TNF-α Rapidly Antagonizes the β-Adrenergic Responses of the Chloride Current in Guinea-Pig Ventricular Myocytes

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The purpose of this study was to test the hypothesis that tumor necrosis factor-α (TNF-α) rapidly antagonizes the β-adrenergic responses of the chloride current and to clarify the intracellular mechanisms responsible for the anti-adrenergic action. The whole-cell patch-clamp technique was used to monitor the anti-adrenergic effects of TNF-α on the cAMP-dependent chloride current (Ici) recorded from isolated guinea-pig ventricular myocytes. Ramp pulses (±120 mV ; dv/dt =±0.4V/s) were applied from the holding potential of 40mv. TNF-α rapidly ( <15min) inhibited the isoproterenol (Iso,0.1μmol/L)-induced Ici in a concentration-dependent manner (30-1,OOOU/ml,IC_50 = 144 U/ml, n=30). The inhibitory action of TNF-α was also observed when lci had been previously stimulated by 1μmol/L forskolin (n=5). Prior exposure of myocytes to 5μg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-α (n=4). However, when lci was induced by both 8-bromo-cAMP (100μmol/L) and isobutyImethylxanthine (0.1 mmol/L), TNF-α (1,000 U/ml) failed to decrease Ici amplitude (n=5). Prior exposure of myocytes to 5 mg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-α(n=4). Furthermore, despite of the presence of nitro-L-arginine methyl ester(0.1 mmol/L), a nitric oxide synthase(NOS)inhibitor, TNF-α reversed the Iso-indiiced increase in lci (n=5). These results suggest that TNF-α rapidly antagonizes the β-adrenergic responses of Ici by reducing cAMP concentration. This anti-adrenergic action is mediated by neither the PTX-sensitive G proteins regulatory pathway nor constitutive NOS activation. (Circ J 2003 ; 67 : 347-353)
社団法人日本循環器学会の論文
2003-03-20

TNF-α Rapidly Antagonizes the β-Adrenergic Responses of the Chloride Current in Guinea-Pig Ventricular Myocytes

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