THE ROLE OF PLATELET-ACTIVATING-FACTOR IN LIPOPOLYSACCHARIDE-INDUCED MYOCARDIAL DEPRESSION IN GUINEA-PIGS

Purpose: To determine if platelet-activating factor (PAF) is a key med iator of lipopolysaccharide (LPS)induced myocardial depression in guin ea pigs. Methods: Hartley guinea pigs of either sex received intraperi toneal (IF) injections of either vehicle (n = 45) or one of three chem ically dissimilar PAF receptor antagonists (n = 38) followed 30 to 60 minutes later by IP injections of either saline (0.8 mt, n = 33) or LP S (2 to 4 mg/kg, n = 50). Left atria (LA) were harvested 16 hours late r, suspended in Krebs-Henseleit buffer and attached to force-displacem ent transducers. Starling and force-frequency curves, contractile func tion in the potentiated and resting states, and inotropic response to either isoproterenol or phenylephrine were measured. Results: LPS caus ed a significant reduction in LA contractile function. Two of the thre e PAF receptor antagonists failed to ameliorate LPS-induced alteration s in cardiac function. The third antagonist, SR27417, was approximatel y 50% effective in preventing LA contractile dysfunction. However, thi s beneficial response appeared to be caused by a primary inotropic eff ect of SR27417 because LA from animals treated with SR27417 and saline showed significantly higher contractile function compared with LA fro m animals treated with vehicle and saline. In vitro tests confirmed th is. Some LA from LPS-treated animals exhibited reduced contractile res ponses when in the potentiated state, a sign of impaired calcium relea se from the sarcoplasmic reticulum (SR). The response of LA from endot oxic animals to isoproterenol was unchanged compared with controls whe reas it was markedly impaired to phenylephrine. Use of SR27417 failed to improve this abnormal response. Conclusions: PAF does not appear to be a primary mediator of LPS induced myocardial depression in guinea pigs. LPS may impair SR calcium release thereby causing cardiac dysfun ction. Copyright (C) 1995 by W.B. Saunders Company