Our objective is to identify mechanisms responsible for chronic abnormalities in pulmonary vascular regulation following single-lung transportation. We will utilize a variety of experimental techniques to delineate the loci in the signal transduction pathways that mediate these defects. These include; 1) in vivo studies of conscious dogs chronically- instrumented for measurement of the pulmonary vascular pressure-flow relationship; 2) in vitro organ bath studies of isolated pulmonary arterial rings; 3) in vitro studies of perfused pulmonary microvessels; 4) single- cell measurements of pulmonary vascular smooth muscle (VSM) membrane potential and ion channel activity 5) biochemical measurements of enzyme activity and second messenger systems; and 6) quantitative morphological measurements of the pulmonary vasculature.
Specific Aims 1 -4 are a direct extension of work completed in the current funding period utilizing the left lung autotransplantation (LLA) model.
Specific Aim 1 tests the hypothesis that LLA is associated with morphological changes in the pulmonary vasculature supplying the transplanted lung.
Specific Aim 2 investigates the cellular mechanism for the attenuated response to nitric oxide (NO)-mediated pulmonary vasodilation post-LLA. In vitro studies test the hypotheses that the endothelial defect involves: a) receptor or G- protein dysfunction; b) a decrement in the intracellular Ca2+ signal for NO synthase activation; c) a decrease in the enzymatic activity of NO synthase; d) a decrease in the effective concentration of NO due to inactivation by superoxide anion; e) co-release of vasoconstrictor metabolites of arachidonic acid.
Specific Aim 3 investigates the cellular mechanism for enhanced pulmonary vascular reactivity to sympathetic alpha1 adrenoreceptor activation post-LLA. In vitro studies test the hypotheses that the VSM defect involves: a) an increase in alpha1 adrenoreceptor density; b) partial membrane depolarization due to dysfunction of ion transporters; c) an increased release of Ca2+ from intracellular stores.
Specific Aim 4 investigates the cellular mechanism for the attenuated response to sympathetic beta adrenoreceptor cAMP- mediated pulmonary vasorelaxation post-LLA. In vitro studies test the hypotheses that the VSM defect involves: a) receptor or G-protein dysfunction; b) a decrease in adenylate cyclase activity; c) an increase in cAMP phosphodiesterase activity; d) an increase in protein kinase C activity.
Specific Aim 5 investigates the effects of LLA on pulmonary vasodilation mediated by ATP-sensitive K+ channels (K+ATP). In vivo studies test the hypotheses that: a) K+ ATP vasodilation is attenuated post-LLA; b) this vasodilator mechanism is involved in the integrative pulmonary vascular response to systemic hypotension. In vitro studies test the hypothesis that a defect in this mechanism alters the pulmonary vasorelaxant response to severe hypoxia post-LLA.
Specific Aim 6 investigates the effects of left lung allotransplantation on the mechanisms of pulmonary vasoregulation detailed in Aims 1-6. These studies should elucidate fundamental cellular mechanisms by which lung transplantation alters chronic pulmonary vascular regulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL040361-06A1
Application #
2219564
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1989-04-01
Project End
1998-11-30
Budget Start
1994-12-01
Budget End
1995-11-30
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Kanaya, Noriaki; Murray, Paul A; Damron, Derek S (2006) Effects of L-type Ca2+ channel modulation on direct myocardial effects of diazepam and midazolam in adult rat ventricular myocytes. J Anesth 20:17-25
Sohn, Ju-Tae; Murray, Paul A (2003) Inhibitory effects of etomidate and ketamine on adenosine triphosphate-sensitive potassium channel relaxation in canine pulmonary artery. Anesthesiology 98:104-13
Damron, Derek S; Kanaya, Noriaki; Homma, Yasuyuki et al. (2002) Role of PKC, tyrosine kinases, and Rho kinase in alpha-adrenoreceptor-mediated PASM contraction. Am J Physiol Lung Cell Mol Physiol 283:L1051-64
Kanaya, Noriaki; Murray, Paul A; Damron, Derek S (2002) The differential effects of midazolam and diazepam on intracellular Ca2+ transients and contraction in adult rat ventricular myocytes. Anesth Analg 95:1637-44, table of contents
Sato, Kosei; Seki, Sumihiko; Murray, Paul A (2002) Effects of halothane and enflurane anesthesia on sympathetic beta-adrenoreceptor-mediated pulmonary vasodilation in chronically instrumented dogs. Anesthesiology 97:478-87
Tanaka, Satoru; Kanaya, Noriaki; Homma, Yasuyuki et al. (2002) Propofol increases pulmonary artery smooth muscle myofilament calcium sensitivity: role of protein kinase C. Anesthesiology 97:1557-66
Ogawa, K; Tanaka, S; Murray, P A (2001) Propofol potentiates phenylephrine-induced contraction via cyclooxygenase inhibition in pulmonary artery smooth muscle. Anesthesiology 94:833-9
Horibe, M; Kondo, I; Damron, D S et al. (2001) Propofol attenuates capacitative calcium entry in pulmonary artery smooth muscle cells. Anesthesiology 95:681-8
Ogawa, K; Tanaka, S; Murray, P A (2001) Inhibitory effects of etomidate and ketamine on endothelium-dependent relaxation in canine pulmonary artery. Anesthesiology 94:668-77
Kondo, U; Kim, S O; Nakayama, M et al. (2001) Pulmonary vascular effects of propofol at baseline, during elevated vasomotor tone, and in response to sympathetic alpha- and beta-adrenoreceptor activation. Anesthesiology 94:815-23

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