The Journal of Thoracic and Cardiovascular Surgery
Volume 137, Issue 5 , Pages 1249-1257 , May 2009

Long-acting oral phosphodiesterase inhibition preconditions against reperfusion injury in an experimental lung transplantation model

  • Eric S. Weiss, MD

      Affiliations

    • Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md
    • ,
  • Hunter C. Champion, MD, PhD

      Affiliations

    • Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md
    • ,
  • Jason A. Williams, MD

      Affiliations

    • Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md
    • ,
  • William A. Baumgartner, MD

      Affiliations

    • Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md
    • ,
  • Ashish S. Shah, MD

      Affiliations

    • Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md
    • Corresponding Author InformationAddress for reprints: Ashish S. Shah, MD, Assistant Professor of Surgery, Division of Cardiac Surgery, The Johns Hopkins Hospital, Blalock 618, 600 N. Wolfe St, Baltimore, MD 21287.

Received 13 May 2008 ,Revised 25 November 2008 ,Accepted 30 December 2008.

  • Image Result

    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

    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).

  • Image Result
    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 cours

    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).

  • Image Result
    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 g

    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.

  • Image Result
    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 endo

    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.

  • Image Result
    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 n

    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.

 Supported by the Mildred and Carmont Blitz Cardiac Research Fund, the Joyce Koons Family Cardiac Endowment Fund, the American Medical Association Foundation (AMA seed grant, E.S.W.), and the National Institutes of Health (NIH 2T32DK007713-12 ESW). Eric Weiss and Jason Williams are Irene Piccinini Investigators in Cardiac Surgery. The study was also supported in part by an American Heart Association Scientist Development Grant, a grant from the W.W.Smith Charitable Trust, a Shih-Chun Wang Young Investigator Award; a Giles F. Filley Award of the American Physiological Society; the Bernard Family Foundation, and NIHP50HL084946 (H.C.C.).

 Read at the Eighty-eighth Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 10–14, 2008.

PII: S0022-5223(09)00032-4

doi: 10.1016/j.jtcvs.2008.12.040

The Journal of Thoracic and Cardiovascular Surgery
Volume 137, Issue 5 , Pages 1249-1257 , May 2009

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