The discovery that bilateral renal sympathetic denervation significantly lowers blood pressure in patients suffering from resistant hypertension[1] has refocused attention to the renal nerves in the development of hypertension. Little is known regarding the influence of the renal nerves upon salt absorption in the aldosterone-sensitive distal nephron (ASDN), a segment characterised by the presence of the epithelial sodium channel (ENaC). Previously, we reported[2, 3] that the adrenergic transmitter norepinephrine (NE) stimulates ENaC-mediated Na+ transport in mCCDcl1 cells, a model of principal cells of the collecting duct. In the present study we further investigated the effects of NE on ENaC-mediated Na+ transport. mCCDcl1 cells were grown on permeable supports and ENaC-mediated Na+ transport was assessed by recording equivalent short circuit currents (ISC) across cell monolayers mounted in Ussing chambers. Data are given as mean ± SEM, analysed by ANOVA. NE produces a complex response consisting of an amiloride-resistant peak, followed by a brief inhibition of ISC over 15min and a sustained stimulation of ISC over 2.5h, both of which are amiloride-sensitive. These responses are concentration-dependent, with 100nM causing a significant inhibition of basal ISC from 6.1 ± 0.8 µA cm-2 to 4.8 ± 0.9 µA cm-2 (n=10, p<0.001). Higher concentrations did not inhibit ISC further. A 10-fold higher concentration (1µM) was required to elicit a stimulation of ISC above baseline from 6.1 ± 0.9 µA cm-2 to 8.7 ± 1.0 µA cm-2 (n=9, p<0.01). Increasing concentrations augment this stimulatory effect. Application of the β-adrenoceptor antagonist propranolol (1µM) did not alter the response to NE (n = 4), but the α-adrenoceptor antagonist phentolamine (20µM) reduced both the inhibitory response by 88.2 ± 0.1 % and the sustained stimulation by 69.8 ± 0.1 % (n=11). Addition of the specific α2-adrenoceptor antagonist yohimbine (100nM) did not alter the amiloride-sensitive inhibitory component or the stimulatory response (n=9). Additionally we confirmed that aldosterone (3nM) stimulates ISC in mCCDcl1 cells. Interestingly, in cells treated with aldosterone, NE failed to increase ISC above the level reached with aldosterone stimulation alone. This indicates that the stimulatory effects of aldosterone and NE are not additive. We conclude that in mCCDcl1 cells the sustained stimulatory effect of NE on ENaC is mediated by basolateral α1-adrenoceptors. ENaC stimulation by locally elevated NE may contribute to the hypertensive effect of increased renal sympathetic activity in particular in patients with low plasma aldosterone levels, i.e. in patients on a high salt diet. Reduced noradrenergic stimulation of ENaC may contribute to the blood pressure lowering effect of renal sympathetic denervation.