THE INHIBITORY EFFECTS OF LOCAL-ANESTHETICS ON SUPEROXIDE GENERATION OF NEUTROPHILS CORRELATE WITH THEIR PARTITION-COEFFICIENTS

Lidocaine and tetracaine suppress superoxide anion (O-2(-)) generation of neutrophils. We examined the effects of eight local anesthetics on O-2(-) generation in human neutrophils and searched for a potential r elationship between the biological activities and the physicochemical properties of presently available eight local anesthetics. Human neutr ophils incubated with local anesthetic and a Cypridina luciferin analo g as a O-2(-)-specific chemiluminescence probe were stimulated by phor bol ester. The chemiluminescence development based on O-2(-) generatio n was monitored by a luminometer. All of the tested local anesthetics suppressed O-2(-) generation in a concentration-dependent manner. The concentration of each of eight local anesthetics that produced 50% inh ibition of peak chemiluminescence (IC50) had a rank order of dibucaine < tetracaine < bupivacaine < ropivacaine < procaine < mepivacaine < l idocaine = prilocaine. A linear relationship was obtained between IC50 values and the values of logarithm of partition coefficient (log P) o f eight local anesthetics; log (IC50 in molarity) = -1.252 - 0.514 x l og P, r(2) = 0.891, P < 0.001. Unlike with staurosporine, which inhibi ts protein kinase C (PKC), no effect was observed on the O-2(-) genera tion in the presence of tetrodotoxin (TTX), veratridine (VTD), or amil oride. These results suggest that the inhibitory effects of local anes thetics on O-2(-) generation of neutrophils are predicted by physicoch emical properties of the drugs, especially partition coefficients.