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

The role of platelet-activating factor (PAF) and nitric oxide (NO) as media tors of the effects of tumor necrosis factor-alpha (TNF-alpha) on skeletal muscle contractility was studied in guinea pig extensor digitorum longus (E DL) muscle. TNF-alpha (5-10 ng/ml) reduced contractility at every stimulati on frequency (1-200 Hz) and shifted the force-frequency relationship to the right. The role of NO and PAF as mediators of TNF-alpha was suggested by t he protective effect of N-G-nitro-L-arginine methyl ester (L-NAME; 1 mM), b ut not of N-G-nitro-D-arginine methyl ester (D-NAME; 1 mM), and by the inhi bitory effect of the PAF-receptor antagonist WEB-2170 (3 muM). TNF-alpha in creased the production of PAF and NO. Similar to TNF-alpha, both S-nitroso- N-acetylpenicillamine (0.5-1 mM), an NO-generating compound, and PAF (10-20 nM) reduced EDL contractility. L-NAME, but not D-NAME, blocked the negativ e effect of PAF. Blockade of phospholipase A(2), which is required for PAF synthesis, significantly reduced the effects of TNF-alpha. WEB-2170 inhibit ed NO synthesis induced by TNF-alpha and PAF-stimulated NO production. Thes e results suggest that both PAF and NO contribute to the development of the mechanical alterations induced by TNF-alpha and that NO production is down stream to the synthesis of PAF.