Interactions of diuretics with the peripheral-type benzodiazepine receptor in rat kidney.
The peripheral-type benzodiazepine receptor (PBR) has been autoradiographically localized to the thick ascending limb and early distal tubule. To elucidate further the role of this receptor in kidney function, we have examined the effects of all classes of diuretics on the binding of labeled PBR-specific ligands (R05-4864, PK 11195) to rat kidney membranes (13,000 X g X 10 min). Drugs capable of inhibiting R05-4864 binding by 50% at less than 200 microM included: metolazone (IC50 = 1 microM), indacrinone (IC50 = 42 microM), indapamide (IC50 = 58 microM), hydrochlorothiazide (HCTZ; IC50 = 117 microM) and trichloromethiazide (IC50 = 175 microM). Conversely, diuretics of the loop (e.g., furosemide), K+-sparing (e.g., triamterene), and carbonic anhydrase inhibitor (e.g., acetazolamide) classes exerted no significant effects on R05-4864 binding (IC50S greater than or equal to 1 mM). Inhibition by indacrinone was stereoselective. Thiazide-like compounds inhibited R05-4864 binding with a rank-order of potencies similar to that for their enhancement of in vivo natriuresis (metolazone greater than HCTZ approximately equal to trichlormethiazide greater than chlorothiazide). Scatchard analysis revealed that metolazone, indacrinone, indapamide and HCTZ inhibited R05-4864 binding by reducing Kd, with no effect on maximum binding. The apparent Kd of metolazone for the renal PBR was 3.8 X 10(-7) M. IC50 values of 14 metolazone derivatives for inhibition of R05-4864 binding correlated well (r = .71, P less than .01) with their natriuretic efficacies. PK 11195 binding to digitonin (1.2 mg/mg of protein)-solubilized membranes displayed the same rank-order of, but was twice as sensitive to inhibition by metolazone, indacrinone, indapamide and HCTZ.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002740:Chlorothiazide / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008788:Metolazone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D012995:Solubility
D001570:Benzodiazepinones; D004232:Diuretics; D007546:Isoquinolines; D011963:Receptors, GABA-A; D006852:Hydrochlorothiazide; C028513:4'-chlorodiazepam; D002740:Chlorothiazide; D008788:Metolazone; C037850:PK 11195