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(Circulation. 1996;94:1941-1947.)
© 1996 American Heart Association, Inc.

Articles

Inhibition of Tissue Angiotensin-Converting Enzyme With Quinapril Reduces Hypoxic Pulmonary Hypertension and Pulmonary Vascular Remodeling

Zengxuan Nong, MD; Jean-Marie Stassen, PhD; Lieve Moons, PhD; Desire Collen, MD, PhD; Stefan Janssens, MD, PhD

the Center for Transgene Technology and Gene Therapy (Z.N., J.-M.S., L.M., D.C.), Flanders Interuniversity Institute for Biotechnology; and Division of Cardiology (S.J.), University Hospital Gasthuisberg, University of Leuven, Belgium.

Correspondence to Stefan Janssens, MD, PhD, Division of Cardiology and Center for Transgene Technology and Gene Therapy, University Hospital Gasthuisberg, 49 Herestraat, B-3000 Leuven, Belgium. E-mail stefan.janssens@med.kuleuven.ac.be.

Background Angiotensin II may contribute to hypoxic pulmonary hypertension via its vasoconstrictor and growth-stimulatory effects on vascular smooth muscle cells (VSMCs). Therefore, the use of ACE inhibitors might reduce hypoxic pulmonary hypertension by decreasing pulmonary vasomotor tone or vascular remodeling.

Methods and Results Pulmonary hemodynamics and vascular remodeling were compared in chronically hypoxic (FIO₂=0.10) rats treated with 0, 1, and 10 mg·kg^-1·d^-1 quinapril, a potent tissue ACE inhibitor, both during and after the development of pulmonary hypertension. Quinapril reduced the development of pulmonary hypertension after 12 days of hypoxia from 26±1 to 19±1 mm Hg (P<.05). When started in established pulmonary hypertension, quinapril reduced pulmonary artery pressure and total pulmonary resistance index from 29±1 to 25±1 mm Hg and from 0.136±0.01 to 0.101±0.005 mm Hg·mL^-1·min^-1 per kg, respectively (P<.05). Chronically hypoxic rats showed a small pulmonary vasoconstrictor response that was not affected by quinapril. In contrast, percent medial thickness in alveolar duct blood vessels was reduced by quinapril treatment both in developing and in established pulmonary hypertension (10.0±0.2% versus 8.9±0.1% [P<.05] and 11.2±0.2% versus 9.1±0.2% [P<.05], respectively). 5'-Bromo-deoxyuridine–positive VSMCs were detected in 56±3% of hypoxic control pulmonary resistance vessels versus 41±3% of vessels after quinapril treatment (P<.05).

Conclusions Pulmonary ACE and angiotensin II contribute to the development and maintenance of hypoxic pulmonary hypertension in rats. ACE inhibition with quinapril reduces the development of hypoxic pulmonary hypertension and in part reverses established pulmonary hypertension, most likely via inhibition of pulmonary VSMC proliferation and/or growth.

Key Words: pulmonary hypertension • vascular remodeling • angiotension-converting enzyme • hypoxia

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