Cardiac dysfunction caused by recombinant human C5A anaphylatoxin: mediation by histamine, adenosine and cyclooxygenase arachidonate metabolites.
We had found previously that complement-derived anaphylatoxins C3a and C5a function as mediators/modulators of cardiac immune hypersensitivity reactions. The purpose of this study was to determine the secondary mediators responsible for the cardiac effects of C5a. Recombinant human C5a (rhC5a) caused dose-dependent tachycardia, slowing of atrioventricular nodal conduction, a short lasting increase followed by a prolonged decrease in left ventricular contractility, and coronary vasoconstriction. These changes were associated with the release of histamine, thromboxane A2 and adenosine into the coronary effluent. Our data indicate that the positive inotropic and chronotropic effects of rhC5a are mediated by histamine release and consequent activation of H2-receptors, the coronary-vasoconstricting effect is due to thromboxane release and the negative dromotropic effect is associated with adenosine release. Furthermore, the decrease in contractility caused by rhC5a is likely to result from the H1-mediated negative inotropic effect of histamine compounded by the ischemic conditions created by the coronary vasoconstricting effects of thromboxane A2 and, perhaps, leukotrienes. Our findings demonstrate that C5a has marked cardiac effects at concentrations approximating those attained in vivo in a multitude of pathophysiological conditions in which complement is activated, including myocardial infarction. Thus, anaphylatoxins may play a role in the development of ischemic cardiac dysfunction.
Department of Pharmacology, Cornell University Medical College, New York, New York.
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del Balzo
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Sakuma
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Levi
D000241:Adenosine / Q000502:physiology*; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D003167:Complement Activation; D015926:Complement C3a / Q000633:toxicity; D015936:Complement C5a / Q000633:toxicity*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006636:Histamine Release; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011738:Pyrilamine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000633:toxicity; D013931:Thromboxanes / Q000502:physiology*
D002867:Chromones; D011994:Recombinant Proteins; D013931:Thromboxanes; D015926:Complement C3a; D015936:Complement C5a; C006312:FPL 55712; D011738:Pyrilamine; D000241:Adenosine