Endotoxin impairs the human pacemaker current If.
LPSs trigger the development of sepsis by gram-negative bacteria and cause a variety of biological effects on host cells, including alterations on ionic channels. Because heart rate variability is reduced in human sepsis and endotoxemia, we hypothesized that LPS affects the pacemaker current I(f) in human heart, which might--at least in part--explain this phenomenon. Isolated human myocytes from right atrial appendages were incubated for 6 to 10 h with LPS (1 and 10 microg/mL) and afterwards used to investigate the pacemaker current I(f). I(f) was measured with the whole-cell patch-clamp technique (at 37 degrees C). Incubation of atrial myocytes with 10 microg/mL LPS was found to significantly impair I(f) by suppressing the current at membrane potentials positive to -80 mV and slowing down current activation, but without effecting maximal current conductance. Furthermore, in incubated cells (10 microg/mL), the response of I(f) to [beta]-adrenergic stimulation (1 microM isoproterenol) was significantly larger compared with control cells (shift of half-maximal activation voltage to more positive potentials amounted to -10 and -14 mV in untreated and treated cells, respectively). Simulations using a spontaneously active sinoatrial cell model demonstrated that LPS-induced I(f) impairment reduced the responsiveness of the model cell to fluctuations of autonomic input. This study showed a direct impact of LPS on the cardiac pacemaker current I(f). The LPS-induced I(f) impairment may contribute to the clinically observed reduction in heart rate variability under septic conditions and in cardiac diseases such as heart failure, where endotoxin can be of pathophysiological relevance.
Zorn-Pauly
Klaus
K
Institut für Biophysik, Zentrum für Physiologische Medizin, Medizinische Universität Graz, Harrachgasse 21, Graz, Austria.
Pelzmann
Brigitte
B
Lang
Petra
P
Mächler
Heinrich
H
Schmidt
Hendrik
H
Ebelt
Henning
H
Werdan
Karl
K
Koidl
Bernd
B
Müller-Werdan
Ursula
U
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D018805:Sepsis / Q000473:pathology / Q000503:physiopathology
D007473:Ion Channels; D008070:Lipopolysaccharides; D007545:Isoproterenol