Thiazide diuretic drug receptors in rat kidney: Identification with ( sup 3 H)metolazone

Journal Article · Fri Apr 01 04:00:00 EST 1988 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.85.7.2311· OSTI ID:6940878

Beaumont, K; Vaughn, D A; Fanestil, D D ^[1]

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1. Univ. of California, San Diego, La Jolla (USA)

Thiazides and related diuretics inhibit NaCl reabsorption in the distal tubule through an unknown mechanism. The authors report here that ({sup 3}H)metolazone, a diuretic with a thiazide-like mechanism of action, labels a site in rat kidney membranes that has characteristics of the thiazide-sensitive ion transporter. ({sup 3}H)Metolazone bound with high affinity to a site with a density of 0.717 pmol/mg of protein in kidney membranes. The binding site was localized to the renal cortex, with little or not binding in other kidney regions and 11 other tissues. The affinities of thiazide-type diuretics for this binding site were significantly correlated with their clinical potency. Halide anions specifically inhibited high-affinity binding of ({sup 3}H)metolazone to this site. ({sup 3})Metolazone also bound with lower affinity to sites present in kidney as well as in liver, testis, lung, brain, heart, and other tissues. Calcium antagonists and certain smooth muscle relaxants had K{sub i} values of 0.6-10 {mu}M for these low-affinity sites, which were not inhibited by most of the thiazide diuretics tested. Properties of the high-affinity ({sup 3}H)metolazone binding site are consistent with its identity as the receptor for thiazide-type diuretics.

• OSTI ID: 6940878
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 85:7; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ABSORPTION
ALKALI METAL COMPOUNDS
ANIMALS
BIOCHEMICAL REACTION KINETICS
BODY
BROMINE
CATIONS
CHARGED PARTICLES
CHLORIDES
CHLORINE
CHLORINE COMPOUNDS
CHLOROTHIAZIDE
CLEARANCE
DISTRIBUTION
DIURETICS
DRUGS
ELEMENTS
EXCRETION
HALIDES
HALOGEN COMPOUNDS
HALOGENS
HYDROGEN COMPOUNDS
INHIBITION
IODINE
IONS
KIDNEYS
KINETICS
MAMMALS
MEMBRANE PROTEINS
NONMETALS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
RATS
REACTION KINETICS
RECEPTORS
RENAL CLEARANCE
RODENTS
SODIUM CHLORIDES
SODIUM COMPOUNDS
TISSUE DISTRIBUTION
TRITIUM COMPOUNDS
VERTEBRATES