THE ROLE OF PROTEIN-KINASE-C IN LIPOPOLYSACCHARIDE-INDUCED MYOCARDIALDEPRESSION IN GUINEA-PIGS

The effect of lipopolysaccharide (LPS) on cardiac protein kinase C (PK C) activation and cardiac depression was evaluated. Guinea pigs (n = 4 4) received intraperitoneal injections of saline or Escherichia coli L PS (2 mg/kg). Left atria were harvested 16 h later and suspended in ox ygenated low calcium (1 mM) (n = 24) or high calcium (5 mm) (n = 20) 3 0-degrees-C Krebs-Henseleit buffer. Atria were treated with H-7 (n = 2 3), a PKC inhibitor, or vehicle (n = 2 1). Contractile responses to ch anges in preload and stimulating frequency, in the resting and potenti ated states, and to escalating doses of phenylephrine were measured. P KC activation in ventricular muscle was also determined. LPS activated ventricular PKC (p < .05) but treatment with H-7 failed to reverse LP S-induced atrial dysfunction in the low calcium buffer. Contractile fu nction in the potentiated state indicated that LPS appears to interfer e with calcium release from the sarcoplasmic reticulum (SR). The contr actile response to phenylephrine was markedly attenuated in atria harv ested from endotoxic animals. These data indicate that LPS-induced car diac depression is mediated, in part, by alterations in SR calcium rel ease. LPS activates cardiac PKC but a causal relationship among LPS, P KC, and cardiac dysfunction remains to be established.