title: Dermatan disulfate (Intimatan) prevents complement-mediated myocardial injury in the human-plasma-perfused rabbit heart.
abstract: Intimatan (dermatan 4,6-O-disulfate), a heparin cofactor II agonist, is a highly sulfated negatively charged semisynthetic polysaccharide. The present study examined the hypothesis that Intimatan reduces complement-mediated myocardial injury. The rabbit isolated heart was perfused with 4% normal human plasma (NHP) as a source of complement in the absence or presence of Intimatan (5 microM). Heat-inactivated human plasma (HIHP) was used as a negative control. Previous studies demonstrated that contact of rabbit tissue with human plasma results in activation of the alternative pathway of the human complement system, leading to irreversible myocardial injury. In the presence of NHP, left ventricular end-diastolic pressure (LVEDP) was increased significantly to 61.8+/-11.7 mm Hg compared to a value of 17.2+/-6.1 mm Hg in hearts perfused in the presence of HIHP. Left ventricular developed pressure (LVDP) was reduced significantly upon exposure to NHP, 19.3+/-10.2 (NHP) vs. 54.0+/-8.0 mm Hg (HIHP). Functional impairment in the presence of NHP was accompanied by a significant release of cardiac troponin I (cTnI; 131.8+/-20.3 ng/ml) as compared to hearts exposed to HIHP (0.8+/-0.8). Intimatan treatment improved cardiac function and maintained viability of cardiac myocytes (LVEDP 14.6+/-5.6, LVDP 58.0+/-8.1 mm Hg and cTnI 6.7+/-5.2 ng/ml). Immunohistochemical staining demonstrated that Intimatan pretreatment prevented deposition of the human membrane attack complex (MAC) in hearts exposed to NHP. The results indicate that Intimatan, a glycosaminoglycan (GAG), 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, 1301C Medical Science Research Building III, Ann Arbor, MI 48109-0632 USA.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Hong
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: White
authors.forename: Benedict R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D003167:Complement Activation / Q000187:drug effects* / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology*; D003871:Dermatan Sulfate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010949:Plasma / Q000502:physiology; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000925:Anticoagulants; C416431:intimatan; D003871:Dermatan Sulfate; D003165:Complement System Proteins