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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002426-05
Application #
2210041
Study Section
Research Manpower Review Committee (MR)
Project Start
1990-08-01
Project End
1996-01-31
Budget Start
1994-08-01
Budget End
1996-01-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Nyhan, D; Gaine, S; Hales, M et al. (1999) Pulmonary vascular endothelial responses are differentially modulated after cardiopulmonary bypass. J Cardiovasc Pharmacol 34:518-25
Zanaboni, P; Murray, P A; Simon, B A et al. (1997) Selective endothelial dysfunction in conscious dogs after cardiopulmonary bypass. J Appl Physiol 82:1776-84
Desai, P M; Nishiwaki, K; Stuart, R S et al. (1994) Humoral pulmonary vasoregulation in conscious dogs after left lung autotransplantation. J Appl Physiol 76:902-8
Nyhan, D P; Redmond, J M; Gillinov, A M et al. (1994) Prolonged pulmonary vascular hyperreactivity in conscious dogs after cardiopulmonary bypass. J Appl Physiol 77:1584-90
Trempy, G A; Nyhan, D P; Murray, P A (1994) Pulmonary vasoregulation by arginine vasopressin in conscious, halothane-anesthetized, and pentobarbital-anesthetized dogs with increased vasomotor tone. Anesthesiology 81:632-40
Nishiwaki, K; Rock, P; Stuart, R S et al. (1993) Pulmonary vascular beta-adrenoreceptor activity in conscious dogs after left lung autotransplantation. J Appl Physiol 75:256-63
Nishiwaki, K; Nyhan, D P; Stuart, R S et al. (1993) Pulmonary vascular alpha 1-adrenoreceptor activity in conscious dogs after left lung autotransplantation. J Appl Physiol 74:733-41
Peterson, W P; Trempy, G A; Nishiwaki, K et al. (1993) Neurohumoral regulation of the pulmonary circulation during circulatory hypotension in conscious dogs. J Appl Physiol 75:1675-82
Nyhan, D P; Pribble, C G; Peterson, W P et al. (1993) Amrinone and the pulmonary vascular pressure-flow relationship in conscious control dogs and following left lung autotransplantation. Anesthesiology 78:1166-74
Nishiwaki, K; Nyhan, D P; Stuart, R S et al. (1993) Abnormal responses to pulmonary vasodilators in conscious dogs after left lung autotransplantation. Am J Physiol 264:H917-25

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