CONTRACTILE ACTIONS OF C5A ON ISOLATED PORCINE MYOCARDIUM

Although intracoronary administration of the complement component, C5a, produces deleterious effects on regional coronary blood flow and segmental ventricular function, it is unclear whether a direct myocardial action contributes to the dysfunction induced by the anaphylatoxin. We therefore evaluated the effects of purified porcine C5a on contractile tension of isolated supported ventricular trabeculae from pig hearts. Muscles were studied in a myograph bath at 30-degrees-C, electrically stimulated 12 times per minute, and stretched to produce maximal isometric developed tension. C5a concentrations of 30, 100, and 300 ng/ml increased tension (P < 0.05) 9.8, 5.5, and 20.9%, respectively. In seven of nine muscles exposed to 300 ng/ml C5a, tension initially decreased 10.5% (P < 0.05) before the positive inotropic effect. Tachyphylaxis was demonstrated by lack of contractile response to a second administration of C5a > 70 min after the initial exposure to the complement fragment. Blockade of histamine H-1 receptors with diphenhydramine (10(-6) M) markedly attenuated both the positive and negative contractile responses to C5a. Beta-Adrenoceptor blockade with propranolol (5.6 x 10(-7) M) did not alter the response to C5a. Levels of thromboxane (Tx)B2, the stable metabolite of TxA2, were augmented in the bath after exposure to C5a (59 +/27. 3 to 104 +/- 28.2 pg/ml, P < 0.05). Although the TxA2 agonist, U-46619 (50 ng/ml), significantly increased tension, TxA2 receptor blockade with SQ 29548 (50 ng/ml) did not alter the response to C5a. Thus, in isolated pig myocardium, purified porcine C5a has a positive inotropic effect that is mediated by H-1 receptor stimulation but not by beta-adrenoceptor stimulation or TxA2. This action is preceded by a negative contractile effect that could contribute to the cardiac dysfunction induced by intracoronary C5a administration in the intact animal.