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Previous studies have shown that chronic activation of sympathetic nervous system is an unfavorable factor of cardiovascular diseases, However, studies have revealed that cardiac denervation often exists in patients with diabetic cardiomyopathy, heart failure or myocardial infarction. Until now, effects of cardiac sympathetic denervation on cardiac structure and function have not been adequately studied, furthermore, no drug was found can effectively alleviate cardiac sympathetic denervation.
Rats were induced sympathectomy by injection of 6-hydroxydopamine (6-OHDA). Methycobal and Guizhi decoctions (with different proportions between Ramulus Cinnamomi and Radix paeoniae Alba at 2:1, 1:2 or 1:1) were pre-administered to the rats before induction of sympathetomy. Distribution of sympathetic and vagal nerve in the left ventricle (LV) were determined by immunofluorescence and ELISA. Heart rate variability (HRV), ECG and echocardiography, and biomarkers of myocytes injury in serum before and after sympathectomy were examined. Morphologic changes by HE staining and masson-trichime staining as well as transmission electron microscope were used to estimate severity of myocardial injury, and inflammatory cytokines were used to reflect the inflammatory reaction.
(1) Following induction of sympathectomy with 6-OHDA, HRV was diminished, and parameters inferring parasympathetic activity (RMSSD and HF) were significantly decreased. Levels of norepinephrine (NE), tyrosine hydroxylase (TH) and growth associated protein 43 (GAP-43) as well as increased nerve growth factor (NGF) were reduced in myocardial tissue, while levels of choline acetyltransferase (ChAT) showed no change. (2) LV contractile dysfunction, abnormal ECG, hemodynamic and myocardial morphology changes, elevated concentrations of biomarkers of myocytes injury (AST, CK, CK-MB) as well as inflammatory cytokines (IL-1β, IL-6, TNF-α) were observed after induction of sympathectomy. (3) Compared with the model group, levels of NE and GAP-43 increased while NGF decreased in the methycobal group and each Guizhi decoction groups. Guizhi decoction at 2:1 and 1:1 significantly increased expression of TH and TH/ChAT ratio. Compared with the methycobal group, levels of NE, TH and GAP-43 increased while NGF levels reduced in the 1:1 group, and levels of NE and GAP-43 increased in the 2:1 group. (4) Methycobal and Guizhi decoction normalized the elevated biomarkers of myocytes injury and the deteriorated histopathological changes after sympathectomy, and Guizhi decoction at 2:1 and 1:1 showed the best efficacy.
Our study showed that injection of 6-OHDA resulted in dysregulation of the cardiac autonomic nervous system. Myocardial injuries and inflammatory reactions in the heart can be partially attributed to cardiac sympathetic denervation. Guizhi decoction with the proportions between Ranulus Cinnamomi and Radix paeoniae Alba at 2:1 and 1:1 effectively alleviate the sympathetic denervation and myocardial injury after cardiac sympathetic denervation.