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Cardiac dysfunction caused by purified human C3a anaphylatoxin
Insights
Complement-derived C3a anaphylatoxin causes significant cardiac dysfunction, including arrhythmias and heart failure, by triggering histamine and other mediators. These findings suggest C3a contributes to cardiac issues in various diseases.
Area of Science:
- Cardiovascular Physiology
- Immunology
- Pharmacology
Background:
- Complement activation is implicated in various disease states.
- Cardiac dysfunction may arise from complement activation.
- C3a anaphylatoxin is a key mediator of complement's inflammatory effects.
Purpose of the Study:
- To investigate the direct cardiac effects of complement-derived C3a anaphylatoxin.
- To elucidate the mechanisms underlying C3a-induced cardiac dysfunction.
- To assess the potential role of C3a in clinical cardiac conditions.
Main Methods:
- Isolated guinea pig hearts were perfused with purified human C3a.
- Dose-dependent cardiac responses were measured.
- Pharmacological interventions (carboxypeptidase B, cimetidine, FPL 55712, indomethacin) were used to identify mediators.
Main Results:
- C3a induced dose-dependent tachycardia, atrioventricular conduction impairment, contractile failure, and coronary vasoconstriction.
- These effects were abolished by carboxypeptidase B, indicating dependence on the intact C3a molecule.
- Tachycardia was mediated by histamine, while contractile failure and vasoconstriction involved leukotrienes and prostaglandins, respectively.
Conclusions:
- C3a anaphylatoxin exerts significant and varied cardiac effects.
- Histamine, leukotrienes, and prostaglandins are key mediators of C3a's cardiac actions.
- C3a-induced cardiac dysfunction may contribute to clinical conditions associated with complement activation.
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.