Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function

Abstract

1 Hypoxic pulmonary hypertension in rats (10% O 2 , 4 weeks) is characterized by changes in pulmonary vascular structure and function. The e ects 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 71 d 71 ) 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 550 mm o.d.) and (ii) medial wall thickness of intralobar pulmonary arteries, assessed histologically (vessels 30 ± 100 and 101 ± 500 mm o.d.). Perindopril 10 and 30 mg kg 71 d 71 attenuated remodelling in vessels 4100 mm (lungs and histology), 30 mg kg 71 d 71 was e ective in vessels 101 ± 500 mm but neither dose prevented hypertrophy of main pulmonary artery. 3 mg kg 71 d 71 was without e ect. 4 Perindopril (30 mg kg 71 d 71 ) 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 a ects only remodelling is unlikely to restore pulmonary vascular function to normal and, like perindopril, may have only a modest e ect on pulmonary artery pressure.

S‐Nitrosocaptopril: in vitro characterization of pulmonary vascular effects in rats

“…Thus with respect to vasorelaxation, the properties of SNOcap on main pulmonary artery are indicative of its properties on intralobar pulmonary arteries. A previous study in main and intralobar pulmonary arteries has shown that this is also true with respect to the inhibition of contractions to angiotensin I by ACE inhibitors (Jeffery & Wanstall, 1999).…”

“…NO donor drugs may be an alternative to these vasodilators and moreover, some NO donor drugs may have the additional advantage of inhibiting platelet aggregation (Sogo et al ., 2000b). There are no specific anti‐remodelling drugs in current use in pulmonary hypertensive patients, but one group of drugs that show promise, based on studies in animal models of pulmonary hypertension, are angiotensin converting enzyme (ACE) inhibitors (Morrell et al ., 1995; Jeffery & Wanstall, 1999).…”

Angiotensin-Converting Enzyme Inhibitor Preserves p21 and Endothelial Nitric Oxide Synthase Expression in Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

“…It clearly shows that the basal pulmonary vascular tone in control animals is maintained, at least in part, by NO, but not in PAH lung. Although the beneficial effect of ACEI against PAH has been investigated experimentally [22][23][24] and clinically, 4,25-29 the conclusions are controversial. Explanations for this discrepancy have been ascribed to inadequate dosing, species difference, or differences between inhibiting established lesions in patients and newly developing lesions in animals.…”

Role of HIF-1α in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells

“…Consistent with these findings, ACE expression is enriched in the walls of newly muscularized small pulmonary arteries (20). Additionally, in patients and experimental models, HPH was attenuated by a specific AT 1 receptor antagonist and by an ACE inhibitor (ACEI) (12,22). These results indicate that ACE mediates an important role in the occurrence of HPH because of the formation of ANG II.…”