The novel glycolipid RC-552 attenuates myocardial stunning and reduces infarct size in dogs

The novel glycolipid RC-552 shares common structural features with the natu ral products lipid A and the previously described cardioprotectant monophos phoryl lipid A. RC-552 administered to dogs as a bolus intravenous dose (35 -70 mu g/kg) either 24 h or 10 min prior to 60 min of regional myocardial i schemia and 3h of reperfusion significantly (P<0.05 v control) reduced infa rct 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) i nhibitor aminoguanidine (30 mg/kg, subcutaneously) 1 h prior to ischemia bl ocked the ability of RC-552 (35 mu g/kg. 74 h pretreatment) to reduce infar ct size, Intravenous pretreatment with RC-552 (35 mu g/kg) either 24 h or 1 0 min prior to five 5 min repetitive cycles of ischemia and reperfusion sig nificantly improved regional myocardial segment shortening (percentage of c ontrol) at all time points during 2 h of reperfusion in dogs. These effects of RC-552 in either cardiac injury model occurred independent of differenc es in AAR, transmural blood flow during ischemia of 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, Likewis e, 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 o n human neutrophils at concentrations up to 10 mu g/ml. MLA was active in t hese systems at concentrations in the range 0.1-1.0 mu g/ml. In conclusion, RC-552 reduces myocardial infarct size and stunning in dogs in the absence of residual immunomodulatory activity. (C) 2000 Academic Press.