ACE-INHIBITION WITH PERINDOPRIL AND ATHEROGENESIS-INDUCED STRUCTURAL AND FUNCTIONAL-CHANGES IN MINIPIG ARTERIES

The effects of angiotensin-converting-enzyme (ACE) inhibition on ather osclerosis-induced changes in arterial function are unknown, as well a s whether they are coupled to improvements of structural alterations i n the arterial wall. An atherogenic (A) diet and the ACE inhibitor per indopril (P) were given concomitantly for 4 months to seven adult Pitm an-Moore minipigs (7 months of age; A+P animals), which were compared with seven A and seven control (C) animals. Perindopril, at a daily do se 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 st udy, the atherosclerosis-induced impairment of arterial How was invest igated via the hemodynamics and vascular rheology of hindlimb arteries in non-barbiturate-anesthetized pigs. Structural alterations were eva luated from the histopathology of lesions in the arterial tree (abdomi nal aorta, left interventricular coronary artery [LIVCA], and brachioc ephalic trunk [BCT]), with particular attention given to the analysis of the structure and composition of aortic elastic fibers. Atheroscler osis 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 respon ses revealed that the stiffness of the aorta was markedly increased be cause of increased wall tension and reduced viscoelasticity, the visco us component being blunted in the arterial wall. Perindopril significa ntly opposed these alterations by reducing BP, HPR, and Zc and by retu rning parietal stiffness values to C values by increasing aortic compl iance. ACE inhibition prevented the alteration of both stress and elas tic 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 ela stin showed that elastic laminae fragmentation was prominent in the ab dominal aorta, less in the LIVCA, and moderate in the BCT. Furthermore , the elastin content was reduced in the atherosclerotic aorta, althou gh this loss of elastin was not associated with changes in the biochem ical nature of alkali-insoluble elastin. Perindopril significantly pre vented the development of atherosclerosis in the abdominal aorta, LIVC A, and BCT by decreasing the cross-sectional area of lesions as well a s the number of lipid-laden cells in the abdominal aorta and LIVCA. In the abdominal aorta, ACE inhibition significantly prevented the alter ation of elastic laminae by specifically preventing elastolytic fragme ntation of dense elastic laminae, but it did not modify elastin conten t. In conclusion, ACE inhibition with perindopril showed a significant preventive action on atherosclerosis-induced deleterious effects on v ascular wall function and structure, especially by reducing fragmentat ion of aortic elastic laminae.