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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Subthreshold Doses of Specific Phosphodiesterase Type 3 and 4 Inhibitors Enhance the Pulmonary Vasodilatory Response to Nebulized Prostacyclin with Improvement in Gas Exchange

Ralph Theo Schermuly, Axel Roehl, Norbert Weissmann, Hossein Ardeschir Ghofrani, Christian Schudt, Herrmann Tenor, Friedrich Grimminger, Werner Seeger and Dieter Walmrath
Journal of Pharmacology and Experimental Therapeutics February 2000, 292 (2) 512-520;
Ralph Theo Schermuly
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Axel Roehl
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Norbert Weissmann
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Hossein Ardeschir Ghofrani
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Christian Schudt
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Herrmann Tenor
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Friedrich Grimminger
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Werner Seeger
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Dieter Walmrath
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Abstract

Aerosolized prostacyclin (PGI2) has been suggested for selective pulmonary vasodilation, but its effect rapidly levels off after termination of nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibition may offer a new strategy for amplification of the vasodilative response to nebulized PGI2. In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was used to establish stable pulmonary hypertension [increase in pulmonary arterial pressure (pPA) from ∼7 to ∼32 mm Hg], which is accompanied by progressive edema formation and severe disturbances in gas exchange with a predominance of shunt flow (increase from <2 to ∼58%, as assessed by the multiple inert gas elimination technique). In the absence of PGI2, dose-effect curves for intravascular and aerosol administration of the specific PDE3 inhibitor motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 inhibitor tolafentrine on pulmonary hemodynamics were established (potency rank order: rolipram > tolafentrine ∼ motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI2 was chosen to effect a moderate pPA decrease (∼4 mm Hg; rapidly returning to prenebulization values within 10–15 min) with only a slight reduction in shunt flow (∼49%). Prior application of subthreshold doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect pulmonary hemodynamics, caused prolongation of the post-PGI2 decrease in pPA. The most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI2 to ∼9 to 10 mm Hg, prolonged the post-PGI2 vasorelaxation to >60 min, reduced the extent of lung edema formation by 50%, and decreased the shunt flow to ∼19% (i.v. rolipram/motapizone) and 28% (aerosolized rolipram/motapizone). We conclude that lung PDE3/4 inhibition, achieved by intravascular or transbronchial administration of subthreshold doses of specific PDE inhibitors, synergistically amplifies the pulmonary vasodilatory response to inhaled PGI2, concomitant with an improvement in ventilation-perfusion matching and a reduction in lung edema formation. The combination of nebulized PGI2 and PDE3/4 inhibition may thus offer a new concept for selective pulmonary vasodilation, with maintenance of gas exchange in respiratory failure and pulmonary hypertension.

Footnotes

  • Send reprint requests to: Dieter Walmrath, Zentrum fur Innere Medizin, Justus-Liebig-Universitat Giessen, Klinikstrasse 36, D-35392 Giessen, Germany.

  • ↵1 This work was supported by the Deutsche Forschungsgemeinschaft (SFB 547). This article includes portions of the doctoral thesis of A.R.

  • Received for publication May 11, 1999.

  • Abbreviations:
    PGI2
    prostacyclin
    PDE
    phosphodiesterase
    pPA
    pulmonary arterial pressure
    pLA
    left atrial pressure
    U46619
    thromboxane A2 mimetic
    V˙a/Q˙ ratio
    ventilation-perfusion ratio
    Q˙
    perfusion flow
    V˙a
    alveolar ventilation per minute
    NO
    nitric oxide
    RSS
    residual sum of squares
    • Accepted October 7, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 2
1 Feb 2000
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Subthreshold Doses of Specific Phosphodiesterase Type 3 and 4 Inhibitors Enhance the Pulmonary Vasodilatory Response to Nebulized Prostacyclin with Improvement in Gas Exchange

Ralph Theo Schermuly, Axel Roehl, Norbert Weissmann, Hossein Ardeschir Ghofrani, Christian Schudt, Herrmann Tenor, Friedrich Grimminger, Werner Seeger and Dieter Walmrath
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 512-520;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Subthreshold Doses of Specific Phosphodiesterase Type 3 and 4 Inhibitors Enhance the Pulmonary Vasodilatory Response to Nebulized Prostacyclin with Improvement in Gas Exchange

Ralph Theo Schermuly, Axel Roehl, Norbert Weissmann, Hossein Ardeschir Ghofrani, Christian Schudt, Herrmann Tenor, Friedrich Grimminger, Werner Seeger and Dieter Walmrath
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 512-520;
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