Our objective is to investigate mechanisms of chronic vasomotor control of the pulmonary circulation following left lung transplantation (LLT). We have developed an entirely new and unique methodology which allows us to generate continuous, multipoint pulmonary vascular pressure-flow (P:Q) plots for both the right (non-transplanted) and left (transplanted) lungs of chronically-instrumented conscious dogs, without altering systemic hemodynamics or the zonal condition of the lungs. This approach avoids the confounding influences of anesthesia and acute surgical trauma, and allows us to distinguish between vasoactive and flow-dependent (passive) effects of physiological and pharmacological intervention. Our first goal is to assess the chronic (3 months) effects of LLT on the baseline P:Q relationship. Both autograft and allograft models of LLt will be investigated. We have observed marked pulmonary vasoconstriction in the auto-transplanted lung even 2 month after LLT. Four mechanisms which could mediate this vasoconstriction will be investigated. Specifically, we will test the hypotheses that: 1) autonomic nervous system (ANS)-mediated vasoconstrictor activity is increased in the transplanted lung (Aim 2). P:Q plots will be generated during administration of ANS agonists and antagonists to assess the response to both exogenous and endogenous ANS activation; 2) vasoconstriction in the transplanted lung is due to enhanced effects of angiotensin II and arginine vasopressin (Aim 3). P:Q plots will be generated during the exogenous administration and endogenous inhibition of these 2 hormones; 3) metabolites of the cyclooxygenase and lipoxygenase pathways mediate vasoconstriction of arachidonic acid and following pharmacologic inhibition of these metabolic pathways; 4) lung transplantation decreases the magnitude of endothelial-dependent pulmonary vasodilation (Aim 5). P:Q plots will be generated during administration of endothelial-dependent and -independent vasodilators.
Aim 6 examines the integrated response of the transplanted lung to a physiological stimulus, alveolar hypoxia, and tests the hypothesis that hypoxic pulmonary vasoconstriction is increased following LLT. Finally, the direct effect of these vasoactive stimuli outlined in Aims 2-5 will be investigated in in vitro experiments using isolated pulmonary vascular smooth muscle from the transplanted lung (Aim 7). These studies represent the first systemic evaluation of the chronic effects of lung transplantation on the pulmonary circulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040361-02
Application #
3357497
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1989-04-01
Project End
1994-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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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