Mechanisms of activation of human mast cells and basophils by general anesthetic 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 anesthesiologic arena should be tested in vitro before their potential histamine-releasing activity is experienced in vivo.
Marone
G
G
Department of Medicine, University of Naples Federico II, School of Medicine, Italy.
Stellato
C
C
Mastronardi
P
P
Mazzarella
B
B
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000707:Anaphylaxis / Q000139:chemically induced / Q000276:immunology; D000777:Anesthetics / Q000494:pharmacology*; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001491:Basophils / Q000187:drug effects*; D001569:Benzodiazepines; D053818:Chymases; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D008407:Mast Cells / Q000187:drug effects*; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000032:analysis; D013189:SRS-A / Q000032:analysis; D012697:Serine Endopeptidases / Q000032:analysis; D053802:Tryptases
D000701:Analgesics, Opioid; D000777:Anesthetics; D014151:Anti-Anxiety Agents; D009466:Neuromuscular Blocking Agents; D013189:SRS-A; D001569:Benzodiazepines; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases; D015230:Prostaglandin D2