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 mediators of the effects of tumor necrosis factor-alpha (TNF-alpha) on skeletal muscle contractility was studied in guinea pig extensor digitorum longus (EDL) muscle. TNF-alpha (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-alpha 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 microM). TNF-alpha increased the production of PAF and NO. Similar to TNF-alpha, both S-nitroso-N-acetylpenicillamine (0.5-1 microM), 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 A(2), which is required for PAF synthesis, significantly reduced the effects of TNF-alpha. WEB-2170 inhibited NO synthesis induced by TNF-alpha and PAF-stimulated NO production. These results suggest that both PAF and NO contribute to the development of the mechanical alterations induced by TNF-alpha and that NO production is downstream to the synthesis of PAF.
Alloatti
G
G
Laboratorio di Fisiologia Generale, Dipartimento di Biologia Animale e dell'Uomo, Università degli Studi di Torino, 10123 Torino, Italy. alloatti@dba.unito.it
Penna
C
C
Mariano
F
F
Camussi
G
G
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D026423:S-Nitroso-N-Acetylpenicillamine; D013237:Stereoisomerism; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D001381:Azepines; D020030:Nitric Oxide Donors; D010972:Platelet Activating Factor; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; C063964:bepafant; D010741:Phospholipases A; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester