Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27
Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27
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抑制组织血管紧张素转换酶活性可预防 TGR(mREN2)27 中的恶性高血压
作者：
H. Montgomery;Linda A. Kiernan;C. Whitworth;S. Fleming;T. Unger;P. Gohlke;J. Mullins;J. McEwan
背景肾素-血管紧张素系统的激活与良性高血压向恶性高血压的转变密切相关。然而，伴随的血压升高也可能通过引发纤维素样坏死和肌内膜增生对血管壁产生直接影响。事实证明，很难确定这两个因素在这一过程中的相对重要性。TGR（mREN 2）27杂合子（HanRen 2/Edin-）先前已被证明自发地发展恶性高血压，并表现出人类恶性高血压的特征。目的组织肾素-血管紧张素系统参与恶性高血压的发病机制。我们着手确定抑制该系统是否可以在大鼠模型中防止疾病的发展。方法雄性TGR（mREN 2）27杂合子（n = 24）于28 ~ 120日龄给予血管紧张素转换酶抑制剂雷米普利（5 mg/kg·d），对照组（n = 40）。比较两组恶性高血压的发生率。在治疗期间通过尾袖体积描记法测量收缩压;在治疗期结束时或发生恶性高血压时评估组织和血浆血管紧张素转换酶水平和肾脏组织学变化。结果63%的对照组大鼠和4%的血管紧张素转换酶受体治疗组大鼠在120天内发生恶性高血压，尽管在整个治疗过程中收缩压没有显著差异。肾脏、心脏和阻力血管中的血管紧张素转换酶活性在治疗组中显著降低，而血浆中的活性则没有显著降低。两组之间的中膜壁增厚程度无差异，而血管紧张素转换酶受体治疗组大鼠中的组织损伤证据（如内膜纤维化、纤维素样坏死和肾单位损伤）明显较不常见。结论：在此模型中，非过度剂量的组织血管紧张素转换酶抑制剂几乎完全预防了恶性高血压的死亡率，并显著降低了组织损伤，提示血管紧张素II而不是高血压是恶性高血压的主要“血管毒性”药物。J Hypertens 16：635-643 © 1998 Lippincott-Raven Publishers.
Background Activation of the renin–angiotensin system has been implicated strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a direct effect on the vascular wall by initiating fibrinoid necrosis and myointimal proliferation. Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heterozygotes (HanRen2/Edin–) have previously been shown to develop malignant hypertension spontaneously and exhibit the characteristic features of human malignant hypertension. Objective Tissue renin–angtiotensin systems have been implicated in the pathogenesis of malignant hypertension. We set out to determine whether inhibition of this system might protect against development of the disease in a rat model. Method Male TGR(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 mg/kg per day) from 28 to 120 days of age, untreated rats acting as controls (n = 40). The incidences of malignant hypertension were compared. Systolic blood pressure was measured by tail-cuff plethysmography during treatment; tissue and plasma angiotensin converting enzyme levels and renal histological changes were assessed at the end of the treatment period or upon development of malignant hypertension. Results Sixty-three per cent of control rats and 4% of angiotensin converting enzyme inhibitor-treated rats had developed malignant hypertension by 120 days despite there having been no significant difference in systolic blood pressure throughout the course of treatment. Angiotensin converting enzyme activities in kidney, heart and resistance vessels, though not that in plasma, were significantly lower in the treated rats. The degree of medial wall thickening did not differ between the two groups whereas evidence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angiotensin converting enzyme inhibitor-treated group. Conclusions Tissue angiotensin converting enzyme inhibition at a non-hypotensive dose almost completely prevented mortality from malignant hypertension and significantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal ‘vasculotoxic’ agent in malignant hypertension. J Hypertens 16:635–643 © 1998 Lippincott-Raven Publishers.
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DOI：
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10.1152/ajpregu.1994.266.4.r1273
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The American journal of physiology
影响因子：
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作者：
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