Further validation of a simple biochemical method for evaluation of local anesthetic effects at sodium channels.
We previously reported that blockade of the phosphoinositide breakdown response to the sodium channel agonist veratrine provides a simple measure of local anesthetic actions at sodium channels. For such a model to be considered useful, it should show specificity for compounds whose primary actions are not upon sodium channels, but which have local anesthetic properties at high concentrations. In addition, it should be able appropriately to distinguish local anesthetic enantiomers. Such results were found in the present study. Thus, (-)-propranolol inhibited the phosphoinositide breakdown response to veratrine with an IC50 value of -20 microM, whereas the response to the sodium ionophore monensin was not affected. With respect to local anesthetic enantiomers, (S)-RAC-109 was 4-fold more potent than the (R)-enantiomer, IC50 values of -5 and -20 microM, respectively, being found. A considerable reduction in potency was, however, found when the side chain was lengthened by one carbon atom (IC50 for the racemate >100 microM). Such a pattern of activity is consistent with the literature, and further validates the use of blockade of veratrine-stimulated phosphoinositide breakdown as a simple biochemical measure of local anesthetic effects at sodium channels.
Department of Pharmacology, Umea University, Sweden.
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D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D009281:Naphthalenes / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects*; D013237:Stereoisomerism; D010738:Type C Phospholipases / Q000378:metabolism; D014702:Veratrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000779:Anesthetics, Local; D009281:Naphthalenes; D010716:Phosphatidylinositols; D011760:Pyrrolidinones; D015222:Sodium Channels; C061605:RAC 109; D011433:Propranolol; D010738:Type C Phospholipases; D014702:Veratrine