Reviparin-sodium prevents complement-mediated myocardial injury in the isolated rabbit heart.
The cytoprotective action of reviparin-sodium (LU-47311: Clivarin), a low-molecular-weight heparin, was examined in an ex vivo model of complement-mediated myocardial injury. The effective concentration of reviparin was determined by using an in vitro rabbit erythrocyte-lysis assay using 4% normal human plasma. Reviparin (0.01-2.73 mg/ml) reduced erythrocyte lysis in a concentration-dependent manner. Subsequently, 0.91 mg/ml of reviparin was evaluated in an ex vivo rabbit isolated-heart model of human complement-mediated injury. Hearts perfused in the presence of 0.91 mg/ml of reviparin (n = 10) demonstrated significant preservation of ventricular function compared with vehicle-treated hearts (n = 10), as evidenced by coronary artery perfusion pressure, left ventricular developed pressure, and left ventricular end-diastolic pressure. A reduction in myocyte creatine kinase release was observed in reviparin-treated hearts compared with controls. Myocardial injury in vehicle-treated hearts was associated with an increased assembly of the membrane-attack complex, as determined by immunohistochemical localization of C5b-9 neoantigen. Reviparin decreased fluid-phase Bb formation detected in the lymphatic drainage of plasma-perfused hearts. The results of this study demonstrate that reviparin inhibits complement-mediated myocardial injury as assessed in an ex vivo experimental model of complement activation.
Park
J L
JL
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, U.S.A.
Tanhehco
E J
EJ
Kilgore
K S
KS
Gralinski
M R
MR
Lucchesi
B R
BR
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000188:drug therapy; D003167:Complement Activation / Q000187:drug effects*; D051561:Complement C3 Convertase, Alternative Pathway; D003179:Complement C3b / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000032:analysis* / Q000037:antagonists & inhibitors; D003402:Creatine Kinase / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D009206:Myocardium / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism; D011817:Rabbits
D000925:Anticoagulants; D015938:Complement Membrane Attack Complex; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D010446:Peptide Fragments; C094240:reviparin; D003179:Complement C3b; D003402:Creatine Kinase; D051561:Complement C3 Convertase, Alternative Pathway