Huang W, Alhenc Gelas F, Osborne-Pellegrin M J
INSERM U367, Paris, France.
Circ Res. 1998 May 4;82(8):879-90. doi: 10.1161/01.res.82.8.879.
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 x kg(-1) x d(-1)) or with the calcium antagonists mibefradil (at 3, 10, 30, and 45 mg x kg(-1) x d(-1)) and amlodipine (at 30 mg x kg(-1) x 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 x kg(-1) x 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.
在大鼠生长和衰老过程中，一些动脉会发生内弹性膜（IEL）的自发性破裂。近交系、血压正常的挪威棕色（BN）大鼠尤其易发生IEL破裂，特别是在腹主动脉（AA）。初步实验表明，不同的血管紧张素转换酶（ACE）抑制剂比肼屈嗪能更有效地预防BN大鼠的IEL破裂，提示肾素-血管紧张素系统（RAS）在这一现象中发挥作用。为探究这种可能性，我们用依那普利或氯沙坦（均为1、3和10 mg·kg⁻¹·d⁻¹）或钙拮抗剂米贝拉地尔（3、10、30和45 mg·kg⁻¹·d⁻¹）和氨氯地平（30 mg·kg⁻¹·d⁻¹）对4.5至14周龄的雄性BN大鼠进行治疗。每周测量收缩压（SBP），在治疗结束时，我们（1）记录体重和心脏重量，（2）测量血浆中RAS的各种参数，（3）对AA “正面” 标本上IEL的中断情况进行量化，（4）对胸主动脉中膜的弹性蛋白、胶原蛋白和细胞蛋白进行量化。结果表明，依那普利和氯沙坦类似地降低SBP和AA中IEL的破裂，提示依那普利通过降低血管紧张素II（Ang II）的生成而非对ACE的其他作用来抑制后者。IEL破裂和SBP的降低以及RAS参数的改变均呈剂量依赖性。米贝拉地尔对RAS影响很小，在最高剂量时，SBP降低程度与依那普利3 mg·kg⁻¹·d⁻¹时相似，但未显著抑制IEL破裂。氨氯地平降低SBP，增加血浆肾素浓度，对IEL破裂无影响。所有最高剂量的治疗对主动脉中膜均有生长抑制作用，但对心脏的影响不同，依那普利和氯沙坦使心脏重量减轻，米贝拉地尔和氨氯地平使心脏重量增加，提示IEL破裂的抑制可能与心脏生长抑制作用有关。综合所有这些结果，提示Ang II在IEL破裂中起作用，且部分独立于SBP。
