Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Apr;91(4):1453–1458. doi: 10.1172/JCI116350

Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits.

J R Schuh 1, D J Blehm 1, G E Frierdich 1, E G McMahon 1, E H Blaine 1
PMCID: PMC288120  PMID: 8473494

Abstract

To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a non-sulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8 +/- 3.5%; treated: 31.1 +/- 8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4 +/- 3.2 mg/g tissue; treated: 7.4 +/- 1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis.

Full text

PDF

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aberg G., Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovasc Pharmacol. 1990;15 (Suppl 5):S65–S72. [PubMed] [Google Scholar]
  2. Alderman M. H., Madhavan S., Ooi W. L., Cohen H., Sealey J. E., Laragh J. H. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med. 1991 Apr 18;324(16):1098–1104. doi: 10.1056/NEJM199104183241605. [DOI] [PubMed] [Google Scholar]
  3. Allain C. C., Poon L. S., Chan C. S., Richmond W., Fu P. C. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed] [Google Scholar]
  4. Bath P. M., Hassall D. G., Gladwin A. M., Palmer R. M., Martin J. F. Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb. 1991 Mar-Apr;11(2):254–260. doi: 10.1161/01.atv.11.2.254. [DOI] [PubMed] [Google Scholar]
  5. Bauer J. H. Angiotensin converting enzyme inhibitors. Am J Hypertens. 1990 Apr;3(4):331–337. doi: 10.1093/ajh/3.4.331. [DOI] [PubMed] [Google Scholar]
  6. Björkhem I., Henriksson-Freyschuss A., Breuer O., Diczfalusy U., Berglund L., Henriksson P. The antioxidant butylated hydroxytoluene protects against atherosclerosis. Arterioscler Thromb. 1991 Jan-Feb;11(1):15–22. doi: 10.1161/01.atv.11.1.15. [DOI] [PubMed] [Google Scholar]
  7. Bomberger R. A., Zarins C. K., Taylor K. E., Glagov S. Effect of hypotension on atherogenesis and aortic wall composition. J Surg Res. 1980 May;28(5):402–409. doi: 10.1016/0022-4804(80)90102-x. [DOI] [PubMed] [Google Scholar]
  8. Bucolo G., David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem. 1973 May;19(5):476–482. [PubMed] [Google Scholar]
  9. Castelli W. P. Epidemiology of coronary heart disease: the Framingham study. Am J Med. 1984 Feb 27;76(2A):4–12. doi: 10.1016/0002-9343(84)90952-5. [DOI] [PubMed] [Google Scholar]
  10. Chobanian A. V., Haudenschild C. C., Nickerson C., Drago R. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension. 1990 Mar;15(3):327–331. doi: 10.1161/01.hyp.15.3.327. [DOI] [PubMed] [Google Scholar]
  11. Daemen M. J., Lombardi D. M., Bosman F. T., Schwartz S. M. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991 Feb;68(2):450–456. doi: 10.1161/01.res.68.2.450. [DOI] [PubMed] [Google Scholar]
  12. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  13. Farhy R. D., Ho K. L., Carretero O. A., Scicli A. G. Kinins mediate the antiproliferative effect of ramipril in rat carotid artery. Biochem Biophys Res Commun. 1992 Jan 15;182(1):283–288. doi: 10.1016/s0006-291x(05)80142-1. [DOI] [PubMed] [Google Scholar]
  14. Geisterfer A. A., Peach M. J., Owens G. K. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res. 1988 Apr;62(4):749–756. doi: 10.1161/01.res.62.4.749. [DOI] [PubMed] [Google Scholar]
  15. Gerrity R. G. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol. 1981 May;103(2):181–190. [PMC free article] [PubMed] [Google Scholar]
  16. Heinecke J. W. Free radical modification of low-density lipoprotein: mechanisms and biological consequences. Free Radic Biol Med. 1987;3(1):65–73. doi: 10.1016/0891-5849(87)90040-2. [DOI] [PubMed] [Google Scholar]
  17. Holme I. Drug treatment of mild hypertension to reduce the risk of CHD: is it worth-while? Stat Med. 1988 Nov;7(11):1109–1120. doi: 10.1002/sim.4780071104. [DOI] [PubMed] [Google Scholar]
  18. Holmquist B., Bünning P., Riordan J. F. A continuous spectrophotometric assay for angiotensin converting enzyme. Anal Biochem. 1979 Jun;95(2):540–548. doi: 10.1016/0003-2697(79)90769-3. [DOI] [PubMed] [Google Scholar]
  19. Islim I. F., Beevers D. G., Bareford D. The effect of antihypertensive drugs on in vivo platelet activity in essential hypertension. J Hypertens. 1992 Apr;10(4):379–383. doi: 10.1097/00004872-199204000-00010. [DOI] [PubMed] [Google Scholar]
  20. Lardinois C. K., Neuman S. L. The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med. 1988 Jun;148(6):1280–1288. [PubMed] [Google Scholar]
  21. Lopez J. A., Armstrong M. L., Harrison D. G., Piegors D. J., Heistad D. D. Responsiveness of iliac collateral vessels to constrictor stimuli in atherosclerotic primates. Circ Res. 1988 Dec;63(6):1020–1028. doi: 10.1161/01.res.63.6.1020. [DOI] [PubMed] [Google Scholar]
  22. MacMahon S. W., Cutler J. A., Furberg C. D., Payne G. H. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. Prog Cardiovasc Dis. 1986 Nov-Dec;29(3 Suppl 1):99–118. doi: 10.1016/0033-0620(86)90038-1. [DOI] [PubMed] [Google Scholar]
  23. Mak I. T., Freedman A. M., Dickens B. F., Weglicki W. B. Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells. Biochem Pharmacol. 1990 Nov 1;40(9):2169–2175. doi: 10.1016/0006-2952(90)90250-o. [DOI] [PubMed] [Google Scholar]
  24. Mao S. J., Yates M. T., Parker R. A., Chi E. M., Jackson R. L. Attenuation of atherosclerosis in a modified strain of hypercholesterolemic Watanabe rabbits with use of a probucol analogue (MDL 29,311) that does not lower serum cholesterol. Arterioscler Thromb. 1991 Sep-Oct;11(5):1266–1275. doi: 10.1161/01.atv.11.5.1266. [DOI] [PubMed] [Google Scholar]
  25. McGill H. C., Jr George Lyman Duff memorial lecture. Persistent problems in the pathogenesis of atherosclerosis. Arteriosclerosis. 1984 Sep-Oct;4(5):443–451. doi: 10.1161/01.atv.4.5.443. [DOI] [PubMed] [Google Scholar]
  26. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  27. Naftilan A. J., Pratt R. E., Dzau V. J. Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest. 1989 Apr;83(4):1419–1424. doi: 10.1172/JCI114032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nakagawa M., Kobayashi K., Sawada S., Toyoda T., Shirai K., Katoh K., Yamamoto K., Tsuji H., Sasaki S., Takeda K. Comparative studies of angiotensin converting enzyme inhibitors with and without the SH-radical. Am J Hypertens. 1991 Jan;4(1 Pt 2):54S–55S. doi: 10.1093/ajh/4.1.54s. [DOI] [PubMed] [Google Scholar]
  29. Nwator I. A., Whalley E. T. Angiotensin converting enzyme inhibitors and expression of des-Arg9-BK (kinin B1) receptors in vivo. Eur J Pharmacol. 1989 Jan 24;160(1):125–132. doi: 10.1016/0014-2999(89)90661-4. [DOI] [PubMed] [Google Scholar]
  30. Olins G. M., Corpus V. M., McMahon E. G., Palomo M. A., Schuh J. R., Blehm D. J., Huang H. C., Reitz D. B., Manning R. E., Blaine E. H. In vitro pharmacology of a nonpeptidic angiotensin II receptor antagonist, SC-51316. J Pharmacol Exp Ther. 1992 Jun;261(3):1037–1043. [PubMed] [Google Scholar]
  31. Overturf M., Sybers H., Schaper J., Taegtmeyer H. Hypertension and atherosclerosis in cholesterol-fed rabbits. Part 1. Mild, two-kidney, one-clip Goldblatt hypertension treated with enalapril. Atherosclerosis. 1986 Mar;59(3):283–299. doi: 10.1016/0021-9150(86)90124-3. [DOI] [PubMed] [Google Scholar]
  32. Platia M. P., Catt K. J., Hodgen G. D., Aguilera G. Regulation of primate angiotensin II receptors during altered sodium intake. Hypertension. 1986 Dec;8(12):1121–1126. doi: 10.1161/01.hyp.8.12.1121. [DOI] [PubMed] [Google Scholar]
  33. Quinn M. T., Parthasarathy S., Fong L. G., Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987 May;84(9):2995–2998. doi: 10.1073/pnas.84.9.2995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Radomski M. W., Palmer R. M., Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol. 1987 Sep;92(1):181–187. doi: 10.1111/j.1476-5381.1987.tb11310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Radomski M. W., Palmer R. M., Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commun. 1987 Nov 13;148(3):1482–1489. doi: 10.1016/s0006-291x(87)80299-1. [DOI] [PubMed] [Google Scholar]
  36. Ross R. The pathogenesis of atherosclerosis--an update. N Engl J Med. 1986 Feb 20;314(8):488–500. doi: 10.1056/NEJM198602203140806. [DOI] [PubMed] [Google Scholar]
  37. Schrör K. Converting enzyme inhibitors and the interaction between kinins and eicosanoids. J Cardiovasc Pharmacol. 1990;15 (Suppl 6):S60–S68. [PubMed] [Google Scholar]
  38. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
  39. Stouffer G. A., Owens G. K. Angiotensin II-induced mitogenesis of spontaneously hypertensive rat-derived cultured smooth muscle cells is dependent on autocrine production of transforming growth factor-beta. Circ Res. 1992 Apr;70(4):820–828. doi: 10.1161/01.res.70.4.820. [DOI] [PubMed] [Google Scholar]
  40. Swartz S. L. The role of prostaglandins in mediating the effects of angiotensin converting enzyme inhibitors and other antihypertensive drugs. Cardiovasc Drugs Ther. 1987;1(1):39–43. doi: 10.1007/BF02125831. [DOI] [PubMed] [Google Scholar]
  41. Ujhelyi M. R., Ferguson R. K., Vlasses P. H. Angiotensin-converting enzyme inhibitors: mechanistic controversies. Pharmacotherapy. 1989;9(6):351–362. doi: 10.1002/j.1875-9114.1989.tb04149.x. [DOI] [PubMed] [Google Scholar]
  42. Warnick G. R., Benderson J., Albers J. J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem. 1982 Jun;28(6):1379–1388. [PubMed] [Google Scholar]
  43. Weidmann P., Uehlinger D. E., Gerber A. Antihypertensive treatment and serum lipoproteins. J Hypertens. 1985 Aug;3(4):297–306. doi: 10.1097/00004872-198508000-00001. [DOI] [PubMed] [Google Scholar]
  44. Wong P. C., Hart S. D., Zaspel A. M., Chiu A. T., Ardecky R. J., Smith R. D., Timmermans P. B. Functional studies of nonpeptide angiotensin II receptor subtype-specific ligands: DuP 753 (AII-1) and PD123177 (AII-2). J Pharmacol Exp Ther. 1990 Nov;255(2):584–592. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES