THE SEMISYNTHETIC POLYSACCHARIDE PENTOSAN POLYSULFATE PREVENTS COMPLEMENT-MEDIATED MYOCARDIAL INJURY IN THE RABBIT PERFUSED HEART

Pentosan polysulfate (PPS) is a highly sulfated semisynthetic polysacc haride possessing a higher negative charge density and degree of sulfa tion than heparin, Like other glycosaminoglycans, the structural and c hemical properties of PPS promote binding of the drug to the endotheli um. Glycosaminoglycans, including heparin, inhibit complement activati on independent of an action on the coagulation system. This ability pr ovides a compelling argument for the implementation of this class of c ompounds in experimental models of cellular injury mediated by complem ent. The objective of this study was to examine whether PPS could redu ce myocardial injury resulting from activation of the complement syste m. We used the rabbit isolated heart perfused with 4% normal human pla sma as a source of complement. Hemodynamic variables were obtained bef ore addition of PPS (0.03 01 mg/ml) and every 10 min after the additio n of human plasma. Compared with vehicle-treated hearts, left ventricu lar end-diastolic pressure was improved at the conclusion of the 60-mi n 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 demon strated by decreased creatine kinase release compared with vehicle (86 .5 +/- 28.5 U/I vs. 631.0 +/- 124.8 U/I). An enzyme-linked immunosorbe nt assay for the presence of the membrane attack complex in lymph and tissue samples demonstrated decreased membrane attack complex formatio n in PPS-treated hearts, which suggests inhibition of complement activ ation. 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.