The objective of this proposed research is to investigate the mechanisms of the interaction between volatile anesthetic agents and catecholamines on the cellular electrophysiologic properties and ionic currents of cardiac Purkinje fibers to better understand their combined effects on generation of arrhythmias with a history of prior myocardial infarction in association with activation or reflex sympathetic activity or during the administration os exogenous catecholamines to support the circulation. Our knowledge of the electrophysiologic mechanisms generating these arrhythmias would be enhanced by use of in vitro models to examine the interactions between the volatile anesthetics and the abnormal electrical activity induced by norepinephrine and selective alpha- and beta-adrenergic agonists in ischemic and nonischemic hearts. Specific objectives are: 1) To determine effects of halothane and isoflurane in combination with adrenergic agonists on electrophysiology of Purkinje fiber and Purkinje fiber-ventricular muscle junction conduction and on regional action potential characteristics. 2) To determine effects of halothane, isoflurane and enflurane on the intracellular calcium changes associated with catecholamine stimulated automaticity of normal Purkinje fibers and the triggered activity of ischemic Purkinje fibers. 3) To determine the mechanisms underlying the separate and combined effects of these drugs by direct measurements of their actions on whole cell ionic currents and single channel activity. Our major achievement over the last several years has been the ability to perform electrophysiological studies of Ca2+, Na+ and K+ currents, single channel K+ kinetics and intracellular calcium ([Ca2+]i) and electrophysiologic properties of Purkinje fibers in the presence of catecholamine. The proposed studies of this application are coordinated as a major effort to understand the mechanisms by which anesthetics in combination with catecholamines modulate cardiac electrophysiology. Previous work on catecholamine-anesthetic interactions has been largely descriptive and focused on adrenergic effects in vivo with less attention paid to cellular electrophysiology. Determination of catecholamine- anesthetic interactions on normal and ischemic cardiac tissues may permit development of specific therapeutic approaches for the perioperative management of cardiac arrhythmias. GRANT=R01HL35027 A continuing investigation of physiological mechanisms underlying regional coronary and myocardial responses to altered O2 supply and demand is proposed. These mechanisms will be delineated for the first time in the working, in situ right ventricle (RV), and differences between right coronary (RC) and left coronary (LC) control mechanisms will be related to differences in right and left ventricular function. The investigation will define: 1) mechanisms which regulate RC blood flow, and will define contributions of RC flow and O2 extraction reserves in supplying O2 to RV myocardium when a) O2 demand is increased and b) RC arterial O2 content is reduced; 2) the role of the pericardium in the RC response to altered RC perfusion pressure, RC vasomotor tone, and RV preload; 3) potencies of alpha adrenoceptor subtypes in the RC circulation, and will define their respective roles in RC pressure-flow autoregulation, modulation of RC oxygen extraction reserve, and possible limitation of RC oxygen supply; 4) the role of myocardial PO2 compared to that of vasoactive metabolites, especially purine nucleosides, in the regulation of RC and LC vascular resistance, and will define subcellular adjustments triggered by states of oxygen deficiency and providing for metabolic control of coronary blood flow; 5) the role of adenosine or its breakdown products in limiting myocardial oxygen demand under conditions of reduced myocardial oxygen supply. Branches of the RC and LC circulations of anesthetized dogs will be perfused selectively with blood of controlled O2 content, and venous blood from the perfused tissue will be collected. O2 supply will be altered by varying selectively and in combination perfusate O2 content, perfusion pressure, and by infusing coronary vasodilators. Myocardial O2 demand will be altered by varying selectively heart rare, ventricular preload and afterload, and myocardial inotropic state. Variables to be measured: 1) coronary blood flow (flowmeter and microsphere distribution); 2) coronary arterial and venous O2 tension and content; 3) coronary arterial and venous concentrations of nucleosides, lactate, and pyruvate (HPLC and enzymatic techniques); 4) coronary small vessel and total vascular volumes (isotope dilution); 5) right and left ventricular diastolic and systolic pressures; 6) systemic and pulmonary arterial pressures and heart rate; 7) regional myocardial diastolic and systolic segment lengths (ultrasonic crystals), PO2 (polarographic electrode), concentrations of high energy phosphates and nucleosides (HPLC and enzymatic techniques), and electrograms. The investigation is in accordance with long term objectives to define mechanisms which adjust coronary blood flow to meet myocardial O2 requirements under changing conditions of O2 demand and supply. The results will have clinical relevance to conditions which alter ventricular and coronary function and to conditions of which alter the O2 content of arterial blood.
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