Teisman A C, Pinto Y M, Buikema H, Flesch M, Böhm M, Paul M, van Gilst W H
Department of Clinical Pharmacology, University of Groningen, The Netherlands.
J Hypertens. 1998 Dec;16(12 Pt 1):1759-65. doi: 10.1097/00004872-199816120-00008.
Since the biochemical disturbance underlying hypertension may be an important determinant of patient outcome, we compared the effects of early treatment with different antihypertensive drugs on end-organ damage in the TGR(mREN2)27 transgenic rat (REN-2). In these REN-2 rats, hypertension is primarily caused by increased activity of the tissue renin-angiotensin system.
Seven-week-old REN-2 rats were either untreated or treated orally with an optimal daily dose of carvedilol (30 mg/kg), hydralazine (30 mg/kg), losartan (10 mg/kg) or quinapril (15 mg/kg). Nontransgenic littermates served as normotensive controls. After 11 weeks of treatment, we determined plasma norepinephrine concentrations, left ventricular atrial natriuretic factor messenger RNA and cardiac and vascular function and hypertrophy.
Chronic treatment with carvedilol and hydralazine significantly decreased blood pressure to a similar level but failed to normalize it, whereas both losartan and quinapril completely normalized blood pressure. Despite a blood pressure reduction in all treatment groups, only losartan, quinapril and hydralazine preserved endothelial function, while carvedilol did not. Furthermore, losartan and quinapril prevented cardiac and medial hypertrophy. The expression of atrial natriuretic factor messenger RNA paralleled the hemodynamic changes. Plasma norepinephrine levels were normalized by losartan or quinapril but remained increased after carvedilol and hydralazine treatment.
In REN-2 hypertensive rats, end-organ damage can be prevented by both inhibition of the angiotensin converting enzyme and blockade of the angiotensin II type 1 receptor, but not by merely lowering blood pressure. When blood pressure is not fully normalized, the effects on end-organs are clearly dissociated from the antihypertensive effects.
鉴于高血压潜在的生化紊乱可能是患者预后的重要决定因素，我们比较了早期使用不同抗高血压药物治疗对TGR（mREN2）27转基因大鼠（REN - 2）靶器官损伤的影响。在这些REN - 2大鼠中，高血压主要由组织肾素 - 血管紧张素系统活性增加引起。
7周龄的REN - 2大鼠不进行治疗或口服给予每日最佳剂量的卡维地洛（30 mg/kg）、肼屈嗪（30 mg/kg）、氯沙坦（10 mg/kg）或喹那普利（15 mg/kg）。非转基因同窝仔鼠作为正常血压对照。治疗11周后，我们测定了血浆去甲肾上腺素浓度、左心室心房利钠因子信使核糖核酸以及心脏和血管功能与肥大情况。
卡维地洛和肼屈嗪的长期治疗显著降低血压至相似水平，但未能使其恢复正常，而氯沙坦和喹那普利均完全使血压恢复正常。尽管所有治疗组血压均降低，但只有氯沙坦、喹那普利和肼屈嗪保留了内皮功能，而卡维地洛没有。此外，氯沙坦和喹那普利预防了心脏和血管中层肥大。心房利钠因子信使核糖核酸的表达与血流动力学变化平行。氯沙坦或喹那普利使血浆去甲肾上腺素水平恢复正常，但卡维地洛和肼屈嗪治疗后仍升高。
在REN - 2高血压大鼠中，抑制血管紧张素转换酶和阻断血管紧张素II 1型受体均可预防靶器官损伤，但单纯降低血压则不能。当血压未完全恢复正常时，对靶器官的影响与抗高血压作用明显分离。
