TNF-.ALPHA. Rapidly Antagonizes the .BETA.-Adrenergic Responses of the Chloride Current in Guinea-Pig Ventricular Myocytes.

Publisher Website
Google Scholar
Abstract
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 (ICl) recorded from isolated guinea-pig ventricular myocytes. Ramp pulses (±120 mV; dv/dt = ±0.4 V/s) were applied from the holding potential of -40 mV. TNF-α rapidly (Cl in a concentration-dependent manner (30-1,000 U/ml, IC 50 = 144 U/ml, n=30). The inhibitory action of TNF-α was also observed when ICl had been previously stimulated by 1 μmol/L forskolin (n=5). Prior exposure of myocytes to 5 μg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-α (n=4). However, when ICl was induced by both 8-bromo-cAMP (100 μmol/L) and isobutylmethylxanthine (0.1 mmol/L), TNF-α (1,000 U/ml) failed to decrease ICl 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-induced increase in ICl (n=5). These results suggest that TNF-α rapidly antagonizes the β-adrenergic responses of ICl 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)