Lack of Effects of Metformin and AICAR Chronic Infusion on the Development of Hypertension in Dahl Salt-Sensitive Rats

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.

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

“…The glomerular damage score was 1.8 ± 0.1 vs. 3.2 ± 0.1 in the NS and HS diet fed groups, respectively. Therefore, the welldeveloped renal injury and BP increase in our model were in accordance with previously published studies (Endres et al, 2017;Palygin et al, 2017;Pavlov et al, 2017;Ilatovskaya et al, 2018;Kumar et al, 2019).…”

Chronic Intracerebroventricular Infusion of Metformin Inhibits Salt-Sensitive Hypertension via Attenuation of Oxidative Stress and Neurohormonal Excitation in Rat Paraventricular Nucleus

“…Moreover, ICV infusion of MET prevented these increases in NE, glutamate, and TH and the reduction in GABA and GAD67 in the PVN of hypertensive rats. In addition, Staruschenko and colleagues investigated the effects of continuous venous infusion (6.9 lL/min) of MET (200 mg/kg per day for 3 weeks) on salt-induced hypertension in Dahl salt-sensitive rats [49]. The MET treatment in the rats with high-Na ?…”

Essential role of Kir5.1 channels in renal salt handling and blood pressure control

“…Following urine collection, designated rats were anesthetized with 2%-3 % (vol/vol) isoflurane and a blood pressure transmitter (PA-C40; DSI) was surgically implanted subcutaneously, with the catheter tip secured in the abdominal aorta via the femoral artery. After a 3-day recovery period, blood pressure and heart rate were measured with a DSI system in conscious, freely moving male SS and SS Kcnj16-/-rats under different diet protocols, similar to those described previously (55,56). Urine measurements were taken weekly during the high-salt challenge; in this case, Na + , K + , Cl -, and Ca 2+ electrolytes were measured with radiometric assay (ABL800 FLEX, Radiometer America Inc.).…”