NKCC1 and hypertension: a novel therapeutic target involved in the regulation of vascular tone and renal function.
OBJECTIVE
The present review summarizes recent advances in our understanding of the mechanisms involving the housekeeping Na+, K+, 2Cl(-) cotransporter (NKCC1) in blood pressure (BP) regulation.


RESULTS
High-ceiling diuretics (HCDs), known potent inhibitors of NKCC1, renal-specific NKCC2 and four isoforms of K+, Cl(-) cotransporters decrease [Cl(-)]i, hyperpolarize vascular smooth muscle cells and suppress myogenic tone and contractions evoked by modest depolarization, phenylephrine, angiotensin II and uridine triphosphate. These actions are absent in NKCC1(-/-) mice, indicating that HCDs interact with NKCC1 rather than with other potential targets. NKCC1-null mice have decreased baseline BP but exhibit augmented BP increment evoked by high-salt diets. NKCC1 deficiency causes approximately three-fold elevation in plasma renin concentrations and attenuates HCD-induced renin production. In addition to HCDs, NKCC1 is also inhibited by extracellular HCO3(-) in the range corresponding to its concentration in ischemic extracellular fluids.


CONCLUSIONS
NKCC1 modulates BP through vascular and renal effects. In addition to BP regulation, the decreased baseline activity of this carrier or its suppression by chronic treatment with HCDs may lead to inhibition of myogenic tone and progression of end-stage renal disease. NKCC1 activation in ischemia-induced acidosis may contribute to stroke via glutamate release caused by astrocyte swelling.
Orlov
Sergei N
SN
Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM)-Technôpole Angus and Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. sergei.n.orlov@umontreal.ca
Tremblay
Johanne
J
Hamet
Pavel
P
D000818:Animals; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D007677:Kidney Function Tests; D009119:Muscle Contraction / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064506:Solute Carrier Family 12, Member 2
C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2