title: Anaphylactic shock depends on PI3K and eNOS-derived NO.
abstract: Anaphylactic shock is a sudden, life-threatening allergic reaction associated with severe hypotension. Platelet-activating factor (PAF) is implicated in the cardiovascular dysfunctions occurring in various shock syndromes, including anaphylaxis. Excessive production of the vasodilator NO causes inflammatory hypotension and shock, and it is generally accepted that transcriptionally regulated inducible iNOS is responsible for this. Nevertheless, the contribution of NO to PAF-induced shock or anaphylactic shock is still ambiguous. We studied PAF and anaphylactic shock in conscious mice. Surprisingly, hyperacute PAF shock depended entirely on NO, produced not by inducible iNOS, but by constitutive eNOS, rapidly activated via the PI3K pathway. Soluble guanylate cyclase (sGC) is generally regarded as the principal vasorelaxing mediator of NO. Nevertheless, although methylene blue partially prevented PAF shock, neither 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) nor sGCalpha1 deficiency did. Also, in 2 different models of active systemic anaphylaxis, inhibition of NOS, PI3K, or Akt or eNOS deficiency provided complete protection. In contrast to the unsubstantiated paradigm that only excessive iNOS-derived NO underlies cardiovascular collapse in shock, our data strongly support the unexpected concept that eNOS-derived NO is the principal vasodilator in anaphylactic shock and define eNOS and/or PI3K or Akt as new potential targets for treating anaphylaxis.
authors.affiliation: Molecular Pathophysiology and Experimental Therapy Unit, Department for Molecular Biomedical Research, Ghent University, Belgium, and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, USA. Anje.Cauwels@dmbr.UGent.be
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
authors.forename: Ben
authors.initials: B
authors.lastname: Janssen
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Buys
authors.forename: Patrick
authors.initials: P
authors.lastname: Sips
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
mesh_terms: D000707:Anaphylaxis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000633:toxicity; D014158:Transcription, Genetic
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010972:Platelet Activating Factor; D011810:Quinoxalines; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases