Abstract
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.
Highlights
Activators of 5′-AMP-activated protein kinase (AMPK) are widely used for treatment of metabolic disorders, type 2 diabetes, heart disease, anti-proliferative therapy and sports medicine
We used chronic intravenous metformin and AICAR treatments to test how these AMPK activators affect the development of SS hypertension and ENaC activity in Dahl SS rats
The experiment revealed that during the 3-week period the 0.4% diet does not alter blood pressure, whereas the 4% diet raised mean arterial pressure (MAP), and the 8% diet augmented the development of hypertension (Figure 1A)
Summary
Activators of 5′-AMP-activated protein kinase (AMPK) are widely used for treatment of metabolic disorders, type 2 diabetes, heart disease, anti-proliferative therapy and sports medicine. AMPK, a heterotrimeric serine/threonine protein kinase, is activated in response to reduced intracellular ATP to AMP ratio and controls numerous metabolic pathways Activation of this kinase improves glucose uptake, fatty acid oxidation and insulin sensitivity in skeletal muscles, carbohydrate and. We and others have shown that in Dahl SS rats abnormal activation of ENaC on a high salt diet contributes to the development of hypertension (Kakizoe et al, 2009; Pavlov et al, 2013; Pavlov and Staruschenko, 2016) It is currently unclear whether AMPK activators may be beneficial in the treatment of salt-sensitive hypertension. We used chronic intravenous metformin and AICAR treatments to test how these AMPK activators affect the development of SS hypertension and ENaC activity in Dahl SS rats
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