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Lysophosphatidylserine is a specific inducer of histamine release in isolated mast cells. To determine whether a similar effect is manifest in vivo, the phospholipid was injected (1-5 mg/kg i.v.) into mice and rats. A dose-dependent rise in blood histamine was observed in both animals. The several-fold increase in blood histamine occurred in the first minutes and was followed by a slower decline toward normal values. A second dose of lysophosphatidylserine was without effect. Systemic manifestations (depression, hypothermia, hypotension) were associated with the increased blood histamine level. When the tissue histamine stores accessible to lysophosphatidylserine were previously decreased by repeated phospholipid injections, no systemic symptoms occurred. Mobilization of carbohydrate reserves was also manifest during the action of lysophosphatidylserine. Prior treatment with compound 48/80 induced sustained refractoriness to lysophosphatidylserine. Structure-activity relationship demonstrated that the property to induce histamine release was linked to the structure of serine head group. Thus, other natural phospholipids or lysophospholipids were inactive. It is concluded that in analogy with the effect seen in vitro lysophosphatidylserine produces in vivo release of mast cell histamine.

The lysophosphatidylserine-induced activation of mast cells has been studied in preparations obtained from different rodents. In mouse and gerbil peritoneal mast cells lysophosphatidylserine behaves as an agonist, inducing noncytotoxic histamine release at 0.2-8 microM. In rat peritoneal and pleural mast cells lysophosphatidylserine is ineffective, but the histamine-releasing activity becomes manifest upon the addition of suboptimal concentrations of other mast cell activators. The common structure-activity relationship shows the link between these effects of lysophosphatidylserine but the calcium requirement indicates differences in the mechanism of action. Histamine release in mouse mast cells is independent of external calcium. Thus, lysophosphatidylserine induces mobilization of endogenous calcium stores in these cells. By contrast, histamine release in gerbil and rat mast cells is dependent on the addition of external calcium indicating that the phospholipid promotes calcium influx. While in gerbil mast cells calcium influx is promoted by lysophosphatidylserine alone, in rat it requires the combined action of the phospholipid and other mast cell agonists. Differently from lysophosphatidylserine, compound 48/80 elicits histamine release in rat and gerbil mast cells. Mouse mast cells are unaffected. Thus, gerbil mast cells are the only preparation in which the action of these two agonists can be observed simultaneously.

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