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Vol. 282, Issue 3, 1650-1657, 1997
Department of Physiology and Biophysics, Indiana University School
of Medicine, Indianapolis, Indiana
Pulmonary artery (PA) relaxation in response to vasodilators is
significantly attenuated in models of hypoxia-induced pulmonary hypertension (HPH). The activity of phosphodiesterases (PDE) which hydrolyze vasodilatory second messengers may be increased by HPH, which
thereby contributes to attenuated vasodilatory responses. The purpose
of this study was to determine the effect of PDE inhibition on
agonist-induced relaxation of PA from normal rats and rats with HPH
(FIO2, 0.1 for 14 days). Isolated PA rings were
suspended in baths containing Krebs-Henseliet salt solution and
contracted with U46619 in the presence or absence of a PDE3 (milrinone)
or PDE4 (rolipram) inhibitor. Isoproterenol and forskolin induced concentration-dependent relaxation of PA rings from normal rats and
rats with HPH, but the degree of relaxation was significantly less
(*P < .05; n = 4) in PA from rats with HPH.
Treatment with either PDE inhibitor significantly improved (*P < .05; n = 4) the magnitude of agonist-induced relaxation
in PA rings from normal rats and rats with HPH. Additionally, PDE3A
transcripts (8 and 10 kb) were increased (3.8 ± 1.6-fold and
3.9 ± 1.2-fold; n = 3, respectively) in PAs from
rats with HPH compared with normal controls. These data show that
inhibition of PDE3 and PDE4 activity can significantly improve PA
relaxation in HPH and that expression of PDE3A mRNA is increased during
HPH. These findings suggest that PDEs play an important role in the
development and maintenance of HPH.
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