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On the Mechanisms of Potentiation of Local Anesthetics by Bicarbonate Buffer

Drug Structure-Activity Studies on Isolated Peripheral Nerve

Anesthesia Research Laboratories, Brigham and Women's Hospital, Harvard School of Dental Medicine, and the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts

Impulse inhibition by local anesthetics (LAs) is potentiated by extracellular solutions containing HCO-CO₂ (BC), relative to the inhibition in BC-free solutions at the same pH. We studied the mechanistic basis of this potentiation by assaying compound action potential amplitudes in desheathed frog sciatic nerves with the sucrose-gap method. We compared the potencies of 12 different impulse-blocking agents in Ringer's buffered with BC (BC-R) and in Ringer's containing only atmospheric CO₂ and buffered by a zwitterionic compound (3-(N-morpholino)propanesulfonic acid-Ringer's). The relative inhibition produced by an agent in BC divided by the inhibition produced in 3-(N-morpholino)propanesulfonic acid, was defined as the potentiation factor (PF). The organic guanidinium blockers of sodium channels, tetrodotoxin and saxitoxin, which act at a different site from that for LAs, were, by our definition, nominally potentiated (PF = 1.33 ± 0.04, ± sem, n = 4, and 1.24 ± 0.07, n = 10, respectively), implying that BC induces a decrease in the safety margin for impulse conduction, a decrease that cannot itself alone account for the much larger potentiation (PF = 5--8) by BC observed with certain LAs. Only nominal potentiations occurred with charged LAs (PF = 1.15), showing that little direct potentiation of the cationic LA species per se occurs. Inhibition by the permanently neutral LA benzocaine had a significantly larger than nominal potentiation (PF = 1.8) showing that BC can potentiate neutral LAs. Among the tertiary amine LAs, potentiation of ester-linked drugs (procaine, RAG505; PF = 3.9, 5.4, respectively), exceeded that of their amide-linked homologues (procainamide, lidocaine; PF = 1.3, 2.8, respectively) which have higher pK_a values. This result is consistent with an ion trapping mechanism whereby CO₂ acidifies the axoplasm and thereby increases the concentration of protonated LA inside the nerve fibers. However, slight differences in the molecular structure of 3°-amine LAs with similar pK_a values resulted in significantly different potentiations (e.g., procaine, PF = 3.9; 2-chloroprocaine, PF = 8.7), suggesting that the HCO^–₃ or CO₂ molecules interact specifically with the LA molecule or with LA binding sites in the nerve membrane. Spectrophotometric measurements of the free [Ca²⁺] in Ringer's showed it to be similar (±0.03 mm) for both buffers, obviating changes in extracellular Ca²⁺as a mechanism of BC potentiation. The resting potential of the nerve was slightly more negative (-4 mV) in BC-R, so membrane depolarization cannot explain the potentiation. These results lead us to conclude that CO₂·HCO^–₃ potentiates the impulse-blocking action of LAs by the combined actions of (a) a nonspecific reduction in margin of conduction safety, (b) ion trapping, and (c) direct modification of LA binding at sites on the Na⁺channel.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999