The Semisynthetic Polysaccharide Pentosan Polysulfate Prevents Complement-Mediated Myocardial Injury in the Rabbit Perfused Heart1
- Kenneth S. Kilgore,
- Keith B. Naylor2,
- Elaine J. Tanhehco,
- James L. Park,
- Erin A. Booth,
- Ruth A. Washington and
- Benedict R. Lucchesi
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.
Footnotes
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Send reprint requests to: Kenneth S. Kilgore, Ph.D., Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Building III, Ann Arbor, MI 48109-0632.
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↵1 This study was funded by the Cardiovascular Research Fund, University of Michigan Medical School, Department of Pharmacology. KSK was supported, in part, by the American Heart Association, Michigan Affiliate (no. 36GB967).
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↵2 Awarded a summer research student fellowship from the American Heart Association, Michigan Affiliate, during the tenure of this study.
- Abbreviations:
- PPS
- pentosan polysulfate
- MAC
- membrane attack complex
- GAG
- glycosaminoglycans
- NHP
- normal human plasma
- GVB
- gelatin veronal buffer
- CK
- creatine kinase
- LVEDP
- left ventricular end-diastolic pressure
- LVDP
- left ventricular developed pressure
- RBC
- red blood cell
- EGTA
- ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- ELISA
- enzyme-linked immunosorbent assay
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- Received July 21, 1997.
- Accepted February 16, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
