level were significantly suppressed in DCM mice compared to WT mice. Medetomidine did not affect the myocardial interstitial ACh response induced by vagal nerve stimulation in WT mice. In this mouse model of DCM, peripheral vagal control including ACh release from vagal nerve endings and the postsynaptic response of pacemaker cells was preserved, but central vagal control through α2-adrenoceptors was impaired.
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan. Electronic address: dyzhan@ncvc.go.jp.
Dong-Yun
DY
Zhan
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Cheng-Kun
CK
Du
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Tsuyoshi
T
Akiyama
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Sachio
S
Morimoto
Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Shuji
S
Shimizu
Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Toru
T
Kawada
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Mikiyasu
M
Shirai
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
James T
JT
Pearson
D000109:Acetylcholine / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000294:innervation / Q000378:metabolism; D008297:Male; D020926:Medetomidine / Q000494:pharmacology; D008822:Mice, Transgenic; D017551:Microdialysis; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D017384:Sequence Deletion; D020107:Troponin T / Q000235:genetics / Q000378:metabolism; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology*; D055536:Vagus Nerve Stimulation
D058647:Adrenergic alpha-2 Receptor Agonists; D018341:Receptors, Adrenergic, alpha-2; D020107:Troponin T; D020926:Medetomidine; D000109:Acetylcholine
Acetylcholine; Cardiac microdialysis; Dilated cardiomyopathy; Heart failure; Medetomidine