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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Arterial remodelling is an important mechanism in the pathophysiology of hypertension and its complications, being involved in the decrease of vascular reserve, the autoregulation of cerebral blood flow and the development of atherosclerosis. There is now evidence that, in addition to several other growth factors, vasoactive peptides such as angiotensin II may act as vascular smooth muscle growth-promoting substances. Based on these data, the effects of perindopril, a potent and long-lasting angiotensin-converting enzyme (ACE) inhibitor, on structural and mechanical properties of the arterial wall have been studied in animal models of hypertension. Perindopril completely reversed the aortic medial hypertrophy and arterial stiffening observed in renovascular hypertensive rats and in spontaneously hypertensive rats. The effect of perindopril was consistent with the potent inhibition of vascular ACE, and emphasized the potential role of angiotensin II as a vascular growth modulator. Whether the time constant of remodelling is similar or not in the heart and large vessels remains an important question that requires further investigation.
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PMID:Remodelling of the vascular system in response to hypertension and drug therapy. 139 15

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. The effects of antihypertensive drugs on this process are important to consider from a mechanistic and a pathogenetic point of view in relation to vascular complications of hypertension, e.g., decrease in vascular reserves, shift in cerebral blood flow autoregulation and atherosclerosis development. There is now evidence that, in addition to several other growth factors, vasoactive peptides such as angiotensin II may act as vascular smooth muscle growth promoting substances. Based on these data, the effects of perindopril, a potent and long-lasting angiotensin-converting enzyme (ACE) inhibitor, on structural and mechanical properties of the arterial wall, have been studied in animal models of hypertension as well as in humans. Perindopril completely reversed aortic medial hypertrophy and arterial stiffening observed in renovascular hypertensive rats. Similar benefits were reported in mesenteric resistance vessels of spontaneously hypertensive rats. The effect of perindopril was totally in keeping with potent inhibition of vascular ACE and emphasized the potential role of angiotensin II as a vascular growth modulator. Clinical studies confirmed animal experiments; both suggest that increases in arterial compliance and distensibility following perindopril is likely to be related to drug-induced modification of the arterial wall, at least partially independently of blood pressure reduction. The increase in arterial compliance was associated with a selective decrease in pulse pressure, a finding that is important, not only for the arterial wall, but also for the structure and function of the hypertensive heart.
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PMID:Vascular effects of perindopril: from experimental to clinical investigation. 172 97

The effects of ACE inhibition with perindopril on the atherosclerosis-induced impairment of arterial flow were investigated via histopathologic studies, hemodynamics, and vascular rheology of hindlimb arteries in 7 adult Pitman-Moore mini-pigs (7 months of age) fed for 4 months with an atherogenic diet and perindopril (at the daily oral dose of 4 mg, which induced a continuous 70% inhibition of serum ACE activity), versus 7 atherogenic and 7 control animals. Major fibroproliferative fatty lesions with medial intimalization were observed in the abdominal aorta. Atherosclerosis impaired the function of both capacitance and resistance hindlimb arteries. In atherogenic mini-pigs, blood pressure (BP) increased significantly due to increased hindlimb peripheral resistance (HPR) and aortic input impedance, although aortic blood flow was not affected. Altered aortic wall rheology revealed that the stiffness of the aorta was markedly increased due to increased wall tension and reduced viscoelasticity, the viscous component being reduced in the arterial wall. Perindopril significantly opposed these alterations by reducing BP, HPR and input impedance and by returning parietal stiffness to control values by increasing aortic compliance. Angiotensin converting enzyme (ACE) inhibition significantly prevented the development of atherosclerosis in the abdominal aorta by decreasing the cross-sectional area of lesions and the presence of lipid-laden cells, as well as by preventing alteration and fragmentation of elastic laminae. In conclusion, ACE inhibition with perindopril showed a significant preventive action on atherosclerosis-induced deleterious effects on vascular wall function and structure in mini-pig arteries.
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PMID:Effects of angiotensin-converting enzyme inhibition with perindopril on hemodynamics, arterial structure, and wall rheology in the hindquarters of atherosclerotic mini-pigs. 832 63

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)
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PMID:ACE inhibition with perindopril and atherogenesis-induced structural and functional changes in minipig arteries. 834 88

In atherosclerotic mini-pigs, we attempted to determine (i) whether high-fat atherogenic diet disturbs the taurocholate transepithelial transport and incorporation in the ileal epithelium mounted in Ussing chambers, and (ii) whether these processes are sensitive to angiotensin converting enzyme (ACE) inhibitors which slow the development of vascular atherosclerosis. In atherosclerotic mini-pigs, the mucosal to serosal transepithelial fluxes were markedly lower (72% inhibition) and free diffusion was more altered than active processes. Taurocholate incorporation into enterocyte (75% inhibition) paralleled the flux reduction. The transport disturbance observed here might be explained by changes in bile salt permeability in relation to alterations of the membrane properties. Taurocholate absorption was lowered by atherogenic diet, whereas bile salts were not trapped in the enterocyte, therefore atherosclerosis-induced alterations preferentially affected the passage through the brush-border. In the ACE inhibitor treated atherosclerotic mini-pigs, perindopril and enalapril similarly inhibited serum ACE activities. Perindopril further corrected taurocholate fluxes by 50% and fully restored taurocholate incorporation. Since enalapril did not restore the atherosclerosis-induced alterations, the involvement of intestinal ACE in bile acid recycling and of an ACE inhibitor class effect on these mechanisms both remain to be ascertained.
Atherosclerosis 1995 Oct
PMID:Abnormal taurocholate ileal transepithelial transport in atherosclerotic mini-pigs and effects of ACE inhibitors. 880 74

The sympathetic nervous system, coronary artery disease and myocardial ischaemia are related in different ways. First, the sympathetic system may be involved in the process of atherosclerosis through platelet activation and subsequent platelet-derived growth factor formation and by inducing mechanical injury to the vascular wall as a result of increased blood pressure and increased flow velocity. Secondly, sympathetic control of coronary vasomotor tone, which under normal conditions is not important, becomes functionally significant once coronary artery disease endothelial dysfunction has occurred. Under these circumstances, increased sympathetic adrenergic tone may lead to coronary vasoconstriction and, as myocardial oxygen demand increases concomitantly, myocardial ischaemia may ensue. Alternatively, myocardial ischaemia activates several neurohormonal systems, such as the sympathetic and, during more severe ischaemia, the circulating renin-angiotensin system. This leads to systemic and, possibly, coronary vasoconstriction and thus to further myocardial ischaemia. Prolonged myocardial ischaemia results in progressive norepinephrine release from the heart, reaching extracellular levels as high as 100-1000 x plasma concentrations. As cardiac beta-receptor density rises simultaneously, sympathetically-induced irreversible myocardial damage may occur, although through concomitantly increased beta-receptor kinase activity the beta-receptor may become functionally inactive. To counteract the detrimental effects of enhanced sympathetic activation on the heart, beta-blockade appears to be the proper choice. However, acute beta-blockade may lead to more profound ischaemia-induced neurohormonal activation and hence to vascular constriction through unoccupied alpha-receptors. In contrast, under ischaemic conditions and with concomitant beta-blockade, acute alpha-blockade does improve subendocardial flow and reduces myocardial ischaemia. A novel approach to anti-ischaemic therapy, which relates to modulating ischaemia-induced sympathetic activation, is through ACE inhibition. ACE inhibitors affect myocardial ischaemia by reducing neurohormonal activation and related systemic and coronary vasoconstriction. These acute effects may become more important over time, as coronary endothelial function improves following long-term ACE inhibition. A large multicentre controlled trial comparing ACE inhibition with placebo in patients with coronary artery disease, the EUROPA (EUopean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease), which is currently underway, addresses the issue of whether ACE inhibition does in fact offer a novel approach in myocardial ischaemia.
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PMID:The sympathetic nervous system and ischaemic heart disease. 965 38

Angiotensin-converting enzyme inhibitors (ACEi) reduce cardiovascular morbidity and mortality by improving coronary perfusion, reducing ventricular hypertrophy and remodeling, and preventing progression of coronary atherosclerosis. However, the cellular mechanisms underlying the beneficial effects of ACEi are not fully understood. We studied the in vivo effects of ACE inhibition with perindopril on cellular expression of ACE, AT(1) receptors and 2 nitric oxide synthase (NOS) isoforms, endothelial (eNOS) and inducible NOS (iNOS), in human blood vessels using quantitative in vitro autoradiography and immunocytochemistry. Seven patients with ischemic heart disease were treated with perindopril (4 mg/d) for up to 5 weeks before elective coronary bypass surgery, whereas controls did not receive the ACEi (n=7). Perindopril decreased plasma ACE by 70% and the plasma angiotensin II to angiotensin I ratio by 57% and reduced vascular ACE to approximately 65% of control levels in both endothelium and adventitia. By contrast, AT(1) receptor binding in vascular smooth muscle cells was increased by 80% in patients treated with perindopril as confirmed by immunocytochemistry. eNOS was expressed primarily in endothelial cells, whereas little iNOS expression occurred in vascular smooth muscle cells of untreated patients. Both eNOS and iNOS expression seemed to increase during perindopril treatment. These results suggest that suppression of angiotensin II formation in the vascular wall and increased expression of eNOS and iNOS during ACE inhibition may be beneficial in reversing endothelial dysfunction in patients with cardiovascular disease. Because vascular AT(1) receptor expression is increased during chronic ACE inhibition, more clinical studies are required to determine whether it is necessary to combine ACE inhibitors and AT(1) receptor antagonists in clinical management of heart failure, coronary heart disease, and hypertension
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PMID:Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease. 1236 66

A number of placebo-controlled randomized clinical trials have clearly established that blood pressure (BP) lowering, based on all antihypertensive drugs studied, lowers the risk of all major BP-related cardiovascular events. However, this does not exclude that some antihypertensive agents are more or less effective in preventing cardiovascular events than to be expected from the extent of BP lowering. Indeed, clinical trials of thiazide diuretics using 'high' doses demonstrated marked prevention of strokes, but little to no prevention of coronary events. Subsequent studies using thiazides at 'lower' doses showed prevention of both strokes and coronary events. Angiotensin converting enzyme inhibitors and calcium channel blockers exert direct vascular effects which may inhibit atherosclerosis and prevent cardiovascular events, in addition to their benefits related to BP lowering. After the publication of the results of Heart Outcome Prevention Evaluation (HOPE) trial, this concept has become widely accepted for angiotensin-converting enzyme inhibitors. However, placebo-controlled trials, such as HOPE and, recently, the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), are confounded by the difference in BP and its impact on outcome. Indeed, as a mirror image of these trials, the blacks subgroup in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) exhibited a 4 to 5 mmHg higher systolic BP on ACE inhibitor as compared with the diuretic, associated with 19% higher combined cardiovascular disease and 40% higher stroke rate. Recent overviews of randomized clinical trials comparing outcomes with different antihypertensive drug classes concluded that outcome benefits beyond BP lowering remain unproven.
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PMID:Blood pressure lowering, not vascular mechanism of action, is the primary determinant of clinical outcome. 1530 9

Endothelial dysfunction is a pivotal early event in the development of atherosclerosis and a characteristic feature of obesity. This study was designed to investigate the effect of angiotensin-converting enzyme (ACE) inhibition on endothelial function in people who were obese but otherwise healthy. We performed a double-blind, randomised, placebo-controlled study examining the effect of the ACE inhibitor perindopril (4 mg per day) on flow-mediated vasodilatation (FMD) of the brachial artery, arterial blood pressure, glucose homeostasis and inflammatory cytokines. Eighteen obese subjects (all body mass index > 30 kg/m2) were randomised to receive perindopril or placebo for four weeks. Perindopril led to a fall in systolic blood pressure from 131 (standard error of mean [SEM] 3) to 117(5) mmHg and diastolic blood pressure from 74(4) mmHg to 68(4) mmHg, both p<0.001. Despite this fall in blood pressure, ACE inhibition had no effect on FMD, 8.2 (1.2)% versus 8.3 (1.5)%, p=0.9. ACE inhibition had no effect on insulin, lipids or circulating cytokines. In healthy obese humans, despite a significant reduction in blood pressure, ACE inhibition had no effect on FMD.
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PMID:Divergent effects of angiotensin-converting enzyme inhibition on blood pressure and endothelial function in obese humans. 1678 79

Angiotensin-converting enzyme inhibitors proved to be effective in the primary and secondary prevention of cardiovascular diseases. Clinical effectiveness of this group of agents may largely depend on their pleiotropic effects. The purpose of this study was to compare the effects of plasma- and tissue-type angiotensin-converting enzyme inhibitors on blood pressure and on systemic inflammation, hemostasis and oxidative functions in normotensive patients with stable coronary artery disease. Ninety patients with stable coronary artery disease enrolled into the study were randomly divided into three different groups, simultaneously treated with enalapril (20 mg/d, n = 30), perindopril (4 mg/d, n = 30) or placebo (n = 30). Plasma lipid profile and the levels of oxidized low density lipoproteins (LDLs), monocyte chemoattractant protein (MCP)-1, interleukin-10, C-reactive protein (CRP), fibrinogen and plasminogen activator inhibitor (PAI)-1 were determined at the beginning of the study and after 30 and 90 days of treatment. Seventy-six patients completed the trial. Neither enalapril nor perindopril affected blood pressure or plasma lipids. Perindopril significantly reduced plasma levels of oxidized LDLs, CRP, MCP-1, fibrinogen and PAI-1, and increased interleukin-10. The effect of enalapril on these markers of systemic inflammation, hemostasis and oxidative functions was much less pronounced. The results showed that enalapril and perindopril were devoid of a blood pressure-lowering effect in normotensive patients with stable coronary artery disease. Perindopril was superior to enalapril in exhibiting antioxidant, antithrombotic and profibrinolytic activities. The treatment-induced changes in the balance between pro- and antiinflammatory cytokines and in hemostasis may contribute to the clinical effectiveness of tissue angiotensin-converting enzyme inhibitors in the therapy of atherosclerosis-related disorders.
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PMID:Pleiotropic effects of angiotensin-converting enzyme inhibitors in normotensive patients with coronary artery disease. 1879 20


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