Ventricular K+ currents are reduced in mice with elevated levels of serum TNFalpha.
In the present study mice were treated with tumor necrosis factor alpha (TNFalpha) for 6 weeks to determine if chronic TNFalpha treatment could produce serum levels of TNFalpha similar to what has been observed in disease states (heart failure, HIV) and to determine if these levels of TNFalpha alter ventricular K(+) currents. Mice chronically treated with TNFalpha and sham treated mice were utilized for experiments. Serum levels were measured with a Searchlight protein array. Patch-clamp techniques, real-time PCR and Western blot analysis were used to study K(+) current densities and K(+) channel expression. Results showed that serum concentrations of TNFalpha were significantly higher in TNFalpha treated mice compared to controls (control: 9.5+/-1.5 pg/ml, TNFalpha: 27.4+/-5.0 pg/ml; p<0.05) and comparable to serum TNFalpha levels observed in heart failure and HIV models. In ventricular myocytes from TNFalpha treated mice the outward K(+) currents I(to) and I(Kur) were significantly reduced (at +30 mV: I(to): control: 45.0+/-2.9 pA/pF, TNFalpha: 34.5+/-2.9 pA/pF; p<0.05; I(Kur): control 34.1+/-2.7 pA/pF, TNFalpha: 25.0+/-2.2 pA/pF; p<0.05). Expression studies revealed that ventricular mRNA and protein expression for the channels underlying I(to) and I(Kur) did not differ between the two groups. However, the recovery from inactivation for I(Kur) was significantly longer in TNFalpha treated mice. Overall, this study shows that pathologically relevant levels of serum TNFalpha modulate K(+) currents in mouse ventricle. These findings could help to explain the role of TNFalpha in the pathogenesis of cardiac arrhythmia.
Grandy
Scott A
SA
Research Center, Montreal Heart Institute, Canada.
Fiset
Céline
C
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000494:pharmacology
D015221:Potassium Channels; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha