Vol. 282, Issue 2, 554-560, 1997

LU 51198, a Highly Sulfated, Low-Molecular-Weight Heparin Derivative, Prevents Complement-Mediated Myocardial Injury in the Perfused Rabbit Heart¹

Michael R. Gralinski, James L. Park, Mark A. Ozeck², Bridget C. Wiater³ and Benedict R. Lucchesi

Department of Pharmacology, University of Michigan Medical School, Ann Arbor Michigan

Evidence is presented that treatment with a highly sulfated low-molecular-weight heparin fraction, LU 51198, protects the ex vivo perfused rabbit heart from human complement-mediated injury. Hearts from male New Zealand White rabbits were perfused under constant flow in the Langendorff mode. After equilibration, normal human plasma was added to the perfusate as a source of complement. Either control (n = 8) or LU 51198 (0.6 mg/ml; n = 7) was added to the perfusion medium 10 min before the addition of human plasma. Hemodynamic variables were obtained for both groups before treatment of human plasma. Hemodynamic variables were obtained for both groups before treatment (baseline), 10 min after treatment (zero) and after the addition of human plasma. Compared to control-treated hearts, variables recorded during perfusion with human plasma, including coronary perfusion pressure, left ventricular developed pressure, and left ventricular end-diastolic pressure, along with a reduction of creatine kinase and potassium efflux, were significantly improved in hearts treated with LU 51198 (P < .05). ELISA assays were used to analyze lymphatic effluent for the presence of iC3b, Bb and SC5b-9 proteins derived from the activation of human complement. The increased presence of the Bb fragment in the effluent obtained from LU 51198-perfused hearts suggests an accelerated dissociation of the convertases responsible for complement amplification, an observation that coincided with protection from complement-mediated damage in the presence of the glycosaminoglycan. The lysis of rabbit red blood cells upon exposure to human plasma was inhibited by LU 51198, which is evidence of the drug's ability to modulate complement reactivity. The results of this study indicate that a highly sulfated heparin fraction, LU 51198, can reduce tissue injury and preserve discordant organ function that otherwise would be compromised during activation of the human complement cascade.