Abstract
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 (Fio 2, 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.
Footnotes
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Send reprint requests to: Robin S. Wagner, DVM, PhD, Departments of Physiology/Biophysics, Indiana University School of Medicine, 635 Barnhill Drive, MS 374, Indianapolis, IN 46202-5120.
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↵1 This study was supported in part by NIH K11 HL02562.
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↵2 Current address: Carolyn J. Smith, Ph.D., Department of Pathology, New York Medical College, Valhalla, NY 10595.
- Abbreviations:
- COPD
- chronic obstructive pulmonary disease
- DEPC
- diethyl pyrocarbonate
- GAPDH
- glyceraldehyde-3-phosphodehydrogenase
- Fio2
- fractional inspired oxygen
- HPH
- hypoxia-induced pulmonary hypertension
- IT
- initial tension
- KHSS
- Krebs-Henseleit salt solution
- Po
- KCl (80 mM) reference contraction
- PDE
- phosphodiesterase
- PA
- pulmonary artery
- PKA
- protein kinase A
- SSC
- standard saline citrate
- SDS
- sodium dodecyl sulfate
- 8-bromo-cAMP
- 8-bromoadenosine-3′,5′-cyclic monophosphate
- dbu-cAMP
- N6,2′-0-dibutyryl-cAMP
- Received January 7, 1997.
- Accepted May 21, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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