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

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.