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

Abstract

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 ⅐ kg Ϫ1 ⅐ d Ϫ1 ) or with the calcium antagonists mibefradil (at 3, 10, 30, and 45 . 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 ⅐ kgbut 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.(Circ Res. 1998;82:879-890.)Key Words: Brown Norway rat Ⅲ enalapril Ⅲ internal elastic lamina Ⅲ losartan Ⅲ mibefradil Ⅲ systolic blood pressure R upture of the IEL occurs spontaneously in rat arteries, to different degrees depending on the artery and the strain studied.1-3 The formation of IIEL is influenced by many factors, including age, 1 sex, 1,4 and hemodynamic factors such as blood pressure 1,2 and flow. 4,5 Although it appears that local factors determine IEL rupture within different arteries of any one rat, the overall susceptibility to this lesion is genetically determined. Indeed, we have previously reported that the inbred BN strain is particularly susceptible to IEL rupture and is the only strain among those we have studied to present significant numbers of ruptures in its AA. 2The reason for this genetically determined susceptibility has not been elucidated at...

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