Fortepiani L A, Rodrigo E, Ortíz M C, Cachofeiro V, Atucha N M, Ruilope L M, Lahera V, García-Estañ J
Departamento de Fisiología, Facultades de Medicina, Murcia, Spain.
J Am Soc Nephrol. 1999 Jan;10(1):21-7. doi: 10.1681/ASN.V10121.
Chronic inhibition of nitric oxide (NO) synthesis has been shown to result in arterial hypertension and an important blunting of the pressure diuresis and natriuresis response (PDN). The mechanisms mediating these abnormalities are not completely understood. In the present study, the role of several antihypertensive drugs to ameliorate these alterations was evaluated. The PDN relationships have been evaluated in rats chronically (8 wk) treated with the NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg per d in the drinking water). Appropriate groups of rats were simultaneously treated with the angiotensin II receptor blocker candesartan at a low (1.5 mg/kg per d) and high (2.5 mg/kg per d) dose, with the converting enzyme inhibitor captopril (60 mg/kg per d) and with the calcium channel blocker verapamil (100 mg/kg per d). Chronic treatment with L-NAME significantly elevated mean BP (163.6 +/- 6.5 mmHg versus 105.1 +/- 3.6 in controls), reduced GFR and renal blood flow (RBF), and shifted to the right the PDN responses. Chronic administration of low-dose candesartan, captopril, or verapamil prevented the arterial hypertension and improved renal hemodynamics, but these levels were not completely normalized. High-dose administration also improved renal hemodynamics but induced reduced BP below the levels of control animals. Despite the normalization of the elevated BP, the PDN responses of these hypertensive treated groups were not normalized, and the slopes of the respective diuretic or natriuretic responses were very similar to those of the hypertensive untreated rats. The results indicate that interruption or blockade of the renin-angiotensin system and calcium channel blockade are effective treatments for the NO-deficient arterial hypertension and renal vasoconstriction. However, the PDN responses are not normalized, and this finding suggests that the antihypertensive treatment is not enough to overcome the renal alterations associated with the chronic deficiency of NO.
慢性抑制一氧化氮（NO）合成已被证明会导致动脉高血压以及压力利尿和利钠反应（PDN）的显著减弱。介导这些异常的机制尚未完全明确。在本研究中，评估了几种抗高血压药物改善这些改变的作用。在长期（8周）用NO合成抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME；每日40mg/kg加入饮用水中）处理的大鼠中评估了PDN关系。将适当的大鼠组同时用低剂量（每日1.5mg/kg）和高剂量（每日2.5mg/kg）的血管紧张素II受体阻滞剂坎地沙坦、转化酶抑制剂卡托普利（每日60mg/kg）以及钙通道阻滞剂维拉帕米（每日100mg/kg）进行处理。用L-NAME进行慢性处理显著升高了平均血压（与对照组的105.1±3.6mmHg相比为163.6±6.5mmHg），降低了肾小球滤过率（GFR）和肾血流量（RBF），并使PDN反应向右偏移。低剂量坎地沙坦、卡托普利或维拉帕米的慢性给药可预防动脉高血压并改善肾血流动力学，但这些水平并未完全恢复正常。高剂量给药也改善了肾血流动力学，但导致血压降至低于对照动物的水平。尽管升高的血压恢复了正常，但这些高血压治疗组的PDN反应并未恢复正常，并且各自的利尿或利钠反应斜率与未治疗的高血压大鼠非常相似。结果表明，肾素-血管紧张素系统的阻断或抑制以及钙通道阻断是治疗NO缺乏性动脉高血压和肾血管收缩的有效方法。然而，PDN反应并未恢复正常，这一发现表明抗高血压治疗不足以克服与慢性NO缺乏相关的肾脏改变。
