Role of NO and PAF in the impairment of skeletal muscle contractility induced by TNF-α

Abstract

The role of platelet-activating factor (PAF) and nitric oxide (NO) as mediators of the effects of tumor necrosis factor-α (TNF-α) on skeletal muscle contractility was studied in guinea pig extensor digitorum longus (EDL) muscle. TNF-α (5–10 ng/ml) reduced contractility at every stimulation frequency (1–200 Hz) and shifted the force-frequency relationship to the right. The role of NO and PAF as mediators of TNF-α was suggested by the protective effect of N G-nitro-l-arginine methyl ester (l-NAME; 1 mM), but not of N G-nitro-d-arginine methyl ester (d-NAME; 1 mM), and by the inhibitory effect of the PAF-receptor antagonist WEB-2170 (3 μM). TNF-α increased the production of PAF and NO. Similar to TNF-α, both S-nitroso- N-acetylpenicillamine (0.5–1 μM), an NO-generating compound, and PAF (10–20 nM) reduced EDL contractility. l-NAME, but not d-NAME, blocked the negative effect of PAF. Blockade of phospholipase A2, which is required for PAF synthesis, significantly reduced the effects of TNF-α. WEB-2170 inhibited NO synthesis induced by TNF-α and PAF-stimulated NO production. These results suggest that both PAF and NO contribute to the development of the mechanical alterations induced by TNF-α and that NO production is downstream to the synthesis of PAF.