Anti-atherosclerotic and plasma lipid lowering effects of the novel calcium blocker with alpha 1-adrenoceptor antagonistic activity, monatepil, in high cholesterol diet-fed Japanese Macaca fuscata monkeys.
1. The preventive effects of atherosclerosis and hyperlipidemia of monatepil ([(+-)-N-(6,11-dihydrodibenzo [b,e]thiepin-11-yl)-4-(4-fluorophenyl)-1-piperazine-butanamide+ + +]monomaleate , AJ-2615, CAS 103377-41-9), a new antihypertensive drug with potent calcium antagonistic and alpha 1-adrenoceptor blocking activities, were investigated in Japanese monkeys (Macaca fuscata) fed with a cholesterol-rich diet (2% cholesterol + 6% corn oil) and compared with those of prazosin. 2. The dose of monatepil selected (30 mg/kg/d, p.o., 6 months) was the plasma concentration dose level of antihypertensive therapy and that of prazosin (2 mg/kg twice daily, p.o., 6 months) was the dose where hypolipidemic effect in cholesterol-fed monkeys has been reported. 3. In the cholesterol diet control group (n = 7), plasma levels of total cholesterol and low-density lipoprotein (LDL) significantly increased and that of high-density lipoprotein-cholesterol (HDL-C) decreased compared with the normal diet group (n = 5). In the monatepil group (n = 5), these changes were significantly suppressed. In the prazosin group (n = 5), these changes were also inhibited but the inhibitory effect was weaker than in the monatepil group. 4. The cholesterol content and sudanophilic area in the aorta indicating atheromatous lesions in the cholesterol-diet fed control group were significantly higher than those in the normal diet control group. In the monatepil group, these changes were significantly suppressed whereas in the prazosin group these changes were partially inhibited. 5. In the histological study, aortic lesions characterized by aggregations of foam cells were observed in the cholesterol-diet control group, while there was little change in the monatepil group. The anti-atherogenic effect of prazosin was weaker than that of monatepil. 6. Coronary atheromatous lesions were found in 4 out of the 7 animals in the cholesterol-diet control group and 3 out of the 5 animals in prazosin group. In contrast, no coronary atheromatous lesion was found in the monatepil group. 7. The treatment with monatepil did not influence food consumption, body weight, physical signs or blood biochemistry. 8. The anti-atherosclerotic and plasma lipid-lowering effects of monatepil may in part be attributable to its calcium antagonistic, alpha 1-adrenoceptor blocking, and anti-lipid peroxidation activities. 9. In conclusion, monatepil is a new class of antihypertensive agent that possesses anti-atherogenic properties and the ability to reduce plasma lipid levels, a main risk factor for atherosclerosis.
Miyazaki
M
M
Department of Pharmacology, Osaka Medical College, Japan.
Hosoki
K
K
Okunishi
H
H
Ishii
K
K
Ikeno
A
A
Okazaki
Y
Y
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D003988:Dibenzothiepins / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004032:Diet; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008251:Macaca; D008297:Male; D010879:Piperazines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D002121:Calcium Channel Blockers; D002791:Cholesterol, Dietary; D003988:Dibenzothiepins; D000960:Hypolipidemic Agents; D008055:Lipids; D008074:Lipoproteins; D010879:Piperazines; C067818:monatepil; D011224:Prazosin