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Trandolapril Inhibits Atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit Aram V. Chobanian, Christian C. Haudenschild, Cynthia Nickerson, and Susan Hope The effects of trandolapril (0.25 ing/kg body wt per 48 hours) on aortic atherosclerosis were examined in the Watanabe heritable hyperlipidemic rabbit treated from 3 to 12 months of age. Trandolapril caused a significant decrease in atherosclerotic involvement of the intimal surface of total aorta from 56.3 ±5.0% in control Watanabe rabbits to 35.0±4.1% with treatment (p.'





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FIOURE 2. Panel A: Photomicrograph shows cross section through a representative intimal lesion in descending thoracic aorta of a 12-month-old control Watanabe heritable hyperiipidemic (WHHL) rabbit. Note the high cellularity of the plaque and the presence of foam cells and cholesterol crystals. Panel B: Photomicrograph shows representative intimal lesion in descending thoracic aorta of a 12-month-old trandolapril-treated WHHL rabbit. This intimal plaque is smaller, shows less cell density, and appears to have more extracellular matrix than the lesion in Panel A. Both panels, hematoxylin-eosin; original magnification x60.

B angiotensin in the rat causes modulation of the steadystate messenger RNA levels of connective tissue proteins as fibronectin, collagen, and tropoelastin.19 Such effects could influence the remodeling process occurring in response to arterial injury. Increased proliferation of arterial SMC and their accumulation in the intima are important features in the development of atherosclerosis, and inhibition of such proliferation might prove effective in reducing plaque formation. Atherosclerotic lesions are composed of a mixed cell population that includes macrophages and lymphocytes as well as SMC and endothelial cells, and ACE inhibitors potentially could act on any of these cell types. In addition, recent studies have shown that inhibition of the renin-angiotensin system with either the ACE inhibitor lisinopril or the angiotensin II antagonist [sar1, ile^angiotensin II, increases the migration rate of cultured bovine aortic endothelial cells and the activity of urokinase-like plasminogen activator.20 Such

effects, if present in vivo, could be beneficial by accelerating the rate of repair of damaged intima and by reducing its thrombogenicity. These studies also have shown that lisinopril reduces SMC migration, another potentially important antiatherosclerotic action. The cellularity of aortic plaques in our WHHL rabbits appeared less in both trandolapril- and captopriltreated animals; both macrophage and SMC populations appeared to be affected. However, although it is tempting to speculate that such changes occurred because of a growth inhibitory action of these drugs, it should be remembered that any therapeutic intervention that causes prevention or regression of atherosclerosis would lead to reduced cellularity of the intima. The pronounced antiatherosclerotic effects of ACE inhibition in the WHHL rabbit are similar to those reported in cholesterol-fed cynomolgus monkeys treated with captopril.3 In contrast, despite their favorable action in cholesterol-fed rabbits,911-21 neither

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Chobanian et al

0-blockers nor calcium channel blockers have inhibited atherogenesis in the WHHL rabbit,22"24 and nifedipine has proven to be ineffective in the cholesterol-fed cynomolgus monkey.25 Thus, differences between the mechanisms for the antiatherosclerotic effects of ACE inhibitors and other antihypertensive drugs would seem likely. Several studies have been performed lately on the effects of ACE inhibitors on plaque development after balloon injury or angioplasty. Cilazapril and captopril have both been reported to reduce myointimal thickening in rat carotid artery after balloon injury.1 The effect appears dose-related and may be potentiated by concurrent therapy with heparin.26 On the other hand, verapamil has been reported to have no effect in the same model and hydralazine may cause much less plaque inhibition than the ACE inhibitors, despite similar lowering of blood pressures.26 The high rate of SMC proliferation in the neointima after balloon injury27 appears associated with high rates of production of platelet-derived growth factor A-chain28 and transforming growth factor /3-1.29 ACE inhibitors appear to reduce the proliferative response in this model. In addition, although ACE inhibitors may inhibit restenosis in rat carotid artery, the effect may not be present in other models of vascular injury. For example, studies in baboons showed no effect of cilazapril on plaque formation after balloon catheter injury of superficial femoral artery or after carotid endarterectomy.30 Furthermore, a recent randomized, placebo-controlled clinical trial in patients treated by percutaneous transluminal coronary angioplasty failed to demonstrate a significant effect of cilazapril on either restenosis, as assessed by coronary angiography, or on clinical outcome.31 No adequate explanation has been provided for these seemingly disparate findings, although differences in species, types of vascular injury used, or treatment protocols all need to be considered. The current findings, though of considerable interest, should not be generalized to clinical practice. Clinical trials are required to determine whether ACE inhibitors will reduce atherosclerosis and its complications in humans. References 1. Powell JS, Clozel J-P, Muller RKM, Kuhn H, Hefti F, Hosang M, Baumgartncr HR: Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989-^245:186-188 2. Chobanian AV, Haudenschild CC, Nickerson C, Drago R: Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1990;15327-331 3. Aberg G, Ferrer P: Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovasc Pharmacol 1990;15:S65-S72 4. Chobanian AV, LJchtenstein AH, Nilakhe V, Haudenschild CC, Drago R, Nickerson C: Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit. Hypertension 1989; 14:203-209 5. Patat A, Surjus A, LeGo A, Granier J: Safety and tolerance of single oral doses of trandolapril (RU 44.570), a new angiotensin converting enzyme inhibitor. EurJ Clin Pharmacol 198936:17-23 6. Kramsch DM, Aspen AJ, Apstein CS: Suppression of experimental atherosclerosis by the Ca++-antagonist lanthanum. J Clin Invest 1980:65:967-981 7. Harrigan JR, Meredith PL, Reid JL: Interspecies differences in in vitro ACE inhibition, (abstract) Presented at Fourth European Meeting on Hypertension; June 18-21, 1989; Milan, Italy

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8. Kannel WB, Sorlie P: Hypertension in Framingham, in Paul O (ed): Epidemiology and Control of Hypertension. New York, Stratton Intercontinental Medical Books, 1975, pp 553-590 9. Chobanian AV, Brecher P, Chan C: Effect of propranolol on atherogenesis in the cholesterol-fed rabbit. Ore Res 1985;56: 755-762 10. Kaplan JR, Manuck SB, Adams MR, Weingand KW, darkson TB: Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atberogenk diet. Circulation 1987; 76:1364-1372 11. Henry PD, Bentley KI: Suppression of atherosclerosis in cholesterol-fed rabbit treated with nifedipine. / Clin Invest 1981;68: 1366-1369 12. Dzau V: Significance of the vascular renin-angiotensin pathway. Hypertension 1986;8:553-559 13. Geisterfer AAT, Peach MJ, Owens GK: Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Ore Res 1988;62:749-756 14. Naftilan AJ, Pratt RE, Dzau VJ: Induction of platelet-derived growth factor A- chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. / Clin Invest 1989; 83:1419-1424 15. CampbeU-Boswell M, Robertson AL: Effects of angiotensin II and vasopressin on human smooth muscle cells in vitro. Exp Mol Pathol 198135:265-276 16. Schelling P, Ganten D, Speck G, Fischer H: Effects of angiotensin II and angiotensin II antagonist saralasin on cell growth and renin in 3T3 and SV3T3 cells. J Cell Physiol 1979;98:503-513 17. Pacquet JL, Bandonim-Legros M, Brunelle G, Meyer P: Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats. / Hypertens 1990;8:565-572 18. Daemen MJAP, Lombardi DM, Bosman FT, Schwartz SM: Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Ore Res 1991;68:450-456 19. Takasaki I, Chobanian AV, Sarzani R, Brecher P: The effect of hypertension on expression of fibronectin in rat aorta. J Biol Chem 1990;265:21935-21939 20. Bell L, Madri JA; Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol 1990;137:7-12 21. Rouleau J-L, Parmley WW, Stevens J, Wilkman-Cofflet JW, Mahley RW, Havel RJ: Verapamil suppresses atherosclerosis in cholesterol-fed rabbits. J Am CoU Cardiol 1983;l:1453-146O 22. Lichtenstein AH, Drago R, Nickerson C, Prescott MF, Lee SQ, Chobanian AV: The effect of propranolol on atherogenesis in the Watanabe heritable hyperlipidemic rabbit / Vase Med Bid 1989; 1:248-254 23. Tilton GD, Buja LM, Bilheimer DW, Apprill P, Ashton J, McNatt J, Kita T, Willerson JT: Failure of a slow channel calcium antagonist, verapamil, to retard atherosclerosis in the Watanabe heritable hyperlipidemic rabbit: An animal model of familial hypercholesterolemia. .Mm CoU Cardiol 1985;6:141-144 24. Van Niekerk JLM, Hendriks Th, DeBoer HHM, Van't Laar A: Does nifedipine suppress atherogenesis in WHHL rabbits? Atherosclerosis 1984^3^1-98 25. Ferrer P, Aberg G: Progression of atherosclerosis in cholesterolfed cynomolgus monkeys during treatment with nifedipine. FASEB J 1990;27:396-399 26. Powell JS, Muller RKM, Baumgartner H: Suppression of the vascular response to injury: The role of angiotensin converting enzyme inhibitors. J Am Coll Cardiol 1991;17:137B-142B 27. Powell JS, Muller RKM, Rouge M, Kuhn H, Hefti F, Baumgartner HR: The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition. / Cardiovasc Pharmacol 1990;16(suppl 4):S42-S49 28. Majesky MW, Reidy MA, Bowen-Pope DF, Hart CE, Wilcox JN, Schwartz SM: PDGF ligand and receptor gene expression during repair of arterial injury. J Cell Biol 1990;lll:2148-2158 29. Majesky MW, Lindner V, Twardzik DR. Schwartz SM, Reidy MA; Production of transforming growth factor B, during repair of arterial injury./ Clin Invest 1991;88:904-910 30. Hanson SR, Powell JS, Dodson T, Lumsden A, Kelly AB, Anderson JS, Clowes AW, Harker LA: Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension 1991; 18(suppl II):II-70-II-76 31. Serruys PW, Hermans WRM: The new angiotensin converting enzyme inhibitor cilazapril does not prevent restenosis after coronary angioplasty: Results of the MERCATOR trial. / Am CoB Cardiol 1992;19:258A

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Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. A V Chobanian, C C Haudenschild, C Nickerson and S Hope Hypertension. 1992;20:473-477 doi: 10.1161/01.HYP.20.4.473 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563

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Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.

The effects of trandolapril (0.25 mg/kg body wt per 48 hours) on aortic atherosclerosis were examined in the Watanabe heritable hyperlipidemic rabbit ...
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