Chronic myocardial infarction (CMI) is associated with remodeling of the ventricle and evokes adaption in the cardiac neurohumoral control systems. To evaluate the remodeling of the intrinsic cardiac nervous system following myocardial infarction, the dorsal descending coronary artery was ligated in the guinea pig heart and the animals were allowed to recover for 7-9 weeks. Thereafter, atrial neurons of the intrinsic cardiac plexus were isolated for electrophysiological and immunohistochemical analyses. Intracellular voltage recordings from intrinsic cardiac neurons demonstrated no significant changes in passive membrane properties or action potential configuration compared to age-matched controls and sham-operated animals. The intrinsic cardiac neurons from chronic infarcted hearts did demonstrate an increase in evoked action potential (AP) frequency (as determined by the number of action potentials produced with depolarizing stimuli) and an increase in responses to exogenously applied histamine as compared to sham and age-matched controls. Conversely, pituitary adenylate cyclase-activating polypeptide (PACAP)-induced increases in intrinsic cardiac neuron evoked AP frequency were similar between control and CMI animals. Immunohistochemical analysis demonstrated a 3-fold increase in percentage of neurons immunoreactive for neuronal nitric oxide synthase (nNOS) in CMI animals compared to control and the additional expression of inducible NOS by some neurons, which was not evident in control animals. Finally, the density of mast cells within the intrinsic cardiac plexus was increased 3-fold in preparations from CMI animals. These results indicate that chronic myocardial infarction induces a differential remodeling of intrinsic cardiac neurons and functional up-regulation of neuronal responsiveness to specific neuromodulators.