It is currently unclear whether AMPK activators may be beneficial in the treatment of salt-sensitive hypertension. Experiments on airway tissue cultures reveal that ENaC-dependent short-circuit currents are substantially inhibited by AMPK activation (Woollhead et al., 2007; Myerburg et al., 2010). Zhang and colleagues did not find any effects of metformin on salt-induced hypertension in Dahl SS rats (Zhang et al., 1994). However, in later studies intracerebroventricular administration of metformin was found to prevent salt-induced blood pressure increase in the spontaneously hypertensive rat (SHR) model (Petersen et al., 2001). Recently, Yu et al. demonstrated that chronic administration of caffeine augments AMPK activity in Dahl SS rats and attenuates hypertension via a decrease of ENaC activity in the ASDN and improved natriuresis (Yu et al., 2016). In the current study, 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.