Male Japanese white rabbits were fed a restricted amount (100 g/head/day) of an atherogenic diet containing 0.2% cholesterol and 6% peanut oil during an 8-week experimental period. Atherosclerotic lesions, characterized by intimal thickening with lipid deposition, were produced by de-endothelialization of the rabbit aorta with a 4 F balloon catheter halfway through the experiment. Clentiazem (TA-3090), a new calcium antagonist, was administered at an oral dose of 30 mg/kg/day for 4 weeks starting on the day of deendothelialization. Clentiazem significantly depressed the intimal thickening without any effect on serum lipid levels. Clentiazem (1, 3, and 10 µM) significantly and dose-dependently inhibited the in vitro proliferation of smooth muscle cells that had been explanted from the neointima of the deendothelialized aorta. At a higher concentration, this drug markedly inhibited collagen-induced aggregation of rabbit platelets. Diltiazem also showed similar effects, but the effects of clentiazem were more potent than those of diltiazem. These results suggest that clentiazem exhibits an antiatherogenic effect, at least partly through prevention of smooth muscle cell proliferation in atheromatous lesions, in addition to its hypotensive action.
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Ross R, Glomset JA. The pathogenesis of atherosclerosis.N Engl J Med 1976;295:369–377, 420–425.
Schaub RG, Simmons CA. Medial smooth muscle cell proliferation in the balloon injured rabbit aorta: Effect of a thiazole compound with platelet inhibitory activity.Thromb Haemostas 1984;51:75–78.
Handley DA, Van Valen RG, Melden MK, Saunders RN. Suppression of rat carotid lesion development by the calcium channel blocker PN 200–110.Am J Pathol 1986;124:88–93.
El Sanadiki M, Cross KS, Mikat EM, Hagen P. Verapamil therapy reduces intimal hyperplasia in balloon injured rabbit aorta.Circulation 1987;76(Suppl IV):314.
Jackson CL, Bush RC, Bowyer DE. Inhibitory effect of calcium antagonists on balloon catheter-induced arterial smooth muscle cell proliferation and lesion size.Atherosclerosis 1988;69:115–122.
Lundergan C, Foegh ML, Vargas R, et al. Inhibition of myointimal proliferation of the rat carotid artery by the peptides, angiopeptin and BIM 23034.Atherosclerosis 1989;80:49–55.
Hendel JL, Faxon DP, Sanborn TA, Ryan TJ. Lack of an effect of nifedipine on angiographic progression of experimental rabbit atherosclerosis.Clin Res 1985;33:193A.
Henry PD, Bentley KI. Suppression of atherogenesis in cholesterol-fed rabbit treated with nifedipine.J Clin Invest 1981;68:1366–1369.
Ginsburg R, Davis K, Bristow MR, et al. Calcium antagonists suppress atherogenesis in aorta but not in the intramural coronary arteries of cholesterol-fed rabbits.Lab Invest 1983;49:154–158.
Blumlein SL, Sievers R, Kidd P, Parmley WW. Mechanism of protection from atherosclerosis by verapamil in the cholesterol-fed rabbit.Am J Cardiol 1984;54:884–889.
Willis AL, Nagel B, Churchill V, et al. Antiatherosclerotic effects of nicardipine and nifedipine in cholesterol-fed rabbits.Arteriosclerosis 1985;5:250–255.
Stender S, Ravn H, Haugegaard M, Kjeldsen K. Effect of verapamil on accumulation of free and esterified cholesterol in the thoracic aorta of cholesterol-fed rabbits.Atherosclerosis 1986;61:15–23.
Sugano M, Nakashima Y, Tasaki H, Takasugi M, Kuroiwa A, Koide O. Effects of diltiazem on suppression and regression of experimental atherosclerosis.Br J Exp Pathol 1988;69:515–523.
Kramsch DM, Aspen AJ, Apstein CS. Suppression of experimental atherosclerosis by the Ca++ antagonist lanthanum.J Clin Invest 1980;65:967–981.
Naito M, Kuzuya F, Asai K, et al. Ineffectiveness of Ca2+-antagonists nicardipine and diltiazem on experimental atherosclerosis in cholesterol-fed rabbits.Atherosclerosis 1984;51:343–344.
Stender S, Stender I, Nordestgaard B, Kjeldsen K. No effect of nifedipine on atherogenesis in cholesterol-fed rabbits.Arteriosclerosis 1984;4:389–394.
Overturf ML, Smith SA. Failure of nifedipine to reduce atherogenesis in cholesterol-fed rabbits.Artery 1986;13:267–282.
Narita H, Murata S, Yabana H, et al. Long-lasting hypotensive and antihypertensive effects of a new 1,5-benzothiazepine calcium antagonist in hypertensive rats and renal hypertensive dogs.Arzneim-Forsch/Drug Res 1988;38:515–520.
Murata S, Kikkawa K, Yabana H, Nagao T. Cardiovascular effects of a new 1,5-benzothiazepine calcium antagonist in anesthetized dogs.Arzneim-Forsch/Drug Res 1988;38:521–525.
Kikkawa K, Murata S, Nagao T. Calcium antagonistic and spasmolytic activities of a new 1,5-benzothiazepine derivative in isolated canine and monkey arteries.Arzneim-Forsch/Drug Res 1988;38:526–531.
Narita H, Ginsburg R. In-vitro study of the effect of clentiazem on rabbit aorta and on myocardium.Cardiovasc Drugs Ther 1990;4:723–730.
Narita H, Zera PH, Ginsburg R. Mechanism of action of clentiazem on human coronary artery and myocardium.Cardiovasc Drugs Ther 1990;4:1097–1104.
Moore S, Belbeck LW, Richardson M, Taylor W. Lipid accumulation in the neointima formed in normally fed rabbits in response to one or six removals of the aortic endothelium.Lab Invest 1982;47:37–42.
Wolinsky H, Daly MM. A method for the isolation of intimamedia samples from arteries.Proc Soc Exp Biol Med 1970;135:364–368.
Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipids from animal tissues.J Biol Chem 1957;226:497–509.
Nakamura M, Mori K. Colorimetric determination of inorganic phosphorus in the presence of glucose-1-phosphate and adenosine triphosphate.Nature 1958;182:1441.
Neuman RE, Logan MA. The determination of hydroxyproline.J Biol Chem 1950;184:299–306.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent.J Biol Chem 1951;193:265–275.
Ross R. The smooth muscle cell. II. Growth of smooth muscle in culture and formation of elastic fibers.J Cell Biol 1971;50:172–186.
Flieiss JL, ed.The design and analysis of clinical experiments, New York: John Wiley, 1986.
Saso Y, Kitamura K, Yasoshima A, et al. Rapid induction of atherosclerosis in rabbits.Histol Histopathol 1992;7:315–320.
De Brux JA, Dorn HF, Duguid JB, et al. Clasification of atherosclerotic lesions. Report of a study group.World Health Organization Tech Rep Ser 1958;143:1–20.
Nilsson J, Sjölund M, Palmberg L, et al. The calcium antagonist nifedipine inhibits arterial smooth muscle cell proliferation.Atherosclerosis 1985;58:109–122.
Witte LD, Kaplan KL, Nossel HL, et al. Studies of release from human platelets of the growth factor for cultured human arterial smooth muscle cells.Circ Res 1978;42:402–409.
Busch C, Wasteson A, Westermark B. Release of a cell growth promoting factor from human platelets.Thromb Res 1976;8:493–500.
Ross R. The pathogenesis of atherosclerosis—An update.N Engl J Med 1986;314:488–500.
Kiyomoto A, Sasaki Y, Odawara A, Morita T. Inhibition of platelet aggregation by diltiazem. Comparison with verapamil and nifedipine and inhibitory potencies of diltiazem metabolites.Circ Res 1983;52(Suppl I):115–119.
Boeynaems JM, Galand N, Ketelbant P. Prostacyclin production by the deendothelialized rabbit aorta.J Clin Invest 1985;76:7–14.
Grodzinska L, Basista M, Basista E, et al. Nitrendipine-stimulated release of prostacyclin-like substance in normal and atherosclerotic animals.Arzneim-Forsch/Drug Res 1987;37:412–415.
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Saso, Y., Ohtani, A., Odawara, A. et al. Inhibitory effect of clentiazem (TA-3090), a new calcium antagonist, on balloon catheter-induced intimal thickening of rabbit aorta. Cardiovasc Drug Ther 7, 257–264 (1993). https://doi.org/10.1007/BF00878516
- balloon injury
- intimal thickening
- smooth muscle cell proliferation
- calcium antagonist