Norepinephrine stimulates the epithelial Na⁺ channel in cortical collecting duct cells via α₂-adrenoceptors

There is good evidence for a causal link between excessive sympathetic drive to the kidney and hypertension. We hypothesized that sympathetic regulation of tubular Na+ absorption may occur in the aldosterone-sensitive distal nephron, where the fine tuning of renal Na+ excretion takes place. Here, the appropriate regulation of transepithelial Na+ transport, mediated by the amiloride-sensitive epithelial Na+ channel (ENaC), is critical for blood pressure control. To explore a possible effect of the sympathetic transmitter norepinephrine on ENaC-mediated Na⁺ transport, we performed short-circuit current (I_sc) measurements on confluent mCCDcl1 murine cortical collecting duct cells. Norepinephrine caused a complex I_sc response with a sustained increase of amiloride-sensitive I_sc by ∼44%. This effect was concentration dependent and mediated via basolateral α₂-adrenoceptors. In cells pretreated with aldosterone, the stimulatory effect of norepinephrine was reduced. Finally, we demonstrated that noradrenergic nerve fibers are present in close proximity to ENaC-expressing cells in murine kidney slices. We conclude that the sustained stimulatory effect of locally elevated norepinephrine on ENaC-mediated Na⁺ absorption may contribute to the hypertensive effect of increased renal sympathetic activity.