sodium potassium chloride symporter inhibitors


Summary: Agents that inhibit SODIUM-POTASSIUM-CHLORIDE SYMPORTERS which are concentrated in the thick ascending limb at the junction of the LOOP OF HENLE and KIDNEY TUBULES, DISTAL. They act as DIURETICS. Excess use is associated with HYPOKALEMIA and HYPERGLYCEMIA.

Top Publications

  1. Kim J, Kim W, Kim Y, Lee Y, Kim Y, Shen F, et al. Chronic hyperosmotic stress converts GABAergic inhibition into excitation in vasopressin and oxytocin neurons in the rat. J Neurosci. 2011;31:13312-22 pubmed publisher
    ..We conclude that the GABAergic responses of MNCs switch between inhibition and excitation in response to physiological needs through the regulation of transmembrane Cl(-) gradients. ..
  2. Mazarati A, Shin D, Sankar R. Bumetanide inhibits rapid kindling in neonatal rats. Epilepsia. 2009;50:2117-22 pubmed publisher
    ..The obtained results provide further evidence that bumetanide may be beneficial for treating neonatal seizures, and that NKCC1 represents a potential target for antiepileptic interventions in the immature brain. ..
  3. Kahle K, Staley K. The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures. Neurosurg Focus. 2008;25:E22 pubmed publisher
  4. Khirug S, Yamada J, Afzalov R, Voipio J, Khiroug L, Kaila K. GABAergic depolarization of the axon initial segment in cortical principal neurons is caused by the Na-K-2Cl cotransporter NKCC1. J Neurosci. 2008;28:4635-9 pubmed publisher
    ..Our findings demonstrate that spatially distinct interneuronal inputs can induce postsynaptic voltage responses with different amplitudes and polarities as governed by the subcellular distributions of plasmalemmal chloride transporters. ..
  5. Cleary R, Sun H, Huynh T, Manning S, Li Y, Rotenberg A, et al. Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures. PLoS ONE. 2013;8:e57148 pubmed publisher
    ..Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures. ..
  6. Brillault J, Lam T, Rutkowsky J, Foroutan S, O Donnell M. Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells. Am J Physiol Cell Physiol. 2008;294:C88-96 pubmed
  7. Sipilä S, Schuchmann S, Voipio J, Yamada J, Kaila K. The cation-chloride cotransporter NKCC1 promotes sharp waves in the neonatal rat hippocampus. J Physiol. 2006;573:765-73 pubmed
    ..Our work indicates that NKCC1 expressed in CA3 pyramidal neurons promotes network activity in the developing hippocampus. ..
  8. Pitcher M, Price T, Entrena J, Cervero F. Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia. Mol Pain. 2007;3:17 pubmed
    ..Moreover, they suggest that endogenous TRPV1 agonists, released in the CNS in painful conditions, might stimulate TRPV1 receptors on primary afferents that, in turn, play a role in increasing NKCC1 activity leading to allodynia. ..
  9. Glykys J, Dzhala V, KUCHIBHOTLA K, Feng G, Kuner T, Augustine G, et al. Differences in cortical versus subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures. Neuron. 2009;63:657-72 pubmed publisher
    ..Regional differences in the ontogeny of Cl(-) transport may thus explain why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks. ..

More Information


  1. Wargo K, Banta W. A comprehensive review of the loop diuretics: should furosemide be first line?. Ann Pharmacother. 2009;43:1836-47 pubmed publisher
    ..Currently, little evidence exists to support either torsemide or bumetanide as first-line treatment over furosemide in patients with other edematous disease states. ..
  2. Brunet G, Gagnon E, Simard C, Daigle N, Caron L, Noël M, et al. Novel insights regarding the operational characteristics and teleological purpose of the renal Na+-K+-Cl2 cotransporter (NKCC2s) splice variants. J Gen Physiol. 2005;126:325-37 pubmed
  3. Versnel H, Agterberg M, de Groot J, Smoorenburg G, Klis S. Time course of cochlear electrophysiology and morphology after combined administration of kanamycin and furosemide. Hear Res. 2007;231:1-12 pubmed
    ..SGC packing density, which rapidly decreased with the period after deafening treatment and correlated to the percentage of surviving inner hair cells, was not a determining factor for the CAP thresholds. ..
  4. Yan Y, Dempsey R, Flemmer A, Forbush B, Sun D. Inhibition of Na(+)-K(+)-Cl(-) cotransporter during focal cerebral ischemia decreases edema and neuronal damage. Brain Res. 2003;961:22-31 pubmed
    ..These results suggest that inhibition of NKCC1 attenuates cytotoxic edema and necrotic neuronal death during focal ischemia. Activation of NKCC1 activity plays a role in the early stage of ischemic damage. ..
  5. Plata C, Meade P, Vazquez N, Hebert S, Gamba G. Functional properties of the apical Na+-K+-2Cl- cotransporter isoforms. J Biol Chem. 2002;277:11004-12 pubmed
  6. Gagnon K. High-grade glioma motility reduced by genetic knockdown of KCC3. Cell Physiol Biochem. 2012;30:466-76 pubmed publisher
    ..Altogether, these experiments suggest that the presence/function of multiple isoforms of the Na(+-)independent K-Cl cotransporter may have a role in glioma cell motility. ..
  7. Zimmermann B, Plank C, Konrad M, Stöhr W, Gravou Apostolatou C, Rascher W, et al. Hydrochlorothiazide in CLDN16 mutation. Nephrol Dial Transplant. 2006;21:2127-32 pubmed
    ..However, the short-term efficacy of HCT to reduce hypercalciuria in FHHNC has not yet been demonstrated in a clinical trial...
  8. Li Y, Ding D, Jiang H, Fu Y, Salvi R. Co-administration of cisplatin and furosemide causes rapid and massive loss of cochlear hair cells in mice. Neurotox Res. 2011;20:307-19 pubmed publisher
  9. Martin F, Chen H, Cataliotti A, Burnett J. Targeting the kidney in acute decompensated heart failure: conventional diuretics and renal-acting vasodilators. Rev Cardiovasc Med. 2008;9:39-45 pubmed
    ..Vasodilators, especially those that are linked to cGMP activation, may provide an alternative approach. ..
  10. Rosas Carrasco O, García Peña C, Sánchez García S, Vargas Alarcon G, Gutierrez Robledo L, Juarez Cedillo T. The relationship between potential drug-drug interactions and mortality rate of elderly hospitalized patients. Rev Invest Clin. 2011;63:564-73 pubmed
    ..This work shows that the occurrence of potential DDIs in the hospital environment for the elderly population is frequent and may be implicated in the cause of death for these patients. ..
  11. Nardou R, Ben Ari Y, Khalilov I. Bumetanide, an NKCC1 antagonist, does not prevent formation of epileptogenic focus but blocks epileptic focus seizures in immature rat hippocampus. J Neurophysiol. 2009;101:2878-88 pubmed publisher
    ..We suggest that an additional mechanism other than NKCC1-mediated contributes to the persistent increase of DF(GABA) in epileptic neurons. ..
  12. Weder A, Gleiberman L, Sachdeva A. Whites excrete a water load more rapidly than blacks. Hypertension. 2009;53:715-8 pubmed publisher
    ..Slower excretion of an acute water load may have been an advantage during natural selection of humans living in arid, hot climates. ..
  13. Yang B, Tadavarty R, Xu J, Sastry B. Activity-mediated plasticity of GABA equilibrium potential in rat hippocampal CA1 neurons. Exp Neurol. 2010;221:157-65 pubmed publisher
    ..These results indicate that activity-mediated plasticity in E(GABA)(-PSC) occurs in hippocampal CA1 pyramidal neurons and theta-burst-induced negative shift in E(GABA)(-PSC) requires KCC2, GABA(B) receptors and G-protein activation. ..
  14. Vaz Pérez A, Otawa K, Zimmermann A, Stockburger M, Muller Werdan U, Werdan K, et al. The impact of impaired renal function on mortality in patients with acutely decompensated chronic heart failure. Eur J Heart Fail. 2010;12:122-8 pubmed publisher
    ..Admission creatinine level strongly predicts medium- and long-term mortality after hospitalization in patients with ADHF, and serves as a cheap and fast clinical marker to identify patients at risk of death. ..
  15. Sarafidis P, Georgianos P, Lasaridis A. Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds. Expert Opin Drug Saf. 2010;9:243-57 pubmed publisher
    ..Knowledge of the pharmacologic properties and mechanisms of action of diuretic agents is a prerequisite for the successful choice and effective clinical use of these compounds. ..
  16. Newton P, Davidson P, Macdonald P, Ollerton R, Krum H. Nebulized furosemide for the management of dyspnea: does the evidence support its use?. J Pain Symptom Manage. 2008;36:424-41 pubmed publisher
    ..Despite the limitations of the studies reported, given the range of conditions reporting effectiveness of nebulized furosemide, further investigation of this potential novel treatment of dyspnea is warranted. ..
  17. Bauser Heaton H, Song J, Bohlen H. Cerebral microvascular nNOS responds to lowered oxygen tension through a bumetanide-sensitive cotransporter and sodium-calcium exchanger. Am J Physiol Heart Circ Physiol. 2008;294:H2166-73 pubmed publisher
    ..Therefore, nNOS activation secondary to Na(+)-K(+)-2Cl(-) cotransporter and Na(+)/Ca(2+) exchanger functions are key to cerebral vascular oxygen responses. ..
  18. Kazory A. Hyponatremia in heart failure: revisiting pathophysiology and therapeutic strategies. Clin Cardiol. 2010;33:322-9 pubmed publisher
    ..These agents can be reserved for patients with HF in whom initial appropriate loop diuretic therapy fails to improve serum sodium levels. ..
  19. Reddy P. Clinical approach to renal tubular acidosis in adult patients. Int J Clin Pract. 2011;65:350-60 pubmed publisher
    ..This article extensively reviews the mechanism of hydrogen ion generation from metabolism of normal diet and various forms of RTA leading to disruptions of normal acid-base handling by the kidneys. ..
  20. Dev S, Shirolkar S, Stevens S, Shaw L, Adams P, Felker G, et al. Reduction in body weight but worsening renal function with late ultrafiltration for treatment of acute decompensated heart failure. Cardiology. 2012;123:145-53 pubmed publisher
    ..Further research to identify the appropriate population for UF, long-term outcomes and the intensity of treatment is required if UF is to gain wide acceptance for HF management. ..
  21. Grieff M, Bushinsky D. Diuretics and disorders of calcium homeostasis. Semin Nephrol. 2011;31:535-41 pubmed publisher
    ..Their use can promote nephrocalcinosis and nephrolithiasis. This review will address the use of diuretics on disorders of calcium homeostasis. ..
  22. Töllner K, Brandt C, Töpfer M, Brunhofer G, Erker T, Gabriel M, et al. A novel prodrug-based strategy to increase effects of bumetanide in epilepsy. Ann Neurol. 2014;75:550-62 pubmed publisher
    ..Our data demonstrate that the goal of designing bumetanide prodrugs that specifically target the brain is feasible and that such drugs may resolve the problems associated with using bumetanide for treatment of neurological disorders. ..
  23. Habela C, Ernest N, Swindall A, Sontheimer H. Chloride accumulation drives volume dynamics underlying cell proliferation and migration. J Neurophysiol. 2009;101:750-7 pubmed publisher
    ..This mechanism that was studied in CNS malignancies may be shared with other immature cells in the brain as well. ..
  24. Farahbakhsh N, Narins P. Slow motility in hair cells of the frog amphibian papilla: Ca2+-dependent shape changes. Hear Res. 2006;212:140-59 pubmed
    ..Such a mechanism might be utilized by the efferent neurotransmitters for adaptive modulation of mechano-electrical transduction, sensitivity enhancement, frequency selectivity, and protection against over-stimulation. ..
  25. Fang X, Hu H, Gao N, Liu S, Wang G, Wang X, et al. Neurogenic secretion mediated by the purinergic P2Y1 receptor in guinea-pig small intestine. Eur J Pharmacol. 2006;536:113-22 pubmed
    ..Our evidence suggests that ATP is released as a neurotransmitter to stimulate neurogenic mucosal secretion by binding to P2Y1 receptors expressed by VIP-ergic secretomotor neurons. ..
  26. Dreisbach A, Rice J, Japa S, Newman J, Sigel A, Gill R, et al. Salt loading increases urinary excretion of linoleic acid diols and triols in healthy human subjects. Hypertension. 2008;51:755-61 pubmed publisher
    ..Prostaglandin E2 excretion was positively correlated with sodium excretion. The salt-stimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load. ..
  27. Daigle N, Carpentier G, Frenette Cotton R, Simard M, Lefoll M, Noël M, et al. Molecular characterization of a human cation-Cl- cotransporter (SLC12A8A, CCC9A) that promotes polyamine and amino acid transport. J Cell Physiol. 2009;220:680-9 pubmed publisher
    ..These findings are of special interest given that intracellular PAs play a key role in cell proliferation. ..
  28. Panet R, Eliash M, Atlan H. Na+/K+/Cl- cotransporter activates MAP-kinase cascade downstream to protein kinase C, and upstream to MEK. J Cell Physiol. 2006;206:578-85 pubmed
    ..Taken together, the results of the present study indicate that the signal transduction protein, controlled by the Na+/K+/Cl- cotransporter, must be downstream of the PKC, and at/or upstream to MEK in the Ras/Raf/MEK/ERK cascade. ..
  29. Rossignol P, Zannad F. Loop diuretics and ultrafiltration in heart failure. Expert Opin Pharmacother. 2013;14:1641-8 pubmed publisher
  30. Preobrazhenskii D, Sidorenko B, Tarykina E, Batyraliev T, Marenich A. [Torasemide--new generation loop diuretic: clinical pharmacology and therapeutic application]. Kardiologiia. 2006;46:75-86 pubmed
    ..Total mortality, cardiovascular mortality and requirements in hospitalization of patients receiving torasemide is substantially less than of patients receiving furosemide. ..
  31. Campbell P, Ryan J. Diuretic dosing in acute decompensated heart failure: lessons from DOSE. Curr Heart Fail Rep. 2012;9:260-5 pubmed publisher
    ..The study also challenges the notion that high-dose diuretics carry clinically important renal toxicity risks for patients. ..
  32. Uvarov P, Ludwig A, Markkanen M, Pruunsild P, Kaila K, Delpire E, et al. A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2. J Biol Chem. 2007;282:30570-6 pubmed
  33. Sica D, CARTER B, Cushman W, Hamm L. Thiazide and loop diuretics. J Clin Hypertens (Greenwich). 2011;13:639-43 pubmed publisher
  34. Dzhala V, Brumback A, Staley K. Bumetanide enhances phenobarbital efficacy in a neonatal seizure model. Ann Neurol. 2008;63:222-35 pubmed
    ..This is a mechanistic demonstration of rational anticonvulsant polypharmacy. The combination of these agents may comprise an effective therapy for early-life seizures. ..
  35. Rocafull M, Romero F, Thomas L, del Castillo J. Isolation and cloning of the K+-independent, ouabain-insensitive Na+-ATPase. Biochim Biophys Acta. 2011;1808:1684-700 pubmed publisher
    ..It has 64% identity and 72% homology with guinea-pig Na+/K+-ATPase ?1-isoform. These structural and biochemical evidences identify the K+-independent, ouabain-insensitive Na+-ATPase as a unique P-type ATPase...
  36. Ishibashi H, Hirao K, Yamaguchi J, Nabekura J. Inhibition of chloride outward transport by gadolinium in cultured rat spinal cord neurons. Neurotoxicology. 2009;30:155-9 pubmed publisher
    ..These results suggest that Gd3+ inhibits a KCC function and gives rise to increase in intracellular Cl- concentration. The reduction of outward chloride transport could be related to the neurotoxic effects of Gd3+. ..
  37. Porcel J. Pleural effusions from congestive heart failure. Semin Respir Crit Care Med. 2010;31:689-97 pubmed publisher
    ..Loop diuretics are the mainstay of therapy, although a therapeutic thoracentesis for very large effusions may occasionally be required. ..
  38. Felker G, Lee K, Bull D, Redfield M, Stevenson L, Goldsmith S, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797-805 pubmed publisher
    ..Funded by the National Heart, Lung, and Blood Institute; number, NCT00577135.). ..
  39. Lynch J, Regan C, Beatch G, Gleim G, Morabito C. Comparison of the intrinsic vasorelaxant and inotropic effects of the antiarrhythmic agents vernakalant and flecainide in human isolated vascular and cardiac tissues. J Cardiovasc Pharmacol. 2013;61:226-32 pubmed publisher
  40. Endo I, Inoue D. [Treatment of malignancy-associated hypercalcemia]. Clin Calcium. 2006;16:665-69 pubmed
  41. Wang D, Kriegstein A. GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci. 2008;28:5547-58 pubmed publisher
    ..Our study identifies an essential role for GABA in the synaptic integration of newborn cortical neurons and suggests an activity-dependent mechanism for achieving the balance between excitation and inhibition in the developing cortex. ..
  42. Wang D, Kriegstein A. Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb Cortex. 2011;21:574-87 pubmed publisher
  43. Shoji T, Takatori E, Oyama R, Kumagai S, Fukushima A, Yoshizaki A, et al. Tako-Tsubo cardiomyopathy caused immediately following cesarean section delivery of triplets: a case report. Gynecol Obstet Invest. 2012;74:84-8 pubmed publisher
    ..She was extubated from the ventilator after 3 days of catecholamine, furosemide and carperitide administration. She was discharged from the hospital on day 53 without symptoms. ..
  44. Mazzone S, McGovern A. Sensory neural targets for the treatment of cough. Clin Exp Pharmacol Physiol. 2007;34:955-62 pubmed
  45. Hall S, Yang M, Gates M, Steers W, Tennstedt S, McKinlay J. Associations of commonly used medications with urinary incontinence in a community based sample. J Urol. 2012;188:183-9 pubmed publisher
    ..96, 5.10). Although a cross-sectional analysis cannot determine causality, our analysis suggests certain medications should be further examined in longitudinal analyses of risk to determine their influence on urological symptoms. ..
  46. Masuyama T, Tsujino T, Origasa H, Yamamoto K, Akasaka T, Hirano Y, et al. Superiority of long-acting to short-acting loop diuretics in the treatment of congestive heart failure. Circ J. 2012;76:833-42 pubmed
    ..60, 95%CI 0.36-0.99: P=0.048). Azosemide, compared with furosemide, reduced the risk of cardiovascular death or unplanned admission to hospital for congestive HF. ..
  47. Vormfelde S, Brockmoller J. The genetics of loop diuretic effects. Pharmacogenomics J. 2012;12:45-53 pubmed publisher
    ..This exceeded the fraction of variation explained by differences in the pharmacokinetics: 13, 10, 11 and 6%. Thus, genetic variation seems to be a stronger predictor of the loop diuretic drug response than pharmacokinetic variation. ..
  48. Payne J. Molecular operation of the cation chloride cotransporters: ion binding and inhibitor interaction. Curr Top Membr. 2012;70:215-37 pubmed publisher
    ..These homology models provide our first glimpse into the fine details of the molecular operation of the CCCs. ..
  49. Aspromonte N, Cruz D, Valle R, Bonello M, Tubaro M, Gambaro G, et al. Metabolic and toxicological considerations for diuretic therapy in patients with acute heart failure. Expert Opin Drug Metab Toxicol. 2011;7:1049-63 pubmed publisher
    ..This would allow clinicians to identify high-risk patients and possibly reduce the incidence of complications secondary to fluid management strategies. ..
  50. Brincat S, Hilton R. Prevention of acute kidney injury. Br J Hosp Med (Lond). 2008;69:450-4 pubmed
    ..This review discusses current interventions to prevent acute kidney injury and reviews the evidence base for each. ..
  51. Tsujino T, Nakao S, Wakabayashi K, Lee M, Kimura T, Yoshikawa H, et al. Loop diuretic precipitated beriberi in a patient after pancreaticoduodenectomy: a case report. Am J Med Sci. 2007;334:407-9 pubmed
  52. Agterberg M, Versnel H, van Dijk L, de Groot J, Klis S. Enhanced survival of spiral ganglion cells after cessation of treatment with brain-derived neurotrophic factor in deafened guinea pigs. J Assoc Res Otolaryngol. 2009;10:355-67 pubmed publisher
    ..These morphological and functional findings demonstrate that neurotrophic intervention had a lasting effect, which is promising for future clinical application of neurotrophic factors in implanted human cochleae. ..
  53. Kahle K, Barnett S, Sassower K, Staley K. Decreased seizure activity in a human neonate treated with bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) cotransporter NKCC1. J Child Neurol. 2009;24:572-6 pubmed publisher
    ..These results suggest bumetanide may exert antiepileptic effects in human neonates. ..