Tumor necrosis factor-alpha inhibits the cardiac delayed rectifier K current via the asphingomyelin pathway.
Tumor necrosis factor-alpha (TNF-alpha) affects contractility and ionic currents in the heart. However, the electrophysiological effects, especially on delayed rectifier K currents (IK), have not yet been fully elucidated. We examined the effects of TNF-alpha on IK. Using a voltage-clamp method, IK was measured in guinea pig ventricular myocytes in the basal state and after pharmacological intervention. To specify the site of the action of TNF-alpha, the myocytes were incubated with pertussis toxin or N-oleoylethanolamine, a ceramidase inhibitor, and IK was measured. TNF-alpha suppressed IK when it was enhanced by isoproterenol, histamine or forskolin but not in the basal state or when IK was augmented by an internal application of cyclic AMP. Both pre-incubation with pertussis toxin and N-oleoylethanolamine abolished the inhibitory action of TNF-alpha on isoproterenol-augmented IK. TNF-alpha inhibits IK, mainly IKs, when it is augmented by PKA as a result of the generation of sphingosine.
Hatada
Katsuharu
K
Division of Cardiology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
Washizuka
Takashi
T
Horie
Minoru
M
Watanabe
Hiroshi
H
Yamashita
Fumio
F
Chinushi
Masaomi
M
Aizawa
Yoshifusa
Y
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D055572:Ceramidases; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D063388:Endocannabinoids; D004983:Ethanolamines / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009829:Oleic Acids; D037342:Pertussis Toxin / Q000494:pharmacology; D013109:Sphingomyelins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051668:Delayed Rectifier Potassium Channels; D063388:Endocannabinoids; D004983:Ethanolamines; D009829:Oleic Acids; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; C033595:N-oleoylethanolamine; D037342:Pertussis Toxin; D000581:Amidohydrolases; D055572:Ceramidases; D007545:Isoproterenol