This laboratory has been engaged in a systematic examination of the causes of perioperative hypoxemia. The work has demonstrated, quantitatively, the importance of hypoxic pulmonary vasoconstriction (HPV) for arterial oxygenation in health and disease, by the regulation of ventilation/perfusion ratios, as well as it's critical role in causing or contributing to pulmonary hypertension in acute and chronic lung disease. The induction of general anesthesia is associated with the development of dependent atelectasis. Normally HPV reduces the blood flow to atelectatic lung regions. However, inhalational, but not injectable, anesthetics variably inhibit HPV and oxygenation may become seriously compromised, particularly in the presence of lung disease or invasive techniques such as one-lung anesthesia for thoracic surgery,. Recent work by us and others have permitted the synthesis of an hypothesis that explains the fundamental HPV response in terms of pulmonary vascular smooth muscle cell properties. Following oxygen sensing the hypoxic response is a triphasic sequence with a transient Phase 1 constriction, a more or less transient (depending on wall tension conditions) Phase 2 dilation and a persistent Phase 3 constriction. Each of the Phases in the triphasic response can be understood in terms of the intracellular free calcium concentration (Ca2+), but the sources of the calcium combines features of both the electromechanical coupling of KCl induced constriction and the pharmacomechanical coupling of receptor agonist constriction but are not identical to either. Hypoxia Phase 1 is due to graded depolarization with Ca2+ induced Ca2+ release from the sarcoplasmic reticulum. Phase 2 is due to reuptake by the SR Ca2+ pumps and Phase 3 is due to increased force sensitization and some entry of Ca2+ through L-type sarcolemmal channels. The proposed studies will investigate the quantitative effects of inhalational and injectable (Propofol) general anesthetics on each step of this triphasic response. The methods employed will combine measurement of wall tension during exposure to hypoxia in isolated rat pulmonary arteries both intact and permeabilized and will measure intracellular Ca2+ using dye fluorescence as well as pharmacologic methods. Understanding the sites of anesthetic action is of fundamental importance but may also lead to improved patient management.
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