Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control.
Drugs that bound to the peripheral-type or mitochondrial benzodiazepine receptors in rat kidney mitochondria produced several effects on mitochondrial respiration with succinate and malate/pyruvate as substrates. These drugs increased state IV and decreased state III respiration rates, which resulted in a significant decrease in the respiratory control ratio. ADP: O ratios were not affected. The receptor binding affinities of a set of 10 compounds (Ro5-4864, PK11195, diazepam, mesoporphyrin IX, flunitrazepam, deuteroporphyrin IX, dipyridamole, dibutylphthalate, cyclosporin A, and CL259,763) correlated over a concentration range of almost 4 orders of magnitude with their potencies at inhibiting respiratory control (r = 0.95). The anxiolytic benzodiazepine clonazepam had no effect on mitochondrial respiratory control and bound with negligible affinity to the receptor. The magnitude of the effect of Ro5-4865 on respiration increased in parallel with the density of mitochondrial benzodiazepine receptors in mitochondria from liver, kidney, and adrenal. These results suggest that ligand binding to mitochondrial benzodiazepine receptors results in inhibition of mitochondrial respiratory control. This effect may help to explain the pleiotropic effects of receptor ligands on intact cells.
Hirsch
J D
JD
Department of Central Nervous System Research, American Cyanamid Company, Pearl River, New York 10965.
Beyer
C F
CF
Malkowitz
L
L
Beer
B
B
Blume
A J
AJ
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*
D001570:Benzodiazepinones; D007473:Ion Channels; D007546:Isoquinolines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; C037850:PK 11195