The novel glycolipid RC-552 attenuates myocardial stunning and reduces infarct size in dogs. J Mol Cell Cardiol 2000 Jul;32(7):1327-39
Date
06/22/2000Pubmed ID
10860773DOI
10.1006/jmcc.2000.1166Scopus ID
2-s2.0-0033840408 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
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 (35-70 microg/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 microg/kg, 24 h pretreatment) to reduce infarct size. Intravenous pretreatment with RC-552 (35 microg/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 10 microg/ml. MLA was active in these systems at concentrations in the range 0.1-1.0 microg/ml. In conclusion, RC-552 reduces myocardial infarct size and stunning in dogs in the absence of residual immunomodulatory activity.
Author List
Elliott GT, Sowell CG, Walker EB, Weber PA, Moore J, Gross GJMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Blood Flow Velocity
Dogs
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Glycolipids
Hemodynamics
Humans
Intercellular Adhesion Molecule-1
Interleukin-6
Interleukin-8
L-Selectin
Leukocytes, Mononuclear
Lipid A
Lipopolysaccharides
Male
Myocardial Infarction
Myocardial Stunning
Neutrophils
Rabbits
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha
