Abstract 13592: Contribution of Peripheral versus Central a7-Nicotinic Acetylcholine Receptors to Cardio-protective Effects of Donepezil in Chronic Heart Failure Rats
Introduction: Parasympathetic activation by donepezil, a cholinesterase inhibitor, improves prognosis in chronic heart failure (CHF) rats, but its mechanisms remain unclear. a7-nicotinic acetylcholine receptors (a7-nAChR) reportedly play an important role in inflammation and angiogenesis. This study examined if blockade of a7-nAChR either centrally or peripherally cancels the beneficial effect of donepezil on CHF rats.
Methods: One week after extensive (48±4%) myocardial infarction (MI), survived rats were implanted with an ECG transmitter for monitoring heart rate. Seven days after surgery, these MI rats (n=57) were all treated with donepezil (5 mg/kg/day) and were randomly assigned to the following 4 groups: central (a7BDT) or peripheral (a7PDT) infusion of a7-nAChR blocker (methyllcaconitine), and central (SBDT) or peripheral (SPDT) infusion of vehicle. After 4 weeks treatment, the role of a7-nACR was evaluated by means of hemodynamic parameters, neurohumoral states, and histological examination.
Results: In central infusion groups, a7BDT (vs. SBDT) showed no changes in either cardiac remodeling (2.90±0.19 vs. 2.87±0.18 g/kg) or hemodynamics (cardiac index 111±28 vs. 111±31 ml/min/kg; LVEDP 25±13 vs. 28±7 mmHg; dp/dtmax 3811±579 vs. 3981±647 mmHg/s). In contrast, in peripheral infusion groups, a7PDT (vs. SPDT) had significantly higher heart weight and cardiac fibrosis (3.02±0.28 vs. 2.74±0.24 g/kg, p<0.01; 5.93±1.45 vs. 2.19±0.87%, p<0.01), deteriorated hemodynamics (cardiac index 65±12 vs. 128±29 ml/min/kg, p<0.01; LVEDP 29±3 vs. 20±3 mmHg, p<0.01; dp/dtmax 2582±260 vs. 3956±714 mmHg/s, p<0.01), and increased plasma neurohumoral and cytokine states (BNP 655±209 vs.461±99 pg/ml, p<0.01; norepinephrine 2648±771 vs.669±203 pg/ml, p<0.05; cardiac tissue TNF-a 4212±390 vs.2939±149 pg/g, p<0.01), and micro-vessel density labeled by v-WF positive cells was significantly decreased (377±74 vs.961±181 cells/field, p<0.01).
Conclusions: Peripheral blockade of a7-nAChR significantly erases the cardio-protective effects of donepezil in CHF rats, while central blockade does not; suggesting peripheral activation of a7-nAChR plays an important role in cholinergic pharmacotherapy for severe CHF with extensive MI.
- Autonomic nervous system
- Heart failure
- Myocardial infarction
- Ventricular remodeling
- Ventricular function
- © 2012 by American Heart Association, Inc.