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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1985 Feb;82(3):886–890. doi: 10.1073/pnas.82.3.886

Cardiac dysfunction caused by purified human C3a anaphylatoxin.

U H del Balzo, R Levi, M J Polley
PMCID: PMC397152  PMID: 2579381

Abstract

The purpose of this investigation was to define the cardiac effects of complement-derived C3a anaphylatoxin, in view of the possibility that cardiac dysfunction may occur as a result of complement activation. Purified human C3a was administered by intracoronary bolus injections into isolated guinea pig hearts. As a function of dose, C3a caused tachycardia, impairment of atrioventricular conduction, left ventricular contractile failure, coronary vasoconstriction, and histamine release. These effects were abolished by cleavage of the COOH-terminal arginine by carboxypeptidase B. The magnitude of C3a-induced tachycardia correlated with the amount of endogenous cardiac histamine released into the coronary effluent. Whereas the tachycardia was markedly reduced by the histamine H2 antagonist cimetidine, the contractile failure and the coronary vasoconstriction caused by C3a were antagonized by the leukotriene antagonist FPL 55712 and by the cyclooxygenase inhibitor indomethacin, respectively. This suggests that histamine, leukotrienes, and vasoactive prostanoates may mediate the various cardiac effects of C3a. Our findings indicate that C3a anaphylatoxin has marked cardiac effects at concentrations that are likely to be attained with a degree of C3 activation commonly seen in various disease states. Thus, our data are compatible with the hypothesis that generation of anaphylatoxins may induce cardiac dysfunction in clinical conditions.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allan G., Levi R. Thromboxane and prostacyclin release during cardiac immediate hypersensitivity reactions in vitro. J Pharmacol Exp Ther. 1981 Apr;217(1):157–161. [PubMed] [Google Scholar]
  2. Beaven M. A., Robinson-White A., Roderick N. B., Kauffman G. L. The demonstration of histamine release in clinical conditions: a review of past and present assay procedures. Klin Wochenschr. 1982 Sep 1;60(17):873–881. doi: 10.1007/BF01716943. [DOI] [PubMed] [Google Scholar]
  3. Bernauer W., Hahn F., Nimptsch P., Wissler J. Studies on heart anaphylaxis. V. Cross-desensitisation between antigen, anaphylatoxin, and compound 48-80 in the guinea-pig papillary muscle. Int Arch Allergy Appl Immunol. 1972;42(1):136–151. [PubMed] [Google Scholar]
  4. Bokisch V. A., Müller-Eberhard H. J., Cochrane C. G. Isolation of a fragment (C3a) of the third component of human complement containing anaphylatoxin and chemotactic activity and description of an anaphylatoxin inactivator of human serum. J Exp Med. 1969 May 1;129(5):1109–1130. doi: 10.1084/jem.129.5.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Burke J. A., Levi R., Guo Z. G., Corey E. J. Leukotrienes C4, D4 and E4: effects on human and guinea-pig cardiac preparations in vitro. J Pharmacol Exp Ther. 1982 Apr;221(1):235–241. [PubMed] [Google Scholar]
  6. Capurro N., Levi R. Anaphylaxis in the guinea-pig isolated heart: selective inhibition by burimamide of the positive inotropic and chronotropic effects of released histamine. Br J Pharmacol. 1973 Aug;48(4):620–628. doi: 10.1111/j.1476-5381.1973.tb08249.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Capurro N., Levi R. The heart as a target organ in systemic allergic reactions: comparison of cardiac analphylaxis in vivo and in vitro. Circ Res. 1975 Apr;36(4):520–528. doi: 10.1161/01.res.36.4.520. [DOI] [PubMed] [Google Scholar]
  8. Chenoweth D. E., Cooper S. W., Hugli T. E., Stewart R. W., Blackstone E. H., Kirklin J. W. Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med. 1981 Feb 26;304(9):497–503. doi: 10.1056/NEJM198102263040901. [DOI] [PubMed] [Google Scholar]
  9. Dawson P., Turner M. W., Bradshaw A., Westaby S. Complement activation and generation of C3a anaphylatoxin by radiological contrast agents. Br J Radiol. 1983 Jul;56(667):447–448. doi: 10.1259/0007-1285-56-667-447. [DOI] [PubMed] [Google Scholar]
  10. Fehr J., Rohr H. In vivo complement activation by polyanion--polycation complexes: evidence that C5a is generated intravascularly during heparin--protamine interaction. Clin Immunol Immunopathol. 1983 Oct;29(1):7–14. doi: 10.1016/0090-1229(83)90002-8. [DOI] [PubMed] [Google Scholar]
  11. GREEFF K., BENFEY B. G., BOKELMANN A. [Anaphylactic reactions in the isolated guinea pig auricle preparation and their influencing by antihistaminics. BOL, dihydroergotamine and reserpine]. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1959;236:421–434. [PubMed] [Google Scholar]
  12. Hakim R. M., Breillatt J., Lazarus J. M., Port F. K. Complement activation and hypersensitivity reactions to dialysis membranes. N Engl J Med. 1984 Oct 4;311(14):878–882. doi: 10.1056/NEJM198410043111403. [DOI] [PubMed] [Google Scholar]
  13. Hedin H., Smedegård G. Complement profiles in monkeys subjected to aggregate (immune complex) anaphylaxis, and following injection of soluble and particulate polysaccharides. Int Arch Allergy Appl Immunol. 1979;60(3):286–294. doi: 10.1159/000232353. [DOI] [PubMed] [Google Scholar]
  14. Hugli T. E., Stimler N. P., Gerard C., Moon K. E. Possible role of serum anaphylatoxins in hypersensitivity reactions. Int Arch Allergy Appl Immunol. 1981;66 (Suppl 1):113–120. doi: 10.1159/000232882. [DOI] [PubMed] [Google Scholar]
  15. Levi R., Burke J. A., Corey E. J. SRS-A, leukotrienes, and immediate hypersensitivity reactions of the heart. Adv Prostaglandin Thromboxane Leukot Res. 1982;9:215–222. [PubMed] [Google Scholar]
  16. Levi R., Burke J. A., Guo Z. G., Hattori Y., Hoppens C. M., McManus L. M., Hanahan D. J., Pinckard R. N. Acetyl glyceryl ether phosphorylcholine (AGEPC). A putative mediator of cardiac anaphylaxis in the guinea pig. Circ Res. 1984 Feb;54(2):117–124. doi: 10.1161/01.res.54.2.117. [DOI] [PubMed] [Google Scholar]
  17. Levi R., Chenouda A. A., Trzeciakowski J. P., Guo Z. G., Aaronson L. M., Luskind R. D., Lee C. H., Gay W. A., Subramanian V. A., McCabe J. C. Dysrhythmias caused by histamine release in guinea pig and human hearts. Klin Wochenschr. 1982 Sep 1;60(17):965–971. doi: 10.1007/BF01716956. [DOI] [PubMed] [Google Scholar]
  18. Levi R. Effects of exogenous and immunologically released histamine on the isolated heart: a quantitative comparison. J Pharmacol Exp Ther. 1972 Aug;182(2):227–238. [PubMed] [Google Scholar]
  19. Pinckard R. N., O'Rourke R. A., Crawford M. H., Grover F. S., McManus L. M., Ghidoni J. J., Storrs S. B., Olson M. S. Complement localization and mediation of ischemic injury in baboon myocardium. J Clin Invest. 1980 Nov;66(5):1050–1056. doi: 10.1172/JCI109933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Polley M. J., Nachman R. L. Human platelet activation by C3a and C3a des-arg. J Exp Med. 1983 Aug 1;158(2):603–615. doi: 10.1084/jem.158.2.603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Regal J. F., Hardy T. M., Casey F. B., Chakrin L. W. Effects of C5a on guinea pig lung: histamine release and mechanism of contraction. Immunopharmacology. 1983 Apr;5(4):315–327. doi: 10.1016/0162-3109(83)90047-4. [DOI] [PubMed] [Google Scholar]
  22. Ruddy S., Gigli I., Austen K. F. The complement system of man. 4. N Engl J Med. 1972 Sep 28;287(13):642–646. doi: 10.1056/NEJM197209282871306. [DOI] [PubMed] [Google Scholar]
  23. Smith P. L., Kagey-Sobotka A., Bleecker E. R., Traystman R., Kaplan A. P., Gralnick H., Valentine M. D., Permutt S., Lichtenstein L. M. Physiologic manifestations of human anaphylaxis. J Clin Invest. 1980 Nov;66(5):1072–1080. doi: 10.1172/JCI109936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Stimler N. P., Bach M. K., Bloor C. M., Hugli T. E. Release of leukotrienes from guinea pig lung stimulated by C5ades Arg anaphylatoxin. J Immunol. 1982 May;128(5):2247–2252. [PubMed] [Google Scholar]
  25. Stimler N. P., Bloor C. M., Hugli T. E. C3a-induced contraction of guinea pig lung parenchyma: role of cyclooxygenase metabolites. Immunopharmacology. 1983 Feb;5(3):251–257. doi: 10.1016/0162-3109(83)90031-0. [DOI] [PubMed] [Google Scholar]
  26. Tack B. D., Prahl J. W. Third component of human complement: purification from plasma and physicochemical characterization. Biochemistry. 1976 Oct 5;15(20):4513–4521. doi: 10.1021/bi00665a028. [DOI] [PubMed] [Google Scholar]
  27. Zavecz J. H., Levi R. Separation of primary and secondary cardiovascular events in systemic anaphylaxis. Circ Res. 1977 Jan;40(1):15–19. doi: 10.1161/01.res.40.1.15. [DOI] [PubMed] [Google Scholar]

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