Protection of the Arterial Internal Elastic Lamina by Inhibition of the Renin-Angiotensin System in the Rat

From INSERM U367, Paris, France.

Correspondence to Dr M.J. Osborne-Pellegrin, INSERM U460, UFR de Médecine Xavier Bichat, 16 rue Henri Huchard, 75870 Paris Cedex 18, France. E-mail osborne{at}bichat.inserm.fr

Abstract—Spontaneous rupture of the internal elastic lamina (IEL) occurs in some arteries of the rat during growth and aging. Inbred, normotensive, Brown Norway (BN) rats are particularly susceptible to rupture of the IEL, especially in the abdominal aorta (AA). Preliminary experiments showed that different angiotensin-converting enzyme (ACE) inhibitors protect against rupture of the IEL in the BN rat to a greater extent than hydralazine, suggesting a role of the renin-angiotensin system (RAS) in this phenomenon. To explore this possibility, we have treated male BN rats from 4.5 to 14 weeks of age with either enalapril or losartan (both at 1, 3, and 10 mg · kg^-1 · d^-1) or with the calcium antagonists mibefradil (at 3, 10, 30, and 45 mg · kg^-1 · d^-1) and amlodipine (at 30 mg · kg^-1 · d^-1). Systolic blood pressure (SBP) was measured weekly, and at the end of treatment we (1) recorded body and heart weights, (2) measured various parameters of the RAS in plasma, (3) quantified interruptions in the IEL on "en face" preparations of AA, and (4) quantified elastin, collagen, and cell proteins in the media of the thoracic aorta. Results showed that enalapril and losartan similarly decrease SBP and rupture of the IEL in the AA, suggesting that enalapril inhibits the latter via a decrease in the production of angiotensin II (Ang II) and not via another effect on ACE. The decrease in IEL rupture and in SBP, as well as the modifications in the parameters of the RAS, were all dose dependent. Mibefradil had little effect on the RAS and, at the highest doses, decreased SBP to an extent similar to that for enalapril at 3 mg · kg^-1 · d^-1 but did not significantly inhibit IEL rupture. Amlodipine decreased SBP, increased plasma renin concentration, and was without effect on IEL rupture. All treatments at the highest doses had a hypotrophic effect on the aortic media but differed in their effects on the heart, with enalapril and losartan decreasing and mibefradil and amlodipine increasing heart weight, suggesting that the inhibition of IEL rupture may be related to a cardiac hypotrophic effect. All these results, taken together, suggest that Ang II plays a role in the rupture of the IEL that is, in part, independent of SBP.

Key Words: Brown Norway rat • enalapril • internal elastic lamina • losartan • mibefradil • systolic blood pressure

This article has been cited by other articles:

				Z. Fu, M. Wang, M. Gucek, J. Zhang, J. Wu, L. Jiang, R. E. Monticone, B. Khazan, R. Telljohann, J. Mattison, et al. Milk Fat Globule Protein Epidermal Growth Factor-8: A Pivotal Relay Element Within the Angiotensin II and Monocyte Chemoattractant Protein-1 Signaling Cascade Mediating Vascular Smooth Muscle Cells Invasion Circ. Res., June 19, 2009; 104(12): 1337 - 1346. [Abstract] [Full Text] [PDF]

				G. H. Turner, A. R. Olzinski, R. E. Bernard, K. Aravindhan, H. W. Karr, R. C. Mirabile, R. N. Willette, P. J. Gough, and B. M. Jucker In Vivo Serial Assessment of Aortic Aneurysm Formation in Apolipoprotein E-Deficient Mice via MRI Circ Cardiovasc Imaging, November 1, 2008; 1(3): 220 - 226. [Abstract] [Full Text] [PDF]

				G. T. Jones, A. R. Thompson, F. M. van Bockxmeer, H. Hafez, J. A. Cooper, J. Golledge, S. E. Humphries, P. E. Norman, and A. M. van Rij Angiotensin II Type 1 Receptor 1166C Polymorphism Is Associated With Abdominal Aortic Aneurysm in Three Independent Cohorts Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 764 - 770. [Abstract] [Full Text] [PDF]

				F. Anan, T. Masaki, Y. Umeno, T. Iwao, H. Yonemochi, N. Eshima, T. Saikawa, and H. Yoshimatsu Correlations of high-sensitivity C-reactive protein and atherosclerosis in Japanese type 2 diabetic patients Eur. J. Endocrinol., September 1, 2007; 157(3): 311 - 317. [Abstract] [Full Text] [PDF]

				S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF]

				E. Suganuma, V. R. Babaev, M. Motojima, Y. Zuo, N. Ayabe, A. B. Fogo, I. Ichikawa, M. F. Linton, S. Fazio, and V. Kon Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2311 - 2319. [Abstract] [Full Text] [PDF]

				N. Mercier, K. El Hadri, M. Osborne-Pellegrin, J. Nehme, C. Perret, C. Labat, V. Regnault, J.-M. D. Lamaziere, P. Challande, P. Lacolley, et al. Modifications of Arterial Phenotype in Response to Amine Oxidase Inhibition by Semicarbazide Hypertension, July 1, 2007; 50(1): 234 - 241. [Abstract] [Full Text] [PDF]

				L. Kota, M. Osborne-Pellegrin, H. Schulz, J. Behmoaras, M. Coutard, M. Gong, and N. Hubner Quantitative genetic basis of arterial phenotypes in the Brown Norway rat Physiol Genomics, June 19, 2007; 30(1): 17 - 25. [Abstract] [Full Text] [PDF]

				N. Mercier, M. Osborne-Pellegrin, K. El Hadri, A. Kakou, C. Labat, L. Loufrani, D. Henrion, P. Challande, S. Jalkanen, B. Feve, et al. Carotid arterial stiffness, elastic fibre network and vasoreactivity in semicarbazide-sensitive amine-oxidase null mouse Cardiovasc Res, November 1, 2006; 72(2): 349 - 357. [Abstract] [Full Text] [PDF]

				M. Wang, J. Zhang, G. Spinetti, L.-Q. Jiang, R. Monticone, D. Zhao, L. Cheng, M. Krawczyk, M. Talan, G. Pintus, et al. Angiotensin II Activates Matrix Metalloproteinase Type II and Mimics Age-Associated Carotid Arterial Remodeling in Young Rats Am. J. Pathol., November 1, 2005; 167(5): 1429 - 1442. [Abstract] [Full Text] [PDF]

				S. S. Najjar, A. Scuteri, and E. G. Lakatta Arterial Aging: Is It an Immutable Cardiovascular Risk Factor? Hypertension, September 1, 2005; 46(3): 454 - 462. [Abstract] [Full Text] [PDF]

				D. Gauguier, J. Behmoaras, K. Argoud, S. P. Wilder, C. Pradines, M. T. Bihoreau, M. Osborne-Pellegrin, and M. P. Jacob Chromosomal Mapping of Quantitative Trait Loci Controlling Elastin Content in Rat Aorta Hypertension, March 1, 2005; 45(3): 460 - 466. [Abstract] [Full Text] [PDF]

				A. Nobuhiko, E. Suganuma, V. R. Babaev, A. Fogo, L. L. Swift, M. F. Linton, S. Fazio, I. Ichikawa, and V. Kon Angiotensin II Amplifies Macrophage-Driven Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2143 - 2148. [Abstract] [Full Text] [PDF]

				M. Wang, G. Takagi, K. Asai, R. G. Resuello, F. F. Natividad, D. E. Vatner, S. F. Vatner, and E. G. Lakatta Aging Increases Aortic MMP-2 Activity and Angiotensin II in Nonhuman Primates Hypertension, June 1, 2003; 41(6): 1308 - 1316. [Abstract] [Full Text] [PDF]

				M. W Manning, L. A Cassis, J. Huang, S. J Szilvassy, and A. Daugherty Abdominal aortic aneurysms: fresh insights from a novel animal model of the disease Vascular Medicine, February 1, 2002; 7(1): 45 - 54. [Abstract] [PDF]

				G. Cohuet, P. Challande, M. Osborne-Pellegrin, S. M. Arribas, A. Dominiczak, H. Louis, S. Laurent, and P. Lacolley Mechanical Strength of the Isolated Carotid Artery in SHR Hypertension, November 1, 2001; 38(5): 1167 - 1171. [Abstract] [Full Text] [PDF]

				S. Boumaza, S. M. Arribas, M. Osborne-Pellegrin, J. C. McGrath, S. Laurent, P. Lacolley, and P. Challande Fenestrations of the Carotid Internal Elastic Lamina and Structural Adaptation in Stroke-Prone Spontaneously Hypertensive Rats Hypertension, April 1, 2001; 37(4): 1101 - 1107. [Abstract] [Full Text] [PDF]

				M. Coutard, W. Huang, M. Osborne-Pellegrin, and H. A. Kontos Heritability of Intracerebral Hemorrhagic Lesions and Cerebral Aneurysms in the Rat Editorial Comment Stroke, November 1, 2000; 31(11): 2678 - 2684. [Abstract] [Full Text] [PDF]