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Vol. 292, Issue 2, 512-520, February 2000
Department of Internal Medicine, Justus-Liebig-University Giessen,
Giessen (R.T.S., A.R., N.W., H.A.G., F.G., W.S., D.W.); and Byk Gulden
Pharmaceuticals, Konstanz (C.S., H.T.), Germany.
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.
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