The two objectives of this proposal are to test the hypothesis that there are significant postnatal changes in the properties of ionic channels expressed in human atrial tissue, and to determine whether there are postnatal changes in the effects of neurotransmitters and antiarrhythmic drugs on human cardiac ion channels. Over the past decade studies conducted on rat, rabbit and canine heart tissue have revealed the existence of marked postnatal changes in the characteristics of cardiac action potentials, the density and gating behavior of ion channels, th number and subtypes of adrenergic receptors expressed, the amount and subtypes of G protein isoforms expressed, and both qualitative and quantitative changes in the effects of neurotransmitters on ion channels. While much has been learned from animal experiments, at present it is unclear whether similar changes occur during postnatal development in the heart as well. Our preliminary studies indicate that postnatal changes of major outward currents (Ito and Ik1) in human atrial tissue differ from those previously observed in rat and rabbit. Therefore previous conclusions based upon animal models may not accurately reflect the pattern of postnatal development that occur in the human heart. The goal of this proposal will be to provide the first in-depth characterization of the how the physiology an pharmacology of cardiac ionic channels change during postnatal development in human heart tissue. This goal will be achieved by investigating the behavior of ionic currents in single atrial myocytes isolated from samples of human right atrial appendage obtained from patients of different age.
The specific aims of this proposal are; 1) To test the hypothesis that the human L-type ICa undergoes developmental changes in terms of its current density, gating properties, ionic selectivity and dependence upon internal [Ca]; 2) To test the hypothesis that there are postnatal changes in the time dependent outward current IK; 3) To test the hypothesis there are postnatal changes in the modulation of human Ito, IK1, IK and iCa by alpha- and beta- adrenoreceptor agonists and G proteins; 4) To test the hypotheses that there are significant postnatal changes in the inhibitory effects of antiarrhythmic drugs on I to associated with postnatal changes in Ito inactivation; 5) To test the hypothesis that there is a postnatal change in the interaction of antiarrhythmic drugs with human atrial sodium channels. The results of these studies will provide the first clear explanation of the ionic mechanisms underlying the marked postnatal changes in the electrophysiology of the human atrium, and will provide the first direct test of the hypothesis that there are postnatal changes in the effects of antiarrhythmic drugs on the human heart.
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