Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits.
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-1 day-1. 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 acetylcoholine (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.
Mitani
H
H
Department of Pharmacology, Sandoz Tsukuba Research Institute, Ibaraki, Japan.
Bandoh
T
T
Ishikawa
J
J
Kimura
M
M
Totsuka
T
T
Hayashi
S
S
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000187:drug effects*; D011817:Rabbits
D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008054:Lipid Peroxides; D008055:Lipids; D000077340:Fluvastatin; D007703:Peptidyl-Dipeptidase A