The Novel Glycolipid RC-552 Attenuates Myocardial Stunning and Reduces Infarct Size in Dogs

• Published in: Journal of molecular and cellular cardiology Vol. 32; no. 7; pp. 1327 - 1339
• Main Authors: Elliott, G.T, Sowell, C.G, Walker, E.B, Weber, P.A, Moore, J, Gross, G.J
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2000
• Subjects: Aminoguanidine; Animals; Antibodies, Monoclonal; Blood Flow Velocity; Cardioprotection; Dogs; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Glycolipid; Glycolipids - chemistry; Glycolipids - pharmacology; Hemodynamics; Humans; Infarction; Intercellular Adhesion Molecule-1 - biosynthesis; Interleukin-6 - biosynthesis; Interleukin-8 - biosynthesis; Ischemia; L-Selectin - blood; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lipid A - analogs & derivatives; Lipid A - chemistry; Lipid A - pharmacology; Lipopolysaccharides - pharmacology; Male; Myocardial Infarction - drug therapy; Myocardial Stunning - drug therapy; Neutrophils - drug effects; Neutrophils - metabolism; Nitric oxide; Rabbits; RC-552; Reperfusion; Stunning; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - biosynthesis; Aminoguanidine; Reperfusion; Cardioprotection; Stunning; RC-552; Ischemia; Nitric oxide; Infarction; Glycolipid
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1006/jmcc.2000.1166

The novel glycolipid RC-552 shares common structural features with the natural products lipid A and the previously described cardioprotectant monophosphoryl lipid A. RC-552 administered to dogs as a bolus intravenous dose (35–70μ g/kg) either 24 h or 10 min prior to 60 min of regional myocardial ischemia and 3 h of reperfusion significantly (P<0.05 v control) reduced infarct size (IS) as assessed by triphenyltetrazolium staining from 27.0±2.3% of the area-at-risk (AAR) to 13.3±2.2% and 15.0±3.0%, respectively. Administration of the non-specific inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (30 mg/kg, subcutaneously) 1 h prior to ischemia blocked the ability of RC-552 (35 μ g/kg, 24 h pretreatment) to reduce infarct size. Intravenous pretreatment with RC-552 (35 μ g/kg) either 24 h or 10 min prior to five 5 min repetitive cycles of ischemia and reperfusion significantly improved regional myocardial segment shortening (percentage of control) at all time points during 2 h of reperfusion in dogs. These effects of RC-552 in either cardiac injury model occurred independent of differences in AAR, transmural blood flow during ischemia or hemodynamics throughout the experiment. In contrast with monophosphoryl lipid A (MLA), which has also been reported to be cardioprotective at similar doses in dogs, RC-552 was approximately 100 times less prone to cause fever in the USP rabbit pyrogen test. Likewise, RC-552 did not induce secretion of the proinflammatory cytokines TNF, IL-6 or IL-8 from THP-1 cells or alter the expression of adhesion molecules on human neutrophils at concentrations up to 10μ g/ml. MLA was active in these systems at concentrations in the range 0.1–1.0 μ g/ml. In conclusion, RC-552 reduces myocardial infarct size and stunning in dogs in the absence of residual immunomodulatory activity.