Toblli Jorge E, DeRosa Graciela, Rivas Carlos, Cao Gabriel, Piorno Pablo, Pagano Patricia, Forcada Pedro
Laboratory of Experimental Medicine, Hospital Alemán, CONICET, Av. Pueyrredon 1640, Buenos Aires 1118, Argentina.
J Hypertens. 2003 Mar;21(3):611-20. doi: 10.1097/00004872-200303000-00028.
Obesity, non-insulin-dependent diabetes mellitus (NIDDM) and hypertension are leading causes associated with increased cardiovascular morbidity and mortality. In modern times, the combined first line antihypertensive therapy with at least two drugs with a different mechanism of action to achieve a better blood pressure control, is increasing in acceptance worldwide. The aim of the present study was to determine possible beneficial effects of the low-dose combination (LDC) of an angiotensin-converting enzyme (ACE) inhibitor, perindopril (PER), and the diuretic indapamide (IND), regarding myocardial and vessels protection in an animal model of hypertension, obesity and NIDDM, such as the obese Zucker rat (OZR), and control lean Zucker rats (LZR).
Ten-week-old male OZR (fa/fa) and LZR (Fa/fa) were used in this study. OZR group (G1, n=8), OZR with LDC group (G2, n=8); LZR group (G3, n=8) and LZR with LDC group (G4, n=8). During 6 months, G2 and G4 received a daily dose of 1 mg/kg combination of 0.76 mg/kg PER + 0.24 mg/kg IND, (ratio of doses 0.32), by gavage, and G1 and G3 received an equal volume of vehicle throughout the experiment. In order to evaluate cardiac dimensions and left ventricular mass (LVM) transthoracic echocardiograms were performed, at baseline and at the end of the experiment. Urine and blood samples for biochemical determination were obtained. After 6 months of treatment all rats were sacrificed, hearts were harvested for light microscopy (LM), high-resolution light microscopy (HRLM), immunohistochemistry including monoclonal antibodies against transforming growth factor beta (TGFbeta1) and anti-collagen type I (COL I) and type III (COL III) and electron microscopy (EM) studies.
At the end of the study OZR treated with LDC presented: (1) lower blood pressure (128.9 +/- 4 versus 150.3 +/- 3.6 mmHg, P< 0.05); (2) smaller cardiac dimensions (P< 0.01); (3) lower LVM/100 g body weight (0.17 +/- 0.02 versus 0.30 +/- 0.05, P< 0.01); (4) higher fractional shortening (34.5 +/- 3.2 versus 23.3 +/- 5.9%, P< 0.01) than OZR untreated. Moreover, OZR that received LDC showed higher: (1) myocyte density (48 +/- 1.5 versus 20 +/- 2.5 myocytes/area, P< 0.01); (2) capillary density (30.5 +/- 3.1 versus 9.5 +/- 1.6 capillaries/area, P<0.01); (3) myofilament thickness (12.05 +/- 0.27 versus 9.83 +/- 0.39 nm, P<0.01); and lower amounts of: (1) TGFbeta1 in myocytes (P< 0.01), interstitium (P< 0.01) and vessel wall (P< 0.05); (2) COL I and COL III (P< 0.01), and COL I /COL III ratio (P< 0.01), compared with untreated OZR. Finally, OZR-treated with LDC showed not only unsubstantial modification in carbohydrate and lipid metabolism when compared with untreated OZR, but also an improvement in insulin/glucose ratio (P< 0.05).
These results suggest that LDC of PER + IND can control cardiovascular damage in OZR providing an additional help in the metabolic scenario likewise.
肥胖、非胰岛素依赖型糖尿病（NIDDM）和高血压是导致心血管疾病发病率和死亡率增加的主要原因。在现代，联合使用至少两种作用机制不同的一线抗高血压药物以更好地控制血压，在全球范围内越来越被接受。本研究的目的是确定血管紧张素转换酶（ACE）抑制剂培哚普利（PER）和利尿剂吲达帕胺（IND）的低剂量组合（LDC）对高血压、肥胖和NIDDM动物模型（如肥胖 Zucker 大鼠（OZR））心肌和血管保护的可能有益作用，并与对照瘦 Zucker 大鼠（LZR）进行比较。
本研究使用 10 周龄雄性 OZR（fa/fa）和 LZR（Fa/fa）。OZR 组（G1，n = 8）、接受 LDC 的 OZR 组（G2，n = 8）；LZR 组（G3，n = 8）和接受 LDC 的 LZR 组（G4，n = 8）。在 6 个月期间，G2 和 G4 每天通过灌胃给予 1 mg/kg 组合药物（0.76 mg/kg PER + 0.24 mg/kg IND，剂量比为 0.32），G1 和 G3 在整个实验过程中接受等量的赋形剂。为了评估心脏大小和左心室质量（LVM），在基线和实验结束时进行经胸超声心动图检查。采集尿液和血液样本进行生化测定。治疗 6 个月后，处死所有大鼠，取出心脏进行光学显微镜（LM）、高分辨率光学显微镜（HRLM）、免疫组织化学（包括针对转化生长因子β（TGFbeta1）的单克隆抗体以及抗 I 型胶原（COL I）和 III 型胶原（COL III））和电子显微镜（EM）研究。
在研究结束时，接受 LDC 治疗的 OZR 表现为：（1）血压较低（128.9±4 与 150.3±3.6 mmHg，P<0.05）；（2）心脏尺寸较小（P<0.01）；（3）LVM/100 g 体重较低（0.17±0.02 与 0.30±0.05，P<0.01）；（4）与未治疗的 OZR 相比，缩短分数较高（34.5±3.2 与 23.3±5.9%，P<0.01）。此外，接受 LDC 治疗的 OZR 显示：（1）心肌细胞密度较高（48±1.5 与 20±2.5 个心肌细胞/面积，P<0.01）；（2）毛细血管密度较高（30.5±3.1 与 9.5±1.6 条毛细血管/面积，P<0.01）；（3）肌丝厚度较高（12.05±0.27 与 9.83±0.39 nm，P<0.01）；并且（1）心肌细胞、间质（P<0.01）和血管壁（P<0.05）中的 TGFbeta1 含量较低；（2）与未治疗的 OZR 相比，COL I 和 COL III（P<0.01）以及 COL I/COL III 比值（P<0.01）较低。最后，与未治疗的 OZR 相比，接受 LDC 治疗的 OZR 不仅在碳水化合物和脂质代谢方面没有实质性改变，而且胰岛素/葡萄糖比值有所改善（P<0.05）。
这些结果表明，PER + IND 的 LDC 可以控制 OZR 中的心血管损伤，同样在代谢方面也提供了额外的帮助。
