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.
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