The applicant has completed residency training in both Internal Medicine and Anesthesiology,as well as subspecialty training in Cardiac Anesthesia. He was appointed to the faculty of Anesthesiology and Critical Care Medicine 3 years ago. In addition to administrative, patient care and teaching activities, the applicant has participated in laboratory research concerned with vasoactive regulation of the pulmonary circulation, under the direction of Dr. Paul A. Murray (sponsor). This application is a direct extension of this previous work. The overall goal of this study is to determine whether cardiopulmonary bypass (CPB) alters fundamental mechanisms that regulate the pulmonary circulation. The effects of CPB will be assessed by examining changes in the pulmonary vascular pressure-flow relationship, utilizing a unique methodology that we have developed.
Aim 1 will identify the extent to which CPB alters the pulmonary circulation in the acute perioperative phase, as well as delineate the time course of these changes in the 1 month period following CPB. Our preliminary results indicate that CPB results in active, nonflow-dependent pulmonary vasoconstriction. Thus, aims 2-5 investigate 4 separate mechanisms that could mediate the CPB-induced vasoconstriction.
Aim 2 tests the hypothesis that CPB-induced vasoconstriction is the result of increased sympathetic alpha adrenergic activation, increased angiotensin II production, or increased release of endogenous arginine vasopressin. The effects of selective inhibition of each of these 3 neurohumoral pathways will be investigated.
Aim 3 tests the hypothesis that CPB-induced vasoconstriction is the result of a decrease in endothelium-dependent pulmonary vasodilation. The effects of endothelium-dependent and independent pulmonary vasodilators will be investigated.
Aim 4 tests the hypothesis that CPB-induced vasoconstriction is due to the increased production of vasoconstrictor metabolites of the arachidonic acid metabolic pathway. The effects of selective inhibition of the cyclooxygenase and lipoxygenase pathways will be investigated.
Aim 5 tests the hypothesis that leukocyte sequestration and/or oxygen-derived free radical production mediate CPB-- induced vasoconstriction. The effects of leukocyte filtration and administration of free radical scavengers will be investigated. These studies should yield fundamental information concerning mechanisms of pulmonary vascular regulation, and will provide a rational basis for the clinical management of patients following CPB.
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