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Activation of the third complement component (C3) and C3a generation in cardiac anaphylaxis: histamine release and
U del Balzo1, M J Polley, R Levi
1Department of Pharmacology, Cornell University Medical College, New York, NY.
Insights
Complement activation and anaphylatoxin generation are key to cardiac anaphylaxis. These molecules, C3a and C5a, mediate immediate hypersensitivity reactions in the heart, causing dysfunction and histamine release.
Area of Science:
- Immunology
- Cardiovascular Physiology
Background:
- Complement system activation generates anaphylatoxins (C3a, C5a).
- Anaphylatoxin administration to isolated hearts mimics cardiac anaphylaxis.
- Immediate hypersensitivity reactions involve complement activation.
Purpose of the Study:
- To investigate complement activation and anaphylatoxin generation during cardiac anaphylaxis.
- To determine the role of anaphylatoxins in immediate hypersensitivity reactions of the heart.
Main Methods:
- Challenging presensitized guinea pig atria and papillary muscles with specific antigen and complement.
- Measuring C3a generation, histamine release, and functional effects (inotropic, chronotropic).
- Utilizing DL-2-mercapto-methyl-3-guanidino-ethylthiopropanoic acid to inhibit anaphylatoxin inactivation.
- Administering C3a to nonsensitized cardiac preparations and assessing responses with/without cimetidine.
Main Results:
- Anaphylactic reactions in cardiac preparations showed complement activation and C3a generation.
- C3a generation and histamine release correlated with C3 consumption.
- Inhibiting anaphylatoxin inactivation enhanced and prolonged anaphylactic responses.
- Exogenous C3a induced anaphylaxis-like effects in nonsensitized tissues, mediated by histamine and H2 receptors.
Conclusions:
- Complement activation and anaphylatoxin generation are characteristic of cardiac anaphylaxis.
- Anaphylatoxins (C3a, C5a) act as mediator-modulators in immediate hypersensitivity reactions of the heart.
Abstract:
Activation of the complement system with generation of C3a and C5a anaphylatoxins occurs during immediate hypersensitivity reactions; furthermore, the administration of C3a and/or C5a into isolated hearts causes a dysfunction that closely resembles cardiac anaphylaxis. To determine whether complement is activated and anaphylatoxins are generated in the course of immediate hypersensitivity reactions of the heart, we have challenged presensitized isolated guinea pig atria and papillary muscles with the specific antigen in the presence of a source of complement. We have found that the anaphylactic reaction of these cardiac preparations is characterized by complement activation and C3a generation, as well as by histamine release and positive inotropic and chronotropic effects. The amounts of C3a generated and histamine released directly correlated with the extent of C3 consumption. Furthermore, when C3a and C5a inactivation by serum carboxypeptidase N was prevented by DL-2-mercapto-methyl-3-guanidino-ethylthiopropanoic acid, anaphylactic histamine release was enhanced, and chronotropic and inotropic responses were potentiated and prolonged. Notably, the administration of C3a to nonsensitized guinea pig atria and papillary muscles caused positive chronotropic and inotropic effects, which were associated with histamine release and were antagonized by the H2 receptor blocker cimetidine, thereby mimicking the effects of anaphylaxis. Our findings indicate that complement activation and anaphylatoxin generation are typical of cardiac anaphylaxis and suggest that anaphylatoxins function as mediator-modulators of immediate hypersensitivity reactions of the heart.