Pulmonary edema resulting from cardiac failure is a major clinical problem. Non-cardiogenic pulmonary edema following cardiac surgery (cardiopulmonary bypass, inflammatory response, etc.) is one of the leading causes of delayed extubation and extended length of stay in the ICU. Pulmonary venous tone is one of the key determinants of transvascular fluid flux into the lung. However, there are only a handful of studies that have investigated the cellular mechanismsthat regulate pulmonary venous tone. Moreover, the extent to which exposure to anesthetic agents alters cellular mechanisms of pulmonary venous tone is entirely unknown. Vascular smooth muscle tone is regulated by the intracellular free Ca2+ concentration and myofilament Ca2+ sensitivity. Vascular smooth muscle tone is modulated by endothelium-derived relaxing and contracting factors. The overall goals of this application are: 1) to elucidate fundamental mechanisms that regulate pulmonary venous tone; and 2) to identify the extent and the cellular mechanisms of action by which general anesthetics alter pulmonary venous tone. The overarching hypothesis for these studies is that the protein kinase C (PKC), tyrosine kinase (TK) and Rho-kinase (ROK) signaling pathways are the primary targets for anesthesia-induced changes in pulmonary venous tone.
Aim 1 will investigate the effects of vasoconstrictor stimuli, alone and in combination with general anesthetics (inhalational and intravenous), on cellular mechanisms that regulate intracellular free Ca2+ concentration in pulmonary venous smooth muscle (PVSM).
Aim 2 will investigate the effects of vasoconstrictor stimuli, alone and in combination with general anesthetics, on cellular mechanisms that regulate myofilament Ca2+ sensitivity in PVSM.
Aim 3 will investigate the effects of general anesthetics on cellular mechanisms (cAMP, cGMP, K+ATP channel) that regulate vasodilator responses in pulmonary veins, including endothelium-dependent and PVSM components of the response. We believe these studies represent the first comprehensive attempt to identify cellular mechanisms that regulate pulmonary venous tone. Moreover, these studies should elucidate cellular mechanisms of anesthetic action on pulmonary veins, which should provide insight concerning the optimal choice of anesthetic agent to minimize increases in pulmonary venous tone in the perioperative period.
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