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Sci Rep. 2018 Jun 29;8(1):9877. doi: 10.1038/s41598-018-27995-w.

Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium-potassium-chloride-cotransporter human variants hNKCC1A and hNKCC1B.

Author information

1
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hanover, Germany.
2
Center for Systems Neurosciences Hannover, Hanover, Germany.
3
Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
4
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hanover, Germany. wolfgang.loescher@tiho-hannover.de.
5
Center for Systems Neurosciences Hannover, Hanover, Germany. wolfgang.loescher@tiho-hannover.de.

Abstract

The Na+-K+-2Cl- cotransporter NKCC1 plays a role in neuronal Cl- homeostasis secretion and represents a target for brain pathologies with altered NKCC1 function. Two main variants of NKCC1 have been identified: a full-length NKCC1 transcript (NKCC1A) and a shorter splice variant (NKCC1B) that is particularly enriched in the brain. The loop diuretic bumetanide is often used to inhibit NKCC1 in brain disorders, but only poorly crosses the blood-brain barrier. We determined the sensitivity of the two human NKCC1 splice variants to bumetanide and various other chemically diverse loop diuretics, using the Xenopus oocyte heterologous expression system. Azosemide was the most potent NKCC1 inhibitor (IC50s 0.246 µM for hNKCC1A and 0.197 µM for NKCC1B), being about 4-times more potent than bumetanide. Structurally, a carboxylic group as in bumetanide was not a prerequisite for potent NKCC1 inhibition, whereas loop diuretics without a sulfonamide group were less potent. None of the drugs tested were selective for hNKCC1B vs. hNKCC1A, indicating that loop diuretics are not a useful starting point to design NKCC1B-specific compounds. Azosemide was found to exert an unexpectedly potent inhibitory effect and as a non-acidic compound, it is more likely to cross the blood-brain barrier than bumetanide.

PMID:
29959396
PMCID:
PMC6026185
DOI:
10.1038/s41598-018-27995-w
[Indexed for MEDLINE]
Free PMC Article

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