C3a57-77, a C-terminal peptide, causes thromboxane-dependent pulmonary vascular constriction in isolated perfused rat lungs

Abstract

Pulmonary hypertension occurs after the intravascular activation of complement. However, it is unclear which activated complement fragments are responsible for the pulmonary vascular constriction. We investigated the 21-carboxy-terminal peptide of C3a (C3a57-77) to see if it would cause pulmonary vascular constriction when infused into isolated buffer-perfused rat lungs. Injection of C3a57-77 (225 to 450 micrograms) caused mean pulmonary arterial pressure (Ppa) to rapidly increase. However, the response was transient, with Ppa returning to baseline within 10 min of its administration. C3a57-77 also resulted in an increase in lung effluent thromboxane B2 (TXB2), concomitant with the peak increase in Ppa. C3a57-77 did not affect the amount of 6-keto-PGF1 alpha in the same effluent samples. Indomethacin inhibited the C3a57-77-induced pulmonary artery pressor response and the associated TXB2 production. Indomethacin also decreased lung effluent 6-keto-PGF1 alpha. The thromboxane synthetase inhibitors CGS 13080 and U63,357 inhibited the C3a57-77-induced pulmonary artery pressor response and TXB2 production without affecting 6-keto-PGF1 alpha. These inhibitors did not inhibit pulmonary artery pressor responses to angiotensin II. Tachyphylaxis to C3a57-77 occurred because a second dose of C3a57-77 administered to the same lung failed to cause a pulmonary artery pressor response or TXB2 production. The loss of the pressor response was not due to a C3a57-77-induced decrease in pulmonary vascular responsiveness because pressor responses elicited by angiotensin II were not altered by lung contact with C3a57-77. Thus, C3a57-77 caused thromboxane-dependent pulmonary vascular constriction in isolated buffer perfused rat lungs.