Abstract 12116: Peripheral α7-Nicotinic Acetylcholine Receptors Contribute to Cardio-Protective Effects of Central Donepezil Infusion in Chronic Heart Failure Rats
Introduction: Previous studies have proven that oral administration of donepezil improves prognosis in chronic heart failure (CHF) rats, and most of the cardioprotection has been reproduced by central donepezil infusion. α7-Nicotinic acetylcholine receptors (α7-nAChR) reportedly play an important role in cholinergic anti-inflammation and angiogenesis. The present study aimed to examine whether peripheral blockade of α7-nAChR attenuates beneficial effects of central donepezil infusion in CHF rats.
Methods: One week after extensive (50±3%) myocardial infarction (MI), survived rats were implanted with an ECG or a blood pressure transmitter for monitoring chronic hemodynamics. Seven days after surgery, these rats (n=30) were treated with central donepezil infusion (0.1 mg/kg/day) and were randomly assigned to peripheral saline (SDT) or peripheral α7-nAChR blocker, methyllcaconitine (α7DT) infusion groups. After 6-week treatment, the effects of peripheral α7-nAChR blockade were evaluated by hemodynamics, neurohumoral states and histological examination.
Results: α7DT had significantly higher heart rate and biventricular weight compared with SDT (346±6 vs.313±5 bpm, P<0.001; 3.19±0.08 vs.2.91±0.06g/kg, P<0.05). α7DT also promoted cardiac fibrosis (12.64±0.86 vs.4.75±0.59%, P<0.001), deteriorated hemodynamics [Cardiac index 112±20 vs.168±16 ml/min/kg, P<0.05; Left ventricular (LV) dp/dt max 3429±122 vs.4042±111 mmHg/sec, P<0.05; LV dp/dt min 2547±126 vs.3158±218 mmHg/sec, P<0.05; LV end-diastolic pressure (LVEDP) 19±3 vs.12±2mmHg, P<0.05], and increased plasma neurohumoral states (norepinephrine 8249±3578 vs.1269±333 pg/ml, P<0.05; BNP 505±28 vs.433±13 pg/ml, P<0.05).
Conclusion: Peripheral blockade of α7-nAChR significantly attenuates the cardioprotection by central donepezil infusion in CHF rats, suggesting peripheral activation of α7-nAChR plays an important role in cholinergic pharmacotherapy for severe CHF with extensive MI.
Author Disclosures: M. Li: None. C. Zheng: None. T. Kawada: None. M. Inagaki: None. K. Uemura: None. M. Sugimachi: None.
- © 2014 by American Heart Association, Inc.