Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model Eric S. Weiss, MD,

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Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model Eric S. Weiss, MD, Hunter C. Champion, MD, PhD, Jason A. Williams, MD, William A. Baumgartner, MD, Ashish S. Shah, MD The Journal of Thoracic and Cardiovascular Surgery Volume 137, Issue 5, Pages 1249-1257 (May 2009) DOI: 10.1016/j.jtcvs.2008.12.040 Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Partial pressures of arterial oxygen (A) and carbon dioxide (B) between control animals (dashed line) and animals treated with tadalafil (solid black line). Measurements by arterial blood gas sampling were taken at 15-minute intervals over the course of the experiment. Data points are mean values with error bars corresponding to standard error of the mean (SEM). P values were obtained by repeated measures analysis of variance (RE ANOVA) between groups and modeling with generalized estimating equation (GEE). The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1249-1257DOI: (10.1016/j.jtcvs.2008.12.040) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Mean pulmonary artery pressure (mPAP) between control animals (dashed line) and animals treated with tadalafil (solid black line). Measurements of mPAP were taken at 15-minute intervals over the course of the experiment. Data points are mean values with error bars corresponding to standard error of the mean (SEM). P value corresponds to repeated measures analysis of variance (RM ANOVA) between groups modeling with generalized estimating equation (GEE). The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1249-1257DOI: (10.1016/j.jtcvs.2008.12.040) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Levels of reactive oxygen species (ROS) as measured by luminal chemiluminescence activity (relative light units, RLU) at 4 distinct time points during the experiment. Control animals are seen in the gray shaded bars, and tadalafil-treated animals are shown with black solid bars. Means values are provided above the bars with error bars corresponding to standard deviations. P values correspond to results obtained by comparison of means via the Student t test. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1249-1257DOI: (10.1016/j.jtcvs.2008.12.040) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Nitric oxide synthase (NOS) activity for control (gray shaded bars) versus tadalafil-treated (solid black bars) animals as measured by citruline formation. Levels of both inducible NOS (iNOS) and endothelial NOS (eNOS) are provided. Means values are provided about the bars with error bars corresponding to standard deviations. P values correspond to results obtained by comparison of means via the Student t test. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1249-1257DOI: (10.1016/j.jtcvs.2008.12.040) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Mechanism of NOS signaling and PDE inhibition. Active inhibition of PDE5 by tadalafil leads to increases in cyclic GMP and PKG, which has a variety of potential protective effects. eNOS, Endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; O2, oxygen; NO, nitric oxide; GC, guanyl cyclase; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; PDE5, phosphodiesterase type 5; PKG, protein kinase G; ROS, reactive oxygen species; mitoKATP, mitochondrial potassium channels. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1249-1257DOI: (10.1016/j.jtcvs.2008.12.040) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions