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Abstract-Aldosterone may be involved in the pathogenesis of atherosclerosis. We investigated the effect of eplerenone, a selective mineralocorticoid receptor blocker, on atherosclerosis in monkeys fed a high-cholesterol diet. Monkeys fed a high-cholesterol diet for 9 months were divided into 3 groups: those treated with a low dose of eplerenone (30 mg/kg per day); those treated with a high dose of eplerenone (60 mg/kg per day); and the placebo-treated group. The normal group consisted of monkeys fed a normal diet. There were no significant differences in blood pressure and cholesterol levels between the placebo-and eplerenone-treated groups. On the other hand, monocyte chemoattractant protein-1 and malondialdehyde-modified LDL were significantly higher in the placebo-treated group than in the normal group, whereas they were suppressed in the eplerenone-treated groups. The ratio of intimal volume to total volume by intravascular ultrasound analysis imaging of the aortas was dose-dependently lower in the eplerenone-treated groups than in the placebo-treated group. Acetylcholine-induced vasorelaxation was significantly weaker in the placebo-treated group than in the normal group, but the vasorelaxation was strengthened in the eplerenone-treated groups. A significant upregulation of angiotensin-converting enzyme activity was observed in the placebo-treated group, but the activity was suppressed in the eplerenone-treated groups. In conclusion, eplerenone may strengthen the endothelium-dependent relaxation and suppress angiotensin-converting enzyme activity in the vasculature, thus preventing the development of atherosclerosis in nonhuman primates. Key Words: aldosterone Ⅲ angiotensin Ⅲ atherosclerosis Ⅲ endothelium Ⅲ hypercholesterolemia A ldosterone is a mineralocorticoid hormone that plays an important role in regulating electrolyte balance and blood pressure. 1,2 Aldosterone also participates in endothelial dysfunction, vascular fibrosis, and inflammation in the vasculature, and is involved in the pathogenesis of hypertension. [3][4][5][6] Hypertension and hyperlipidemia are risk factors for atherosclerosis, but reductions in blood pressure and lipid levels do not necessarily result in the prevention of atherosclerotic lesions in nonhuman primates. [7][8][9] On the other hand, in the nonhuman primate atherosclerotic model, angiotensinconverting enzyme (ACE) inhibitor and angiotensin II type 1 receptor blocker (ARB) significantly reduce the progression of atherosclerosis without reducing blood pressure and plasma cholesterol levels. 7-9 Such reports suggest that angiotensin II blockage may be useful for preventing the development of atherosclerosis.In the Randomized Aldosterone Evaluation Study (RALES), a significant 30% survival advantage in chronic heart failure patients was observed with the use of a mineralocorticoid receptor blocker spironolactone in addition to standard therapy, including diuretics and ACE inhibitors. 10 It has been shown that ACE inhibitors only transiently suppress aldosterone production, a...

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Vascular smooth muscle cells in spontaneously hypertensive rats (SHR) express angiotensin II-forming chymase (rat vascular chymase [RVCH]), which may contribute to blood pressure regulation. In this study, we studied whether chymase-dependent angiotensin II formation contributes to the regulation of blood pressure in SHR. The systolic blood pressure in 16-week-old Wistar-Kyoto (WKY) rats was 113 ± 9 mmHg, compared to 172 ± 3 mmHg in SHR. Using synthetic substrates for measuring angiotensin-converting enzyme (ACE) and chymase activities, it was found that both ACE and chymase activities in extracts from SHR aortas were significantly higher than in those from WKY rat aortas. Using angiotensin I as a substrate, angiotensin II formation in SHR was found to be significantly higher than that in WKY rats, and its formation was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. RVCH mRNA expression could not be detected in aorta extracts from either WKY rats or SHR. In carotid arteries isolated from WKY rats and SHR, angiotensin I-induced vasoconstriction was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. Angiotensin I-induced pressor responses in both WKY rats and SHR were also completely inhibited by an ACE inhibitor, but they were not affected by a chymase inhibitor. In SHR, an ACE inhibitor and an angiotensin II receptor blocker showed equipotent hypotensive effects, but a chymase inhibitor did not have a hypotensive effect. These results indicated that chymase-dependent angiotensin II did not regulate blood pressure in SHR in the present study. (Hypertens Res 2005; 28: 457-464)

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ABSTRACT-We investigated the effects of a novel chymase inhibitor, BCEAB (4-[1-{[bis-(4-methyl-phenyl)-methyl]-carbamoyl}-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid). The IC50 value of BCEAB for purified human chymase was 5.4 nM, whereas BCEAB did not inhibit the angiotensin-converting enzyme, elastase and tryptase. In isolated dog arteries, the IC50 value of BCEAB for the angiotensin I-induced contraction in the presence of 1 mM lisinopril was 2.8 mM. In the hamster, the heart chymase activities were significantly suppressed to 42.0% and 26.9% 3 h after oral administration of 100 and 300 mg of BCEAB / kg of body weight, respectively. In conclusion, BCEAB is a useful chymase inhibitor for studying the role of chymase in vivo.

Angiotensin II receptor blockers could prevent the development of atherosclerosis beyond reducing blood pressure in monkeys fed a high-cholesterol diet. However, it has been unclear whether hypotensive effects improve atherosclerosis in primates. We investigated whether antihypertensive agents, an angiotensin II receptor antagonist, candesartan, and a calcium channel blocker, amlodipine, prevent areas of atherosclerotic lesions in the aorta of monkeys fed a high-cholesterol diet. Seventeen male monkeys fed a high-cholesterol diet for 6 months were grouped as follows: a high-cholesterol diet group (n 5), a candesartan-treated group Angiotensin II has been shown to be a potent vasoconstrictor, and it also promotes vascular proliferation via induction of several growth factors and cytokines (4, 5). We previously reported that ACE activity in atherosclerotic lesions in monkeys fed a high-cholesterol diet was increased significantly compared with that in normal lesions (6,7). In this atherosclerotic model, an ACE inhibitor or an angiotensin II receptor blocker (ARB) significantly reduced the progression of atherosclerosis beyond reduction of blood pressure and plasma cholesterol levels (6-8). The mechanism of angiotensin II in the development of atherosclerosis is thought to be various angiotensin II-induced actions such as the induction of growth factors, inflammatory cytokines, adhesion

We investigated whether a lipoxygenase inhibitor, panaxynol, affected the vascular contraction induced by angiotensin (Ang) II and the mean arterial pressure in spontaneously hypertensive rats (SHR). Panaxynol suppressed dose-dependently the contractile responses induced by 30 nM Ang II in isolated intact and endothelial cell-denuded aorta in the hamster. IC50 values in the intact and endothelial cell-denuded aorta were 23 and 20 microM, respectively. In SHR, the mean arterial pressure after injection of 30 and 60 mg/kg panaxynol was reduced, and the maximum hypotensive values were 23 and 48 mmHg, respectively. Thus, lipoxygenase products may affect the renin-angiotensin system.