ENDOTHELIN-1 AMELIORATES CONTRACTILE DEPRESSION BY LIPOPOLYSACCHARIDEIN CARDIAC MYOCYTES

Lipopolysaccharide (LPS) induces cardiac depression by activating nitr ic oxide pathways to increase guanosine 3',5'-cyclic monophosphate (cG MP), a second messenger of nitric oxide. Endothelin-1 (ET-1) may inter act with nitric oxide pathways. We hypothesized that ET-1 modulates LP S-induced contractile depression in cardiac myocytes. Adult rabbit car diac myocytes exposed to LPS (10 ng/ml) developed decreased cell short ening after 6 h, with an increase in cardiac cGMP levels [606 +/- 36 ( SE) fmol/mg protein] compared with control myocytes (360 +/- 26 fmol/m g protein, P < 0.05). LPS effects were completely blocked by coincubat ion with the nitric oxide synthase inhibitor N-G-monomethyl-L-arginine (1 mM). Coincubation with ET-1 (10 nM) attenuated the contractile dep ression and increase in cGMP with LPS (482 +/- 28 fmol/mg protein, P < 0.05 vs. LPS alone). ET-1 alone did not alter cGMP levels (350 +/- 30 fmol/mg protein). ET-1 effects on contractile function were blocked b y BQ-123 (10 mu M), a selective ET-1 type A receptor antagonist. We co nclude that ET-1 ameliorates LPS-induced contractile depression in car diac myocytes by attenuating LPS effects on nitric oxide-cGMP pathways .