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This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/H1050    most recent 00622.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Szebeni, J. Articles by Bünger, R. Search for Related Content PubMed PubMed Citation Articles by Szebeni, J. Articles by Bünger, R.

Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function

¹Division of Retrovirology, Department of Vaccine Production and Delivery, United States Military Human Immunodeficiency Virus Research Program, ²Vaccine and Immunology Research Institute and Departments of ³Resuscitation Medicine and ⁴Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, District of Columbia; and ⁵Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Submitted 10 June 2005 ; accepted in final form 27 September 2005

Cardiac anaphylaxis is a severe, life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs. Earlier studies highlighted an amplifying effect of locally applied C5a on the process; however, the role of systemic complement (C) activation with C5a liberation in blood has not been explored to date. In the present study, we used the porcine liposome-induced cardiopulmonary distress model for 1) characterizing and quantifying peripheral C activation-related cardiac dysfunction; 2) exploring the role of C5a in cardiac abnormalities and therapeutic potential of C blockage by soluble C receptor type 1 (sCR1) and an anti-C5a antibody (GS1); and 3) elucidating the role of adenosine and adenosine receptors in paradoxical bradycardia, one of the symptoms observed in this model. Pigs were injected intravenously with different liposomes [Doxil and multilamellar vesicles (MLV)], zymosan, recombinant human (rhu) C5a, and adenosine, and the ensuing hemodynamic and cardiac changes (hypotension, tachy- or bradycardia, arrhythmias, ST-T changes, ventricular fibrillation, and arrest) were quantified by ranking on an arbitrary scale [cardiac abnormality score (CAS)]. There was significant correlation between CAS and C5a production by liposomes in vitro, and the liposome-induced cardiac abnormalities were partially or fully reproduced with zymosan, rhuC5a, adenosine, and the selective adenosine A₁ receptor agonist cyclopentyl-adenosine. The use of C nonactivator liposomes or pretreatment of pigs with sCR1 or GS1 attenuated the abnormalities. The selective A₁ blocker cyclopentyl-xanthine inhibited bradycardia without influencing hypotension, whereas the A₂ blocker 4-(2-{7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino}ethyl)phenol (ZM-24135) had no such effect. These data suggest that 1) systemic C activation can underlie cardiac anaphylaxis, 2) C5a plays a causal role in the reaction, 3) adenosine action via A₁ receptors may explain paradoxical bradycardia, and 4) inhibition of C5a formation or action or of A₁-receptor function may alleviate the acute cardiotoxicity of liposomal drugs and other intravenous agents that activate C.

adenosine receptors; allergy; anaphylactoid reactions; bezold-jarisch reflex; electrocardiography; cyclopentyl-xanthine; hemodynamic changes; hypersensitivity reactions; pseudoallergy