Arterial hypoxemia is a constant threat during general anesthesia and the purpose of this work is ultimately to understand why this is so and how it may be prevented or treated. A principal cause is hypothesized to be inhibition of hypoxic pulmonary vasoconstriction (HPV) by the inhalational anesthetic agents resulting in loss of homeostatic regulation of the distribution of ventilation/perfusion ratios (VA/OC). This general concept will be evaluated in the first part of the proposal by extending the development of the computer model of the actively regulated pulmonary circulation, to include the VA/QC. In this way all of the factors associated with anesthetic drug actions and techniques can be explored for their influence on gas exchange and pulmonary hemodynamics. These results will be tested in a series of in vivo animal studies and ultimately in anesthetized human subjects. The second part of this proposal will utilize a new preparation of isolated pulmonary arteries that retain the HPV response. The direct and indirect (e.g., via endothelium) effects of isoflurane, enflurane and halothane (and ketamine for comparison) will be examine with the expectation that the influence of each on the vascular smooth muscle and the endothelial cell sites will differ. The general mechanism for the anesthetic action of HPV will be sought by investigating changes in the requirement for activator Ca2++ and the excitation-contraction coupling mechanisms (cAMP, cGMP, and IP3). The results of these studies will provide a fundamental basis for the therapeutic manipulations of HPV, and hence of oxygenation in pathophysiologic states.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM029628-11
Application #
3277275
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1981-07-01
Project End
1994-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ozaki, M; Marshall, C; Amaki, Y et al. (1998) Role of wall tension in hypoxic responses of isolated rat pulmonary arteries. Am J Physiol 275:L1069-77
Marshall, B E; Chen, L; Frasch, H F et al. (1998) Improved oxygenation with prostaglandin F2alpha with and without inhaled nitric oxide in dogs. J Appl Physiol 84:1350-8
O'Hara, D A; Hexem, J G; Derbyshire, G J et al. (1997) The use of a PID controller to model vecuronium pharmacokinetics and pharmacodynamics during liver transplantation. Proportional-integral-derivative. IEEE Trans Biomed Eng 44:610-9
Hanson 3rd, C W; Marshall, B E; Frasch, H F et al. (1996) Causes of hypercarbia with oxygen therapy in patients with chronic obstructive pulmonary disease. Crit Care Med 24:23-8
Marshall, C; Mamary, A J; Verhoeven, A J et al. (1996) Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction. Am J Respir Cell Mol Biol 15:633-44
Marshall, B E; Marshall, C; Frasch, F et al. (1994) Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. 1. Physiologic concepts. Intensive Care Med 20:291-7
Marshall, B E; Hanson, C W; Frasch, F et al. (1994) Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. 2. Pathophysiology. Intensive Care Med 20:379-89
Marshall, B E; Clarke, W R; Costarino, A T et al. (1994) The dose-response relationship for hypoxic pulmonary vasoconstriction. Respir Physiol 96:231-47
Marshall, C; Marshall, B E (1992) Hypoxic pulmonary vasoconstriction is not endothelium dependent. Proc Soc Exp Biol Med 201:267-70
Cohen, P J (1992) Allopurinol administered prior to hepatic ischaemia in the rat prevents chemiluminescence following restoration of circulation. Can J Anaesth 39:1090-3

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