Benzodiazepines inhibit transport-related oxygen consumption in thick ascending limb.
Specific binding sites for benzodiazepines (BZD) have been identified in several nonneuronal tissues including the kidney where they are localized predominantly to the tubular epithelium of the thick ascending limb of Henle's loop (TALH). The physiological function of these nonneuronal (peripheral) BZD-binding sites is undefined, but it has been suggested that they may represent receptors for putative endogenous ligands that may modulate cell function. In the current study, we examined the in vitro effects of diazepam and Ro5-4864, a specific peripheral BZD-receptor agonist, on the oxygen consumption of medullary TALH tubule suspensions of rabbit kidney. Maximal inhibition of total oxygen consumption was achieved at a dose of 5 X 10(-4) M of either agent. On average, diazepam and Ro5-4864 reduced total oxygen consumption by 41 and 44%, respectively. The predominant inhibition was in the ouabain-sensitive component of oxygen consumption, which suggests that BZDs inhibit active sodium-chloride transport in the TALH. To assess whether this inhibition depends on sodium uptake, TALH tubules were pretreated with amphotericin B (2 X 10(-6) M) to enhance sodium uptake and stimulate basal oxygen consumption; subsequent addition of Ro5-4864 (5 X 10(-4) M) still reduced oxygen consumption to a residual value that was not different from that in TALH tubules treated with Ro5-4864 but without pretreatment with amphotericin B. This suggests that BZD inhibition of transport-related oxygen consumption is not caused by diminution of sodium uptake into cells and thus appears to be distinct from the effect of furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)
Ziyadeh
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Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Agus
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D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D003292:Convulsants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008138:Loop of Henle / Q000187:drug effects / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D011817:Rabbits; D012016:Reference Values; D012965:Sodium Chloride / Q000378:metabolism
D001570:Benzodiazepinones; D003292:Convulsants; C028513:4'-chlorodiazepam; D012965:Sodium Chloride; D010042:Ouabain; D003975:Diazepam