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Effect of local anesthetic ropivacaine on isolated rat liver mitochondria
A Floridi1, M Di Padova, R Barbieri
1Department of Experimental Medicine, University of L'Aquila, Italy.
Abstract:
Ropivacaine is a new long-acting aminoamide local anesthetic with a reduced systemic and cardiac toxicity. Since the latter seems to be related, at least partially, to an interference with mitochondrial energy transduction, the effect of ropivacaine on the metabolism of rat liver mitochondria was studied. Ropivacaine alone exhibited little effect on mitochondrial metabolism, whereas effects were strongly enhanced by tetraphenylboron (TPB-) anion. At low drug concentrations, state 4 respiration was stimulated and mitochondrial membrane potential collapsed. At higher concentrations, state 4 and uncoupled respiration were inhibited by impairment of electron transfer from NAD- and flavine adenine dinucleotide-linked substrates to the respiratory chain. The fact that TPB- increased drug effects indicated that stimulation of respiration was due to dissipation of the electrochemical proton gradient caused by its electrophoretic uptake, although a classical uncoupling mechanism cannot be excluded. The mechanism for the lower toxicity of ropivacaine in vivo was ascribed to low liposolubility leading to reduced access to the mitochondrial membrane, resulting in a minimal perturbation of mitochondrial metabolism.
Insights
Ropivacaine, a local anesthetic, minimally affects mitochondrial metabolism. Its reduced toxicity in vivo is linked to low liposolubility, limiting mitochondrial access and metabolic disruption.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Ropivacaine is a long-acting aminoamide local anesthetic with reduced toxicity.
- Cardiac toxicity may involve interference with mitochondrial energy transduction.
Purpose of the Study:
- To investigate the effects of ropivacaine on rat liver mitochondrial metabolism.
- To elucidate the mechanism behind ropivacaine's reduced systemic and cardiac toxicity.
Main Methods:
- Isolated rat liver mitochondria were used to study metabolic effects.
- Ropivacaine's impact was assessed with and without tetraphenylboron (TPB-).
- Mitochondrial respiration, membrane potential, and electron transport were measured.
Main Results:
- Ropivacaine alone had minimal effects on mitochondrial metabolism.
- TPB- enhanced ropivacaine's effects, stimulating respiration and collapsing membrane potential at low concentrations.
- Higher ropivacaine concentrations inhibited respiration by impairing electron transfer.
- TPB- suggests effects are related to proton gradient dissipation.
Conclusions:
- Ropivacaine's low liposolubility reduces mitochondrial membrane access, minimizing metabolic perturbation.
- This limited interaction explains ropivacaine's reduced in vivo toxicity.
- Mitochondrial energy transduction is a key factor in local anesthetic toxicity.
