The effects of the peripheral-type benzodiazepine acceptor ligands, Ro 5-4864 and PK 11195, on mitochondrial respiration

The role of the peripheral-type benzodiazepine acceptor is unclear. It has been suggested that the acceptor ligands, Ro 5-4864 and PK 11195, stimulate mitochondrial respiration by binding to the peripheral-type benzodiazepine acceptor. We determined the effect of the benzodiazepine Ro 5-4864 and of the isoquinoline carboxamide PK 11195 on the respiration rates of liver, kidney and adrenal mitochondria during coupled, uncoupled and phosphorylating respiration. These ligands inhibited uncoupled and phosphorylating respiration, but only at concentrations substantially greater than their K(D) values for binding to the acceptor. There was a slight stimulation of coupled respiration by these ligands at concentrations similar to their K(D) values for the acceptor, but this stimulation was markedly greater at higher concentrations. These results suggest that the ligands Ro 5-4864 and PK 11195 affect respiration in a non-specific way, independently of binding to the acceptor. There was no correlation between the effect of these ligands on respiration and the density of the acceptor in mitochondria from liver, kidney and adrenals. We suggest that the earlier reported alteration of respiration by these ligands was due to non-specific effects and was not mediated by the peripheral-type benzodiazepine acceptor.