Although acute modulation of cardiac membrane currents has been the subject of intensive investigation since the advent of the patch clamp technique, long-term modulation has received much less attention. This application proposes to investigate changes in cardiac electrophysiology that occur over a period of hours to days. Two major questions will be investigated: 1) the role played by the renin-angiotensin system in setting up the gradient in electrical properties across the ventricular wall which gives rise to the normal polarity of the T-wave, and 2) the changes induced in ion channels and pumps by long term exposure to alpha or beta adrenergic agonists. The applicant will employ a multidisciplinary approach including 1) biophysical (patch clamping), 2) molecular biology (RNase protection assays), and 3) protein chemistry (radioimmunoassays and phosphoantibodies). The results should provide insight into normal cardiac electrophysiology, as well as the changes that occur in response to elevated levels of angiotensin II or catecholamines. As the proposal includes studies of animals maintained on chronic ACE inhibition, AT1 receptor blockade, alpha adrenergic blockade, and beta adrenergic blockade, these studies should also be relevant to the electrical changes induced in cardiac cells by chronic exposure to these commonly used cardiovascular medications.
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