Fast frequency-dependent block of action potential upstroke in rabbit atrium by small local anesthetics

Abstract

Local anesthetics depress the rapid depolarizing phase of atrial action potentials in a frequency-dependent manner. Several local anesthetics were tested in this study at doses that only slightly depressed atrial action potential upstrokes at the spontaneous rate near 2 Hz, but that produced marked reductions in atrial fiber upstrokes when the drive rate was increased to 5 Hz. This frequency-dependent blocking action, especially the rate of development of the block during the 5-Hz stimulus train, is compared for several local anesthetics that have a wide range of lipid solubilities. Although the rate of block development does not correlate well with lipid solubility, it does correlate with molecular weight or size of the local anesthetic molecule. Smaller local anesthetics give faster frequency-dependent blocking. The beta-blocker propranolol also induces a frequency-dependent block of action potential upstroke, with the speed of such block development being predictable on the basis of the molecular weight of propranolol. The design of fast frequency-dependent blockers by using the criterion of smaller molecular size represents an important new structure-activity relation that may very well help in the design of better antifibrillatory drugs.