Lack of Effects of Metformin and AICAR Chronic Infusion on the Development of Hypertension in Dahl Salt-Sensitive Rats.
Lack of Effects of Metformin and AICAR Chronic Infusion on the Development of Hypertension in Dahl Salt-Sensitive Rats.
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DOI：
10.3389/fphys.2017.00227
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发表时间：
2017
影响因子：
4
通讯作者：
Staruschenko A
中科院分区：
文献类型：
--
作者：
Pavlov TS;Levchenko V;Ilatovskaya DV;Li H;Palygin O;Pastor-Soler NM;Hallows KR;Staruschenko A
在肾脏中，通过上皮钠通道（ENaC）的重吸收参与长期血压控制。先前我们证明ENaC活动过度与Dahl SS大鼠盐敏感性（SS）高血压的发展相关。AMP激活的激酶（AMPK）在细胞能量稳态中起作用，已被证明可降低ENaC活性。在这里，我们测试了二甲双胍和AICAR，两种激活AMPK的药物，是否影响盐诱导高血压的发展。高盐饮食显著增加Dahl SS大鼠的平均动脉压（MAP）。血压升高伴随着心率的短期下降和昼夜动脉压下降的增加。分别以200和20 mg/kg/天的剂量静脉内递送美托洛尔和AICAR。然而，对照组和药物治疗组在摄入8%NaCl膳食盐的3周内具有相似的高血压发展。二甲双胍组MAP为164.9 ± 9.1 mmHg，与对照组（171.8 ± 5.6 mmHg）相比无显著性差异。膜片钳分析显示二甲双胍处理的大鼠ENaC活性无差异。AICAR治疗也不影响高血压和肾损伤的发展。AICAR和溶剂处理组的MAP分别达到182.8 ± 4.8和178.0 ± 2.8 mmHg。值得注意的是，我们发现高盐饮食激活了Dahl SS大鼠中的AMPK，并且用这些AMPK激活剂治疗对AMPK活性没有显著的进一步影响。我们的结论是，AMPK激活剂，至少在这些条件下，不影响高盐饮食中的Dahl SS大鼠模型的高血压的发展。
In the kidney, reabsorption via the epithelial sodium channel (ENaC) is involved in long-term blood pressure control. Previously we demonstrated that ENaC hyperactivity is associated with development of salt-sensitive (SS) hypertension in Dahl SS rats. AMP-activated kinase (AMPK), playing a role in cellular energy homeostasis, has been shown to decrease ENaC activity. Here, we tested whether metformin and AICAR, two drugs that activate AMPK, affect the development of salt-induced hypertension. High salt diet significantly increased mean arterial pressure (MAP) in Dahl SS rats. Blood pressure elevation was accompanied by a short-term decline of heart rate and increased circadian arterial pressure dipping. Metformin and AICAR were delivered intravenously at doses of 200 and 20 mg/kg/day, respectively. However, both control and drug-treated groups had similar development of high blood pressure within 3 weeks of 8% NaCl dietary salt intake. In the metformin-treated animals MAP reached 164.9 ± 9.1 mmHg, which was not significantly different from the control group (171.8 ± 5.6 mmHg). Patch clamp analysis revealed that the metformin-treated rats had no difference in the activity of ENaC. AICAR treatment also did not affect the development of hypertension and kidney injury. MAP reached 182.8 ± 4.8 and 178.0 ± 2.8 mmHg in AICAR and vehicle treated groups, respectively. Of note, we found that high-salt diet activated AMPK in the Dahl SS rats, and treatment with these AMPK activators had no significant further effect on AMPK activity. We conclude that AMPK activators, at least under these conditions, do not affect development of hypertension during high-salt diet in the Dahl SS rat model.