(Chest. 2005;128:616S.)
© 2005
American College of Chest Physicians
Effects of Aerosol vs IV UT-15 on Prostaglandin H2 Analog-Induced Pulmonary Hypertension in Sheep*
Brett L. Sandifer, MD;
Kenneth L. Brigham, MD;
E. Clinton Lawrence, MD and
Richard E. Parker, PhD
* From the Center for Translational Research in the Lung and the Andrew J. McKelvey Lung Transplantation Center, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA.
Correspondence to: Brett L. Sandifer, MD, the Center for Translational Research in the Lung and the Andrew J. McKelvey Lung Transplantation Center, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA
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Introduction
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Prostacyclins provided the first medical treatment for pulmonary hypertension that improved mortality, but these medications have systemic effects and require continuous IV or subcutaneous infusions. We compared the effects of IV vs aerosolized UT-15 (treprostinil) on pulmonary and systemic hemodynamics during acute pulmonary hypertension in a sheep model.
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Materials and Methods
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Three yearling sheep were surgically prepared to measure pulmonary artery pressure, left atrial pressure, mean arterial pressure (MAP), cardiac output (CO), and heart rate (HR). Initially, the sheep received various concentrations of a prostaglandin (PG) H2 analog to determine the dose needed to maintain pulmonary vascular resistance (PVR) at 2.5 to three times baseline values. Then UT-15 was infused IV in increasing doses (200, 400, and 600 ng/kg/min) during the PGH2 infusion, while PVR, CO, HR, and MAP were measured. Subsequently, the sheep received varying doses of aerosolized UT-15 during the PGH2 infusion, and PVR, CO, HR, and MAP were recorded.
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Results
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The concentration of PGH2 required to produce a 2.5-fold to threefold increase in PVR was 1,000 ng/kg/min. At this dose, CO and HR decreased and MAP increased. The UT-15 effect was dose-related; 600 ng/kg/min returned PVR to near baseline, but CO and HR increased and MAP decreased. Aersolized UT-15 at 850 ng/kg/min decreased PVR to near baseline values during the PGH2 infusion with minimal effects on MAP, CO, and HR.
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Conclusions
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Both IV and aerosolized UT-15 reverse PGH2-induced pulmonary hypertension in this model. However, the aerosolized UT-15 has more specific effects on the pulmonary circulation, avoiding the systemic side effects of the IV route.
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Clinical Implications
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The aerosolized delivery of prostacyclins can improve pulmonary vasoconstriction without altering systemic hemodynamics. We speculate that the aerosolized medication may affect pulmonary hemodynamics via effects on airway epithelium (ie, an epithelial-dependent regulation of the pulmonary circulation). Initial microarray studies of prostacyclin effects on human airway epithelial cells have implicated the activation of the transcription factor AP-1 as a possible explanation of the epithelial effects.
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Footnotes
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Abbreviations: CO = cardiac output; HR = heart rate; MAP = mean arterial pressure; PG = prostaglandin; PVR = pulmonary vascular resistance
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Introduction
Materials and Methods
