Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function.
1. Hypoxic pulmonary hypertension in rats (10% O2, 4 weeks) is characterized by changes in pulmonary vascular structure and function. The effects of the angiotensin converting enzyme inhibitor perindopril (oral gavage, once daily for the 4 weeks of hypoxia) on these changes were examined. 2. Perindopril (30 mg kg-1 d-1) caused an 18% reduction in pulmonary artery pressure in hypoxic rats. 3. Structural changes (remodelling) in hypoxic rats included increases in (i) critical closing pressure in isolated perfused lungs (remodelling of arteries <50 microm o.d.) and (ii) medial wall thickness of intralobar pulmonary arteries, assessed histologically (vessels 30 - 100 and 101 - 500 microm o.d.). Perindopril 10 and 30 mg kg-1 d-1 attenuated remodelling in vessels < or = 100 microm (lungs and histology), 30 mg kg-1 d-1 was effective in vessels 101 - 500 microm but neither dose prevented hypertrophy of main pulmonary artery. 3 mg kg-1 d-1 was without effect. 4. Perindopril (30 mg kg-1 d-1) prevented the exaggerated hypoxic pulmonary vasoconstrictor response seen in perfused lungs from hypoxic rats but did not prevent any of the functional changes (i.e. the increased contractions to 5-HT, U46619 (thromboxane-mimetic) and K+ and diminished contractions to angiotensins I and II) seen in isolated intralobar or main pulmonary arteries. Acetylcholine responses were unaltered in hypoxic rats. 5. We conclude that, in hypoxic rats, altered pulmonary vascular function is largely independent of remodelling. Hence any drug that affects only remodelling is unlikely to restore pulmonary vascular function to normal and, like perindopril, may have only a modest effect on pulmonary artery pressure.
Jeffery
T K
TK
Pulmonary Pharmacology Group, Department of Physiology and Pharmacology, The University of Queensland, St Lucia, Queensland, Australia, 4072.
Wanstall
J C
JC
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D006321:Heart / Q000187:drug effects; D006400:Hematocrit; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D007441:Intubation, Gastrointestinal; D008297:Male; D009929:Organ Size / Q000187:drug effects; D020913:Perindopril / Q000008:administration & dosage / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D020913:Perindopril