Background: Decreased synaptic transmission in parasympathetic ganglia contributes to abnormal parasympathetic function in heart failure (HF). Since nicotinic acetylcholine receptor (nAChR) mediate synaptic transmission at the ganglion and up-regulate in response to chronic exposure to agonist in vitro, we tested the hypothesis that repeated exposure of ganglionic neurons to nAChR agonist can prevent loss of parasympathetic control in HF. Methods and Results: Two sets of experiments were performed. In set 1, unpaced control, and dogs undergoing pacing induced HF were treated with repeated intravenous nicotinic agonist during development of HF. Under condition of sympathetic blockade, R-R responses to bolus injection of 200µg DMPP (nicotinic agonist) were found to be increased 5 times over the untreated group after 6 weeks. In experimental set 2, dogs treated with weekly DMPP injections and in HF were anesthetized, and underwent electrical stimulation of the right vagus nerve which showed SCL responses greater than 10 times that of controls, p<0.05. Complete ganglionic blockade with hexamethonium abolished all responses, confirming that synaptic transmission was mediated entirely by nAChR in both controls and HF. Conclusions: Despite decreased ganglionic function leading to reduced parasympathetic control of the heart in HF, repeated exposure with nicotinic agonist during the development of HF results in not only preserved, but supra-normal effects of parasympathetic stimulation on the sinus node.