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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Sites of action and active forms of lidocaine and some derivatives on cardiac Purkinje fibers.

We have compared the effects of lidocaine (L) to those of several derivatives in an attempt to determine the sites of action and active forms of the molecules. We studied cardiac Purkinje fibers with intracellular microelectrodes, and drugs were administered by superfusion or by iontophoretic intracellular injection. We compared to L the effects of QX-314 and QX-572, two quaternary derivatives, and also compound 6603, a tertiary analogue with a pKa of 9.81. When administered by superfusion in concentrations of 10(-5) and 10(-4) M, all four agents exerted qualitatively similar effects on the transmembrane action potential. The rate of onset of action of the quaternary derivatives was considerably slower than that of L and their actions were not reversed by superfusion for 1 hour with drug-free solution. Comparison of effects of L and QX-314 after intracellular injection showed that attenuation of Vmax, and thus of the fast inward current, results from interaction of the charged form acting form acting from the inner surface of the sarcolemma. After intracellular injection, QX-314 diffused readily along the long axis of fiber bundles, and it was thus possible to expose the inner surface of a large number of contiguous cells to drug. Comparison of results of extracellular and intracellular application suggests that effects on the voltate during phase 2 result from the charged form acting from the inner surface, but effects on total action potential duration result only from drug acting from the outer surface of the sarcolemma. Unlike L, the three derivatives did not decrease the slope of normal phase 4 depolarization. The results may help relate antiarrhythmic action to specific effects on transmembrane potentials.[1]


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