Anesthetic management of patients with coronary artery disease remains an important clinical problem. The long term goal is an in-depth analysis of actions and mechanisms by which anesthetic agents affect ischemic myocardium. The majority of previous investigations elucidating the cardiovascular pharmacology of anesthetic agents has been conducted in acute, frequently open chest preparations, with a baseline anesthetic. Additionally, more previous work completed in vivo has involved use of experimental preparations with only a small region of ischemia. In this proposal, the effects of 3 volatile anesthetics (halothane, enflurane and isoflurane) and 2 narcotic agonists (fentanyl and sufentanil) on ischemic myocardium will be investigated in chronically instrumented dogs. This preparation offers the advantage of direct comparison of anesthetic and conscious states. Specific studies will be directed towards elucidating anesthetic actions on oxygen supply-demand balance in normal regions and in regions with various degrees of ischemia. Dose response relationships of each agent will be studied in dogs with acute or chronic occlusion of the left anterior descending coronary artery. Prior implantation of Ameroid constrictors will allow for study of each agent in myocardium with varying degrees of collateralization. In certain experiments, this will be combined with mild or severe degrees of constriction of the left circumflex coronary artery in models of multivessel coronary artery disease. Regional myocardial perfusion will be measured by radioactive microspheres and regional wall thickness determined by means of Doppler transducers implanted in normal and ischemic zones. In addition, hemodynamics, global cardiac function, regional electrical activity and myocardial oxygen consumption and lactate metabolism will be recorded in the conscious state and after administration of volatile anesthetics or narcotic agonists. The effects of these agents on protection of ischemic myocardium following acute coronary artery occlusion will also be studied. Myocardial infarct size will be measured by a histochemical staining technique. Anesthetic-induced enhancement or decrement in true coronary collateral perfusion and/or myocardial oxygen demand will be correlated with changes in systemic and coronary hemodynamics. These studies will lend insight into mechanisms whereby anesthetics produce alterations in myocardial oxygen balance and provide evidence of which anesthetic is most beneficial for ischemic myocardium.
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