© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Role of nitric oxide and platelet-activating factor in cardiac alterations induced by tumor necrosis factor-
in the guinea-pig papillary muscle
aLaboratorio di Fisiologia Generale, Dipartimento di Biologia Animale e dell’Uomo, Università degli Studi di Torino, Turin, Italy
bLaboratorio di Fisiopatologia Clinica, Università degli Studi di Torino, Turin, Italy
cDipartimento di Scienze Cliniche e Biologiche, II Facoltà di Medicina, Università di Pavia, Varese, Italy
* Corresponding author. Tel.: +39-11-836-350; Fax: +39-11-812-4561.
Objective: Tumor necrosis factor-
(TNF-), a proinflammatory cytokine with negative inotropic properties, is implicated in several pathophysiological events. To clarify the mechanism of action of TNF- on myocardium, we investigated the possible role of platelet-activating factor (PAF) and nitric oxide (NO) as secondary mediators of the depressant effect of this cytokine. Methods: Isometric twitches and intracellular action potentials were recorded from guinea pig papillary muscles. The effects of TNF- (1–10 ng/ml) were studied in controlled conditions and after treatment with 0.5% Triton X-100, to destroy the endocardial endothelium. NG-nitro-L-arginine methyl ester (L-NAME), D-NAME (1 mM) and the two different PAF-receptor antagonists WEB 2170 (3 µM) and CV 3988 (5 µM) were used to study the role of NO and PAF in cardiac depression induced by TNF-. To study the role of NO in cardiac alterations induced by PAF, papillary muscles were pretreated with L-NAME or D-NAME and then challenged with PAF (0.1–1 µM). Nitrite production by papillary muscles challenged with TNF- alone, TNF- in the presence of WEB 2170 or CV 3988, or PAF was studied with the Greiss reagent method. PAF production by papillary muscles stimulated by TNF- was studied by a bioassay method. Results: TNF- induced an initial, transient positive inotropic effect, then reduced the contractility and the action potential duration in a concentration-dependent manner. Treatment of papillary muscle with Triton X-100 did not modify the response to TNF-, suggesting that the effect of TNF- is not mediated by endocardial endothelial cells. Pretreatment with indomethacin reduced the negative effect of TNF-, while propranolol abolished the initial increase of contractility. The role of PAF and NO as mediators of TNF- was suggested by: (1) the protective effect of L-NAME, but not of D-NAME, on electrical and mechanical alterations; (2) the stimulatory effect of TNF- on nitrite production; (3) the inhibitory effect of WEB 2170 and CV 3988, on both the electromechanical alterations and the nitrite production; (4) the synthesis of PAF induced by TNF-. L-NAME blocked the negative effect of PAF and PAF enhanced nitrite production by papillary muscle. Conclusions: The present results suggest that in cardiac muscle: (1) the release of PAF triggered by TNF- may account for the stimulation of NO production; (2) both PAF and NO contribute to the development of the electrical and mechanical alterations induced by TNF-; (3) NO production was down-stream to the synthesis of PAF.
KEYWORDS Cardiac action potential; Cardiac contractility; Nitric oxide; Papillary muscle; Platelet-activating factor; Tumor necrosis factor-
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