Inhibitory effects of fluvastatin, a new HMG‐CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol‐fed rabbits

Abstract

1 The effects of fluvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the vascular angiotensin converting enzyme (ACE) activity in hyperlipidaemic rabbits were compared with those of enalapril, an ACE inhibitor. 2 Rabbits were fed a 1.5% cholesterol containing diet or normal diet for 16 weeks and treated with either fluvastatin or enalapril in the diet at the respective doses of 2 and 10 mg kg-' day-'. The total cholesterol, triglyceride and phospholipid levels in serum were significantly increased in rabbits fed the high cholesterol diet. Treatment with fluvastatin but not enalapril resulted in a decrease in serum lipids. 3 The vascular ACE activities assessed via the cleavage rate from synthetic substrate in the aortic arches and upper thoracic aortae were increased by 8 to 10 times when the rabbits were made hyperlipidaemic. Fluvastatin as well as enalapril significantly lowered the tissue ACE in the aortae. 4 The ACE activities in serum did not alter in hyperlipidaemic rabbits either in the presence or absence of fluvastatin. The serum ACE activity was lowered by enalapril. 5 The lipid peroxide in serum as well as the plaque area in the thoracic aorta was significantly increased in the cholesterol diet-fed rabbits. Treatment with fluvastatin or enalapril reduced both serum lipid peroxide and plaque formation. The relaxant responses to acetylcholine (ACh) were significantly suppressed in the cholesterol-fed rabbits. Treatment with fluvastatin or enalapril significantly reversed the suppression of ACh-induced relaxation. 6 It seems that the reduction of vascular ACE is not coupled to lipids and ACE activity in serum, but rather to lipid peroxidation. Thus, the decrease in vascular ACE activity by fluvastatin as well as the lipid-lowering effect may reduce the risk of atherosclerosis progression in the vasculature.

Fluvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction

“…16 ACE inhibition has been shown to prevent cardiac remodeling and prolong survival in experimental and clinical MI. 1 There is now experimental evidence that the renin-angiotensin system is inhibited by statins in the vasculature 17 and in the myocardium. 18 Statins can directly inhibit angiotensin II-induced cardiac myocyte hypertrophy.…”

Statins and Blockers of the Renin-Angiotensin System

“…94 Patients with severe CHF who were already receiving the maximally recommended dose or the highest tolerated dose of ACE-I proved that peak exercise capacity and heart-related symptoms were improved when losartan was coadministered for 6 months. 95 It has been speculated that the benefits deriving from such an association may relate, in part, to an effect on the sympathetic nervous system: The increased availability of bradykinin during ACE inhibition could stimulate catecholamine release via B2 receptors. In this regard, hypertensive rats receiving candesartan lowered AT-1 receptor-mediated, Ang II-induced noradrenaline release in a dose-dependent manner.…”

“…Thus, the decrease in vascular ACE activity by fluvastatin as well as the lipid-lowering effect may reduce the risk of atherosclerosis progression. 95 In humans, the combination of captopril, hydrochlorothiazide, and pravastatin was well tolerated by Ͼ600 hypertensive, hypercholesterolemic patients. 96 Finally, vascular reactivity and vasodilative capacity were investigated in 30 hypercholesterolemic, hypertensive patients treated with either enalapril or simvastatin for 14 weeks and then with both medications for an additional 14 weeks.…”

Dipeptidyl Peptidase IV Inhibition Improves Impaired Glucose Tolerance in High-Fat Diet-Fed Rats: Study Using a Fischer 344 Rat Substrain Deficient in Its Enzyme Activity

“…Plasma insulin concentrations were measured by using an enzyme-linked immunosorbent assay (ELISA) using commercially available kits (Shibayagi, Gunma). Total cholesterol, triglycerides and phospholipids levels in plasma were measured by cholesterol oxidase-3,5-dimethoxy-N-ethyl-(2-hydroxy-3-sulfoproryl)-aniline sodium (DAOS), glycerol-3-phosphate oxidase-DAOS and choline oxidase-DAOS methods, respectively, using commercially available kits (Wako Pure Chemical Ind., Osaka) (27,28).…”