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The study concerned the effects of lidocaine and mepivacaine on rat mast cell histamine release. At low concentrations these drugs inhibited the histamine release induced by concanavalin A and compound 48 80 although. at high concentrations, they caused cell lysis. The mechanism of their inhibition of histamine release was studied by examining the pH dependence of the inhibitory action. In the absence of drugs, the releaseoof histamine was not affected by the pH of the medium, but the inhibitory effects of the drugs increased with increase in pH. The percent inhibition of histamine release by these drugs at each pH was plotted against the calculated concentration of the nonionized form of the drug, according to the Henderson-Hasselbalch equation. The inhibitory action was correlated with the concentration of nonionized molecules, which readily penetrate the cell membrane. From the interaction of lidocaine with the phospholipid bilayer, it was concluded that this drug penetrates the lipid bilayer and that this effect increases with increasing pH of the medium. Thus, it seems that it is the nonionized form of local anesthetics that inhibits histamine release and that it is nonionized molecules that penetrate the mast cell membrane.

1. 1. Cationic drugs that interact with calmodulin such as chlorpromazine, trifluoperazine, W-7 and lidocaine caused dose-dependent release of mediator from rat mast cells. 2. 2. A significant correlation was observed between the effects of test drugs with different structure in causing mediator release and calmodulin inhibition.

A part of the rDNA plasmid of Zygosaccharomyces bailii IFO 0488 has been cloned. The cloned sequence contained 18S, 25S and probably 5S rRNA sequences. The cloned rDNA of Z. bailii hybridized with rRNAs of Saccharomyces cerevisiae. On using this rDNA sequence as a probe, we found that every sample of closed circular DNA from yeasts tested contained this kind of DNA plasmid. The rDNA unit from Z. bailii carried an ARS that functioned in S. cerevisiae and Z. rouxii. However, the sequence required for the ARS function differed depending on the host. When a vector based on the rDNA of Z. bailii was introduced into S. cerevisiae, it was integrated predominantly into the RDNl locus. These facts imply that the rDNA plasmid is practically useful for contructing vectors suitable for intergeneric gene transfer among yeasts.

The involvement of calmodulin in stimulus-secretion coupling of histamine release from rat mast cells was examined using a specific calmodulin inhibitor, W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide]. W-7 at low concentrations inhibited histamine release induced by either concanavalin A or ionophore A23187 and at high concentrations enhanced the release. But its congener, W-5 [N-(6-aminohexyl)-1-naphthalenesulfonamide], which has virtually no calmodulin-inhibiting activity, did not affect the release. It is concluded that W-7 modulates histamine release by inhibiting some functions of calmodulin in the cells.

Lidocaine, W49091, procaine and benzocaine inhibited mast cell secretion induced by concanavalin A and A23187. They inhibited Ca influx stimulated by concanavalin A, suggesting that they inactivate Ca channel of mast cells. Lidocaine and procaine inhibited Ca influx stimulated by A23187, but W49091 and benzocaine did not.

Lidocaine inhibits the histamine release from rat mast cells, but enhances the release at higher concentrations (H.G.Johnson et al., Agents and Actions 9 , 239-243, 1979). The mode of action of lidocaine was elucidated by comparison with the action of W49091(charged lidocaine) and benzocaine(uncharged procaine-analog). The effects of lidocaine, benzocaine and W49091 on 45Ca uptake stimulated by concanavalin A(con A, 20 μg/ml) or by A23187(10μM) were compared with the inhibitions of the histamine release by these drugs. At the concentrations of these drugs which inhibit the release maximally, lidocaine (10mM) benzocaine (6mM) and W49091 (60mM) reduced con A-stimu-lated 45Ca uptake by 57%, 83% and 28%, respectively. In the case of A23187, lidocaine(30mM) and W49091(100mM) reduced 45Ca uptake by 58% and 27%, respectively, but benzocaine(10mM) had no effect. Then, we examined the effects of lidocaine and benzocaine on Ca transport mediated by A23187(30μM) in Ca-loaded liposomes. Ca transport was not affected by these drugs. Lidocaine, therefore, did not reduce the ability of A23187, but reduced Ca uptake secondarily. It is concluded that lidocaine not only blocks Ca channel but also affects the process after Ca influx and that it subsequently inhibits histamine release. At and above 30mM of lidocaine, lactate dehydrogenase was also released, indicating that the higher concentrations of lidocaine release histamine by a cytotoxic mechanism.