The proposed research intends (1) to define the effects of autonomic nervous system stimulation and blockade on the cardiac electrophysiologic properties of the intact immature (1-15 days) canine heart, and (2) to define how the electrical responses of the neonatal heart to antiarrhythmic agents are modulated by changes in sympathetic and parasympathetic tone. Studies will be conducted utilizing the neonatal canine model developed in our laboratory. Electrophysiologic evaluations of atrial and ventricular refractoriness, SA node function, A-V nodal function and His Purkinje conduction and refractoriness will be performed utilizing multiple endocardial catheter recording and stimulation techniques. Changes in cardiac electrophysiology (conduction, refractoriness and automaticity) will be assessed prior to and following (1) anatomic and pharmacologic parasympathetic blockade, (2) sympathetic beta and alpha-adrenergic blockade and (3) combined autonomic blockade. The response of the neonatal heart to systemic infusions of adrenergic agonists (norepinephrine, epinephrine, isoproterenol, phenylephrine) and acetylcholine will be studied. Finally, the quantitative effects of selective tonic vagal and stellate ganglion stimulation as well as the temporal effects of phasic stimulation on neonatal cardiac conduction, refractoriness and automaticity will be evaluated. Comparative studies will be performed in older puppies (3-11 weeks) and adult dogs in order to assess the effects of maturation on the observed responses. In the second phase of the study, autonomic nervous system modulation of observed electropharmacodynamic changes in the immature heart's response to antiarrhythmic agents will be studied. Electrophysiologic changes resulting from antiarrhythmic drug administration will be quantitated and compared to the changes observed when parasympathetic and sympathetic input to the heart is altered utilizing the methods evaluated in the first phase of the project. Antiarrhythmic agents to be studied will include agents with known important direct (e.g. digoxin) and indirect (e.g. procainamide) autonomic interactions, as well as other selected conventional and investigational antiarrhythmic drugs.
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