Glucagon Effects on3H-Histamine Uptake by the Isolated Guinea-Pig Heart during Anaphylaxis

We estimated the influence of acute glucagon applications on3H-histamine uptake by the isolated guinea-pig heart, during a single3H-histamine passage through the coronary circulation, before and during anaphylaxis, and the influence of glucagon on level of histamine, NO,O2-, and H2O2in the venous effluent during anaphylaxis. Before anaphylaxis, glucagon pretreatment does not change3H-histamine Umax and the level of endogenous histamine. At the same time, in the presence of glucagon,3H-histamine Unet is increased and backflux is decreased when compared to the corresponding values in the absence of glucagon. During anaphylaxis, in the presence of glucagon, the values of3H-histamine Umax and Unet are significantly higher and backflux is significantly lower in the presence of glucagon when compared to the corresponding values in the absence of glucagon. The level of endogenous histamine during anaphylaxis in the presence of glucagon (6.9–7.38 × 10−8 μM) is significantly lower than the histamine level in the absence of glucagon (10.35–10.45 × 10−8 μM). Glucagon pretreatment leads to a significant increase in NO release (5.69 nmol/mL) in comparison with the period before glucagon administration (2.49 nmol/mL). Then, in the presence of glucagon,O2-level fails to increase during anaphylaxis. Also, our results show no significant differences in H2O2levels before, during, and after anaphylaxis in the presence of glucagon, but these values are significantly lower than the corresponding values in the absence of glucagon. In conclusion, our results show that glucagon increases NO release and prevents the increased release of free radicals during anaphylaxis, and decreases histamine level in the venous effluent during cardiac anaphylaxis, which may be a consequence of decreased histamine release and/or intensified histamine capturing by the heart during anaphylaxis.

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.