Mechanisms of activation of human mast cells and basophils by general anaesthetic drugs

A study was performed about the effects of increasing concentrations of muscle relaxants (suxamethonium, d-tubocurarine, vecuronium, and atracurium), hypnotics (propofol, ketamine, and thiopental), opioids (morphine, buprenorphine, and fentanyl), and benzodiazepines (diazepam, flunitrazepam, and midazolam) on the release of preformed (histamine and tryptase) and de novo synthesized (prostaglandin D₂ : PGD₂ and peptide-leukotriene C₄ : LTC₄) chemical mediators from human basophils and mast cells isolated from skin (HSMC), lung parenchyma (HLMC) and heart tissue (HHMC). None of the drugs tested induced the release of histamine or LTC₄ from basophils of normal donors. Suxamethonium did not induce mediator release from any type of human mast cell tested. Only the highest concentration of d-tubocurarine used caused histamine release from HSMC and HLMC. Atracurium, more than vecuronium, induced concentration-dependent histamine release from HSMC and HLMC. Propofol induced a concentration-dependent histamine release from HLMC, but not from HHMC. Only the highest concentrations of ketamine and thiopental used caused a significant release of histamine from HLMC. The muscle relaxants and hypnotics examined did not induce any de novo synthesis of PGD₂ or LTC₄ in mast cells. Morphine only induced histamine and tryptase release from HSMC, but not the de novo synthesis of PGD₂. In contrast, buprenorphine caused histamine and tryptase release from HLMC, and not from HSMC, whilst it also induced de novo synthesis of PGD₂ and LTC₄ in HLMC. Fentanyl did not give any histamine and tryptase release from mast cells. Diazepam and flunitrazepam only induced a small release of histamine from mast cells, whereas midazolam caused the release of histamine from HLMC. The biochemical pathways underlying the release of mediators from human mast cells induced by drugs used during general anaesthesia are different from those underlying the immune release of histamine. From the results obtained with the in vitro model described here, it is clear that new drugs promising for the anaesthesiologic arena should be tested in vitro before their potential histamine-releasing activity is experienced in vivo.