Norepinephrine-Induced Stimulation of Kir4.1/Kir5.1 Is Required for the Activation of NaCl Transporter in Distal Convoluted Tubule

Hypertension. 2019 Jan;73(1):112-120. doi: 10.1161/HYPERTENSIONAHA.118.11621.


The stimulation of β-adrenergic receptor increases thiazide-sensitive NaCl cotransporter (NCC), an effect contributing to salt-sensitive hypertension by sympathetic stimulation. We now test whether the stimulation of β-adrenergic receptor-induced activation of NCC is achieved through activating basolateral Kir4.1 in the distal convoluted tubule (DCT). Application of norepinephrine increased the basolateral 40 pS K+ channel (Kir4.1/Kir5.1 heterotetramer) in the DCT. The stimulatory effect of norepinephrine on the K+ channel was mimicked by cAMP analogue but abolished by inhibiting PKA (protein kinase A). Also, the effect of norepinephrine on the K+ channel in the DCT was recapitulated by isoproterenol but not by α-adrenergic agonist and blocked by propranolol, suggesting that norepinephrine effect on the K+ channel was mediated by β-adrenergic receptor. The whole-cell recording shows that norepinephrine and isoproterenol increased DCT K+ currents and shifted the K+ current ( IK) reversal potential to negative range (hyperpolarization). Continuous norepinephrine perfusion (7 days) increased DCT K+ currents, hyperpolarized IK reversal potential, and increased the expression of total NCC/phosphorylated NCC, but it had no significant effect on the expression of NKCC2 (type 2 Na-Cl-K cotransporter) and ENaC-α (epithelial Na channel-α subunit). Renal clearance study demonstrated that norepinephrine perfusion augmented thiazide-induced urinary Na+ excretion only in wild-type but not in kidney-specific Kir4.1 knockout mice, suggesting that Kir4.1 is required for mediating the effect of norepinephrine on NCC. However, norepinephrine perfusion did not affect urinary K+ excretion. We conclude that the stimulation of β-adrenergic receptor activates the basolateral Kir4.1 in the DCT and that the activation of Kir4.1 is required for norepinephrine-induced stimulation of NCC.

Keywords: hypertension; ion transport; isoproterenol; norepinephrine; propranolol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Ion Transport* / drug effects
  • Ion Transport* / physiology
  • Isoproterenol / pharmacology*
  • Kidney Tubules, Distal / drug effects
  • Kidney Tubules, Distal / metabolism
  • Mice
  • Mice, Knockout
  • Norepinephrine / metabolism
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Propranolol / pharmacology*
  • Receptors, Adrenergic, beta / metabolism*
  • Solute Carrier Family 12, Member 1 / metabolism*
  • Solute Carrier Family 12, Member 3 / metabolism*


  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Kcnj10 (channel)
  • Kir5.1 channel
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Adrenergic, beta
  • Slc12a1 protein, mouse
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 3
  • Propranolol
  • Isoproterenol
  • Norepinephrine