Our objectives are: 1) to characterize the extent to which volatile anesthetics (VA) alter the integrative responses to three distinct pulmonary vasodilator pathways compared to that measured in the conscious state; 2) to identify endogenous mechanisms that modulate the in vivo responses to pulmonary vasodilators in the conscious and anesthetized states; 3) to elucidate the cellular mechanisms responsible for the effects of VA on pulmonary vasorelaxation in vitro by delineating the loci of dysfunction in the signal transduction pathways; and 4) to investigate the effects of inhibiting each of these endogenous vasodilator pathways on the pulmonary vascular response to a physiological stimulus. In vivo studies utilize dogs that are chronically-instrumented for the measurement of continuous left pulmonary vascular pressure-flow plots in the conscious and anesthetized states. In vitro experiments assess the effects of VA on isolated pulmonary vascular smooth muscle via organ bath and bioassay preparations, and include biochemical measurements of cGMP and cAMP content and adenylate cyclase activity. Our overall hypothesis is that VA (halothane, isoflurane, enflurane) inhibit three mechanisms of pulmonary vasodilation.
Specific Aim 1 investigates the effects of VA on cGMP- mediated pulmonary vasodilation. In vivo studies characterize the effects of VA on the integrative responses to endothelium-dependent and - independent vasodilators. In vitro studies investigate the effects of VA on the activity of: endothelial receptors and G-proteins; endothelium-derived relaxing and contracting factors; guanylate cyclase; cGMP phosphodiesterase; and protein kinase C.
Specific Aim 2 investigates the effects of VA on cAMP-mediated pulmonary vasodilation. In vivo studies measure the effects of VA on the integrative responses to receptor and nonreceptor-mediated vasodilators. In vitro studies examine the effects of VA on the activity of: vascular smooth muscle receptors and G-proteins; adenylate cyclase; cAMP phosphodiesterase; and protein kinase C.
Specific Aim 3 investigates the effects of VA on K+- channel-mediated pulmonary vasodilation. In vitro studies investigate the effects of VA on the vasorelaxant responses to K+-channel agonists and severe hypoxia.
In Specific Aims 1 -3, the modulating effects of neuro-humoral activation, superoxide anion and arachidonic acid metabolites on the in vivo vasodilator responses will be investigated.
Specific Aim 4 assesses the involvement of these three vasodilator mechanisms, and the effects of VA, on the pulmonary vascular response to circulatory hypotension. These studies should provide fundamental new information concerning the cellular mechanisms by which VA alter these primary pulmonary vasodilator pathways, which should aid in the pharmacotherapy of patients undergoing surgical procedures utilizing VA.
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