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.
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