title: The semisynthetic polysaccharide pentosan polysulfate prevents complement-mediated myocardial injury in the rabbit perfused heart.
abstract: Pentosan polysulfate (PPS) is a highly sulfated semisynthetic polysaccharide possessing a higher negative charge density and degree of sulfation than heparin. Like other glycosaminoglycans, the structural and chemical properties of PPS promote binding of the drug to the endothelium. Glycosaminoglycans, including heparin, inhibit complement activation independent of an action on the coagulation system. This ability provides a compelling argument for the implementation of this class of compounds in experimental models of cellular injury mediated by complement. The objective of this study was to examine whether PPS could reduce myocardial injury resulting from activation of the complement system. We used the rabbit isolated heart perfused with 4% normal human plasma as a source of complement. Hemodynamic variables were obtained before addition of PPS (0.03 01 mg/ml) and every 10 min after the addition of human plasma. Compared with vehicle-treated hearts, left ventricular end-diastolic pressure was improved at the conclusion of the 60-min protocol in hearts treated with PPS (58.9 +/- 13.6 vs. 15. 2 +/- 4.8 mm Hg). Further evidence as to the protective effects of PPS was demonstrated by decreased creatine kinase release compared with vehicle (86.5 +/- 28.5 U/l vs. 631.0 +/- 124.8 U/l). An enzyme-linked immunosorbent assay for the presence of the membrane attack complex in lymph and tissue samples demonstrated decreased membrane attack complex formation in PPS-treated hearts, which suggests inhibition of complement activation. This conclusion was supported further by the ability of PPS to inhibit complement-mediated red blood cell lysis in vitro. The results of this study indicate that PPS can reduce tissue injury and preserve organ function that otherwise would be compromised during activation of the human complement cascade.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Kilgore
authors.forename: K B
authors.initials: KB
authors.lastname: Naylor
authors.forename: E J
authors.initials: EJ
authors.lastname: Tanhehco
authors.forename: J L
authors.initials: JL
authors.lastname: Park
authors.forename: E A
authors.initials: EA
authors.lastname: Booth
authors.forename: R A
authors.initials: RA
authors.lastname: Washington
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003165:Complement System Proteins / Q000032:analysis / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000032:analysis / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000925:Anticoagulants; D015938:Complement Membrane Attack Complex; D006023:Glycoproteins; C047610:SC5b-9 protein complex; D010426:Pentosan Sulfuric Polyester; D003165:Complement System Proteins; D003402:Creatine Kinase