Since it is well established that volatile halogenated anesthetics alter hepatic performance during anesthesia, the objective of this proposal will be to determine the MECHANISMS OF THESE ALTERATIONS IN HEPATIC PERFORMANCE WITH SPECIAL EMPHASIS ON LIVER PERFUSION. There is a marked differential effect of commonly used inhalation anesthetics on liver perfusion and performance that is not well understood. A chronically instrumented greyhound dog model will be used which alleviates previously confounding surgical trauma induced influences on hepatic perfusion. Specifically my aims are: 1. TO DETERMINE THE DIFFERENTIAL EFFECTS OF HALOGENATED ANESTHETICS ON THE DYNAMICS OF HEPATIC PERFORMANCE IN CHRONICALLY INSTRUMENTED DOGS. Both currently used and newly developed anesthetics (Sevoflurane, Desflurane) will be examined. Hepatic blood flow along with oxygen supply and demand effects will be measured. Complimentary studies will be undertaken to determine anesthetic influences on the hepatic arterial buffer response in our model (see Specific Aim 2). Differential anesthetic effects observed in these studies may have an influence on clinical anesthetic practice in which hepatic perfusion and oxygenation may be crucial. 2. TO DETERMINE THE MECHANISM OF DIFFERENTIAL ANESTHETIC INDUCE DISRUPTION OF THE HEPATIC ARTERIAL BUFFER RESPONSE. Normal hepatic arteria buffer response may be mediated by intrahepatically produced adenosine. Halothane, in contrast to other agents, disrupts this mechanism. Preliminary results suggest reduced adenosine production during halothane anesthesia may play a role. Evaluation of the hepatic arterial buffer response under conscious and anesthetized condition will be performed with the use of a portal vein vascular occluder. Further evaluation of adenosin production and the degree to which the hepatic arterial buffer response is preserved will be evaluated in my model. Additionally, effects of adenosin antagonists will be used in control conditions and with inhalational anesthetics to further define the role of adenosine in the buffer response and the preservation of hepatic artery blood flow in this model. 3. DETERMINE THE EFFECT OF ALTERED HEPATIC BLOOD FLOW ON HEPATIC PERFORMANCE. Altered hepatic perfusion due to inhalational anesthetics results in change hepatic drug handling ability which can be evaluated using our chronic model. Effects on clearance of drugs with varying extraction ratio and pathways of metabolism will be evaluated. Both inhaled anesthetic effects on hepatic intrinsic (metabolism) and total clearance of drugs will be determined using my model. Results may influence clinical drug dosing practices during anesthesia. My proposal will thus allow evaluation of differential anesthetic effects o hepatic perfusion with specific insight into the quantification of the hepatic arterial buffer response both during conscious and anesthetized conditions. Additionally evaluation of the mechanism of the buffer respons will be performed as well as one component of hepatic performance dependent on hepatic perfusion specifically hepatic drug clearance. .

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Arizona
Schools of Medicine
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