Studies on the mechanism of uncoupling by amine local anesthetics. Evidence for mitochondrial proton transport mediated by lipophilic ion pairs.

摘要: The hydrophobic weak acid, carbonyl cyanide m-chlorophenylhydrazone (CCCP), induced rapid swelling of mitochondria suspended in NH4SCN, as predicted from the protonophoretic property CCCP. Butacaine and other amines produced same response As expected a protonophore, CCCP (a) potassium acetate valinomycin, (b) K+ efflux treated with (c) caused an 8-fold stimulation respiration. alone was unable to mimic these effects CCCP; however, all were observed butacaine when SCN- or tetraphenylboron added assay medium. We conclude that amine local anesthetics are not protonophores; rather, their uncoupler-like activity derives ability form lipophilic ion pairs certain anions. Depending on conditions, pair transport may result electroneutral anion uptake electrophoretic proton transport. Uncoupling results transmembrane cycling neutral amine, charged anion, pair. Dose studies carried out for several pharmacologically important anesthetic properties. Their relative potencies NH4SCN followed order: chlorpromazine much greater than quinine dibucaine quinidine propranolol tetracaine lidocaine, procaine, procainamide. Neutral (progesterone benzocaine) low potency (timolol) found ineffective. Among drugs, rates correlate poorly octanol:water partition coefficients, suggesting rate is determined by formation constant pairs.