Minor role of the C3a receptor in systemic anaphylaxis in the guinea pig

Previously, Regal et al. [Regal, J.F., Fraser, D.G., Toth, C.A., 1993. Role of the complement system in antigen-induced bronchoconstriction and change s in blood pressure in the guinea pig. J. Pharmacol. Exp, Ther. 267, 979-98 8] demonstrated that preventing complement system activation resulted in in hibition of anaphylaxis in the guinea pig, and that the C-terminal 21 amino acids of guinea pig C3a (C3a-peptide) mimic the symptoms of anaphylactic s hock in the guinea pig [Regal, J.F., 1997. Role of the complement system in pulmonary disorders. Immunopharmacology 38, 17-25]. To determine if C3a is an essential mediator of systemic anaphylaxis, the anaphylactic response t o ovalbumin (OA) was assessed in guinea pigs genetically deficient in the C 3a receptor (C3aR(-)) compared to their control strain of animals which wer e C3a receptor positive (C3aR(+)), In addition, the response to another con trol strain of animals, Hartley guinea pigs, was determined. Sensitized gui nea pigs were anesthetized, and bronchoconstriction and changes in blood pr essure were monitored in response to intravenous (i.v.) injection of either C3a-peptide, recombinant human C5a (rHuC5a) or OA. Both Hartley guinea pig s and C3aR(+) animals responded similarly to C3a-peptide and rHuC5a. C3aR- animals, however, were unresponsive to C3a-peptide and responded normally t o rHuC5a, confirming their functional deficiency of the C3a receptor. In re sponse to OA, C3aR(+) animals and Hartley guinea pigs responded with a seve re bronchoconstriction, an initial transient hypotension, followed by an in crease in blood pressure and a delayed prolonged hypotensive response. In c ontrast, in C3aR- animals, the increased blood pressure response to OA was significantly prolonged, the delayed hypotensive response was blunted, and the bronchoconstriction was delayed compared to the C3aR(+) animals. The di fference in the anaphylactic response could not be explained by differing a mounts of OA-specific IgG1 antibody or C3a generated during the anaphylacti c response. Thus, these data suggest that C3a plays a minor role in the hyp otension of systemic anaphylaxis and investigation of a role for other prod ucts of complement system activation, either alone or in combination with C 3a, is clearly warranted. (C) 2000 Elsevier Science B.V. All rights reserve d.