Dominiczak A F, Devlin A M, Lee W K, Anderson N H, Bohr D F, Reid J L
Department of Medicine and Therapeutics, University of Glasgow, Scotland, UK.
Hypertension. 1996 Mar;27(3 Pt 2):752-9. doi: 10.1161/01.hyp.27.3.752.
We studied the mechanisms responsible for vascular and cardiac hypertrophy in hypertension (pressure load and humoral and genetic factors) in two experimental approaches: (1) We carried out a cosegregation analysis to correlate cardiac and vascular hypertrophy with subphenotypes of blood pressure in an F2 generation of a cross between stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats; (2) we treated 8-week-old SHRSP with perindopril, an angiotensin-converting enzyme inhibitor; losartan, an angiotensin type 1 receptor antagonist; or perindopril combined with a nitric oxide synthase inhibitor to investigate the relative contributions of blood pressure and angiotensin II to the pathogenesis of cardiac hypertrophy and vascular smooth muscle polyploidy. Vascular smooth muscle polyploidy was measured with flow cytometry DNA analysis. Cardiac hypertrophy was assessed by measuring the ratios of heart weight to body weight and left ventricle + septum weight to body weight. Blood pressure was measured with radiotelemetry in the F2 cosegregation experiment and with tail-cuff plethysmography in the pharmacological study. In the F2 rats, the best predictor of smooth muscle polyploidy by ANCOVA was systolic pressure (F=29.28, P < .0001). The ratio of left ventricle + septum weight to body weight had four major predictors: the male progenitor of the cross, sex, pulse pressure, and change in systolic pressure during salt (F=43.67, P < .0001; F=16.37, P < .0001; F=8.41, P=.0022; and F=12.39, P= .0003, respectively). The ratio of heart weight to body weight had similar predictors. In the pharmacological study, treatment with losartan alone, perindopril alone, or perindopril in combination with N(G)-nitro-L-arginine methyl ester prevented the development of smooth muscle polyploidy and cardiac hypertrophy. The prevention of cardiac hypertrophy was most marked in the SHRSP treated with perindopril plus N(G)-nitro-L-arginine methyl ester, despite blood pressure being higher in this group than in the two other treatment groups. We conclude that vascular and cardiac hypertrophy in this form of hypertension are regulated by different variables. However, suppression of the action of angiotensin II lessens hypertrophy of both types of muscle.
我们采用两种实验方法研究了高血压（压力负荷、体液和遗传因素）中血管和心脏肥大的机制：（1）我们进行了共分离分析，以关联易卒中型自发性高血压大鼠（SHRSP）与正常血压的Wistar-Kyoto大鼠杂交F2代中，心脏和血管肥大与血压亚表型的关系；（2）我们用培哚普利（一种血管紧张素转换酶抑制剂）、氯沙坦（一种血管紧张素1型受体拮抗剂）或培哚普利联合一氧化氮合酶抑制剂治疗8周龄的SHRSP，以研究血压和血管紧张素II对心脏肥大和血管平滑肌多倍体发病机制的相对贡献。通过流式细胞术DNA分析测量血管平滑肌多倍体。通过测量心脏重量与体重之比以及左心室+室间隔重量与体重之比来评估心脏肥大。在F2共分离实验中用无线电遥测法测量血压，在药理学研究中用尾套体积描记法测量血压。在F2大鼠中，通过协方差分析，平滑肌多倍体的最佳预测指标是收缩压（F = 29.28，P <.0001）。左心室+室间隔重量与体重之比有四个主要预测指标：杂交的雄性亲代、性别、脉压以及盐负荷期间收缩压的变化（分别为F = 43.67，P <.0001；F = 16.37，P <.0001；F = 8.41，P =.0022；F = 12.39，P =.0003）。心脏重量与体重之比有类似的预测指标。在药理学研究中，单独使用氯沙坦、单独使用培哚普利或培哚普利与N（G）-硝基-L-精氨酸甲酯联合使用可预防平滑肌多倍体和心脏肥大的发展。尽管该组血压高于其他两个治疗组，但培哚普利加N（G）-硝基-L-精氨酸甲酯治疗的SHRSP对心脏肥大的预防最为显著。我们得出结论：这种形式的高血压中血管和心脏肥大受不同变量调节。然而，抑制血管紧张素II的作用可减轻两种类型肌肉的肥大。
