title: ACE inhibition with perindopril and atherogenesis-induced structural and functional changes in minipig arteries.
abstract: The effects of angiotensin-converting-enzyme (ACE) inhibition on atherosclerosis-induced changes in arterial function are unknown, as well as whether they are coupled to improvements of structural alterations in the arterial wall. An atherogenic (A) diet and the ACE inhibitor perindopril (P) were given concomitantly for 4 months to seven adult Pitman-Moore minipigs (7 months of age; A+P animals), which were compared with seven A and seven control (C) animals. Perindopril, at a daily dose of 4 mg PO that is commonly used in the clinical setting, induced a continuous 70% inhibition of serum ACE activity. At the end of the study, the atherosclerosis-induced impairment of arterial flow was investigated via the hemodynamics and vascular rheology of hindlimb arteries in non-barbiturate-anesthetized pigs. Structural alterations were evaluated from the histopathology of lesions in the arterial tree (abdominal aorta, left interventricular coronary artery [LIVCA], and brachiocephalic trunk [BCT]), with particular attention given to the analysis of the structure and composition of aortic elastic fibers. Atherosclerosis impaired the function of both capacitance and resistance arteries. Blood pressure (BP) rose significantly because of increased hindlimb peripheral resistance (HPR) and aortic input impedance (Zc), although blood flow was not affected. Altered aortic stress and elastic responses revealed that the stiffness of the aorta was markedly increased because of increased wall tension and reduced viscoelasticity, the viscous component being blunted in the arterial wall. Perindopril significantly opposed these alterations by reducing BP, HPR, and Zc and by returning parietal stiffness values to C values by increasing aortic compliance. ACE inhibition prevented the alteration of both stress and elastic responses. Major fibroproliferative fatty lesions were observed in the aorta and LIVCA, while moderate fibrosclerotic lesions were found in the BCT. Computerized densitometric analysis of orcein-stained elastin showed that elastic laminae fragmentation was prominent in the abdominal aorta, less in the LIVCA, and moderate in the BCT. Furthermore, the elastin content was reduced in the atherosclerotic aorta, although this loss of elastin was not associated with changes in the biochemical nature of alkali-insoluble elastin. Perindopril significantly prevented the development of atherosclerosis in the abdominal aorta, LIVCA, and BCT by decreasing the cross-sectional area of lesions as well as the number of lipid-laden cells in the abdominal aorta and LIVCA. In the abdominal aorta, ACE inhibition significantly prevented the alteration of elastic laminae by specifically preventing elastolytic fragmentation of dense elastic laminae, but it didn ot modify elastin content.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: INSERM, Laboratoire de Chimie Biologique, Faculté de Pharmacie, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Charpiot
authors.forename: P H
authors.initials: PH
authors.lastname: Rolland
authors.forename: A
authors.initials: A
authors.lastname: Friggi
authors.forename: P
authors.initials: P
authors.lastname: Piquet
authors.forename: E
authors.initials: E
authors.lastname: Scalbert
authors.forename: H
authors.initials: H
authors.lastname: Bodard
authors.forename: A
authors.initials: A
authors.lastname: Barlatier
authors.forename: V
authors.initials: V
authors.lastname: Latrille
authors.forename: P
authors.initials: P
authors.lastname: Tranier
authors.forename: C
authors.initials: C
authors.lastname: Mercier
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001158:Arteries / Q000473:pathology* / Q000503:physiopathology*; D001161:Arteriosclerosis / Q000097:blood / Q000473:pathology* / Q000503:physiopathology*; D004036:Diet, Atherogenic; D004548:Elasticity; D006439:Hemodynamics; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D020913:Perindopril; D012016:Reference Values; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D020913:Perindopril