Selective pharmacological modulation of renal peripheral-type benzodiazepine binding by treatment with diuretic drugs.
We have assessed the effects of in vivo administration of different classes of diuretic drugs on the expression of the peripheral-type benzodiazepine binding site (PBBS) in crude membranes derived from the cortex and outer medulla of rat kidney by saturation analysis with the PBBS-selective ligands [3H]RO5-4864 and [3H]PK 11195 in cortex and [3H]RO5-4864 in outer medulla. Administration for 14-15 days of furosemide, a drug that blocks NaCl-KCl coupled transport in the thick ascending limb of the loop of Henle, produced a significant doubling in the PBBS density (Bmax) in outer medulla, a region of the kidney rich in thick ascending limbs, and produced a lesser but significant increase in PBBS density in the cortex. Conversely, administration for 14-15 days of the carbonic anhydrase inhibitor acetazolamide, which acts predominantly in the proximal tubule, and hydrochlorothiazide, which acts predominantly in the early distal tubule, elicited statistically significant increases in PBBS density in renal cortex but not in renal outer medulla. Furthermore, all drug treatments were without effect on the equilibrium dissociation constants (Kds) of [3H]RO5-4864 and [3H]PK 11195 binding to cortical and outer medullary membrane preparations. These findings demonstrate that the PBBS can be selectively "up-regulated" in different regions of the kidney by diuretic drugs with different modes/sites of action.
Lukeman
D S
DS
University of California, San Diego Department of Medicine, La Jolla 92093.
Vaughn
D A
DA
Fanestil
D D
DD
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007546:Isoquinolines / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
D001570:Benzodiazepinones; D004232:Diuretics; D007546:Isoquinolines; D011963:Receptors, GABA-A; D006852:Hydrochlorothiazide; C028513:4'-chlorodiazepam; D005665:Furosemide; D000086:Acetazolamide; C037850:PK 11195