title: Delayed inhibition of agonist-induced granulocyte-platelet aggregation after low-dose sevoflurane inhalation in humans.
abstract: BACKGROUND
  Sevoflurane can be used as sedative-analgesic drug with endothelial protective properties. We tested whether low-dose sevoflurane inhalation provides sustained inhibition of detrimental granulocyte-platelet aggregation in humans.
  
  
  METHODS
  Ten healthy male volunteers were enrolled in this crossover study. Each subject inhaled sevoflurane for 1 h at 0.5-1 vol % end-tidal concentration in oxygen (50 vol %). Inhaling oxygen (50 vol %) alone served as control. Venous blood samples were collected at baseline before inhalation, immediately after inhalation, and 24 h thereafter, and were used for flow cytometry to determine platelet surface marker (CD41, CD42b, CD62P/P-selectin, and PAC-1) on platelets and granulocytes and for kaolin-induced clot formation, as assessed by thromboelastography. In flow cytometry experiments, platelets were stimulated with arachidonic acid (AA, 30 microM), adenosine diphosphate (ADP, 1 microM), and thrombin receptor agonist peptide-6 (TRAP-6, 6 microM).
  
  
  RESULTS
  AA, ADP, and TRAP-6 markedly increased the expression of CD62P on platelets, whereas CD42b (shedding) and PAC-1 (heterotypic conjugates) expression decreased. The amount of granulocyte-platelet aggregates increased upon agonist stimulation. Low-dose sevoflurane inhalation reduced ADP-induced CD62P expression on platelets 24 h after inhalation, and inhibited the formation of granulocyte-platelet aggregates under stimulation with AA and ADP after 1 and 24 h, and with TRAP-6 after 24 h compared with control. Inhibition of granulocyte-platelet aggregates was accompanied by reduced clot firmness 24 h after sevoflurane inhalation compared with control.
  
  
  CONCLUSIONS
  We demonstrated for the first time that inhaling low-dose sevoflurane (<1 vol % end-tidal) inhibits agonist-induced granulocyte-platelet interactions 24 h after administration and thus counteracts thromboinflammatory processes.
authors.affiliation: Institute of Anesthesiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wacker
authors.forename: Eliana
authors.initials: E
authors.lastname: Lucchinetti
authors.forename: Marina
authors.initials: M
authors.lastname: Jamnicki
authors.forename: José
authors.initials: J
authors.lastname: Aguirre
authors.forename: Luc
authors.initials: L
authors.lastname: Härter
authors.forename: Marius
authors.initials: M
authors.lastname: Keel
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000280:Administration, Inhalation; D000328:Adult; D018685:Anesthetics, Inhalation / Q000008:administration & dosage*; D016718:Arachidonic Acid / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage*; D019007:P-Selectin / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000097:blood; D058910:Purinergic P2 Receptor Agonists; D058925:Receptors, Purinergic P2Y12; D018179:Receptors, Thrombin / Q000819:agonists; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists; D012107:Research Design; D000077149:Sevoflurane; D013916:Thrombelastography; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D019007:P-Selectin; C548576:P2RY12 protein, human; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D040201:Platelet Membrane Glycoprotein IIb; D058910:Purinergic P2 Receptor Agonists; D058925:Receptors, Purinergic P2Y12; D018179:Receptors, Thrombin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C082835:thrombin receptor peptide (42-47); D016718:Arachidonic Acid; D000077149:Sevoflurane; D000244:Adenosine Diphosphate