© 1995 American Heart Association, Inc.
Articles |
Complement-Mediated Loss of Endothelium-Dependent Relaxation of Porcine Coronary Arteries
Role of the Terminal Membrane Attack Complex
From Brigham and Women's Hospital (G.L.S., G.F.), Department of Anesthesia, Anesthesia Research Laboratories, Ischemia Reperfusion Center, Boston, Mass; the Department of Internal Medicine (G.L.S.), Division of Cardiovascular Medicine, University of California, Davis; and the Department of Dermatology (W.R.R.), Boston (Mass) University, School of Medicine.
Correspondence to Gregory L. Stahl, PhD, Brigham and Women's Hospital, Department of Anesthesia, Ischemia Reperfusion Center, 75 Francis St, Boston, MA 02115. E-mail gstahl@zeus.bwh.harvard.edu.
Abstract Reperfusion of the ischemic myocardium results in the loss of endothelium-dependent relaxation. We have shown recently that the alternate complement pathway is activated immediately on reperfusion of the ischemic porcine myocardium. We hypothesized that complement activation directly attenuates endothelium-dependent relaxation of porcine coronary arteries. Bradykinin (BK) or substance P concentration-dependently relaxed precontracted (U46619, 50 nmol/L) left anterior descending coronary artery (LAD) rings in vitro. Addition of zymosan to human (10%) or porcine (10%) serum for 30 minutes significantly (P<0.05) increased the EC50 of BK-induced LAD relaxation from 4±1 to 418±159 nmol/L (n=8) and from 9±3 to 281±132 nmol/L (n=7), respectively. Similarly, addition of zymosan to 10% human serum (HS) for 30 minutes increased the EC50 of substance P–induced LAD relaxation from 0.4±0.1 to 30±14 nmol/L (n=9, P<.05). Basal release of nitric oxide was reduced significantly in LAD rings exposed to zymosan-activated HS compared with HS alone. Addition of soluble CR1 (sCR1, 10 nmol/L) to zymosan-activated HS preserved BK-induced relaxation (EC50) of the LAD rings (control, 4±1 nmol/L; sCR1+zymosan+serum, 2±1 nmol/L; n=6). Zymosan-activated C8-depleted HS (10%) did not attenuate the EC50 of BK-induced coronary artery relaxation (3±1 to 3±1 nmol/L, n=7, P=NS). Zymosan-activated C8-depleted HS plus C8 (6 µg/mL) increased the EC50 of BK-induced coronary artery relaxation from 4±1 to 423±141 nmol/L (n=12, P<.05). We have further demonstrated that C5b-9 complexes can be found on the luminal surface of LAD endothelial cells after 5 minutes of exposure to zymosan-activated HS by using C5b-9 reactive monoclonal antibody fluorescent immunohistochemistry and confocal microscopy. We conclude that complement activation directly attenuates endothelium-dependent relaxation through the formation of the terminal membrane attack complex (C5b-9).
Key Words: C5b-9 • soluble complement receptor type 1 • bradykinin • substance P • nitric oxide
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