Rationale: 

Recently it was shown that lipopolysaccharide (LPS) impairs pacemaker current in human atrial myocytes. It was speculated that reduced heart rate variability (HRV) as a typical finding in patients with severe sepsis can partially be explained by these interactions. However, details of such interactions are still elusive.

Objective: 

We characterized the effect of LPS on the activity of recombinant human hyperpolarization-activated, cyclic nucleotide-gated channels 2 (hHCN2) and 4 and pinpointed the structures of LPS which seemed to be a prerequisite for the interaction between these two molecules. Furthermore, we tested the hypothesis that LPS inhibits pacemaker channels in murine sino-atrial node (SAN) cells.

Methods and Results: 

HEK293 cells stably expressing hHCN2 were used to study the biophysical properties of pacemaker channels in the presence of LPS. Application of LPS caused a robust inhibition of hHCN2-induced currents owing to a negative shift of the voltage-dependence of current activation In addition, kinetics of channel gating were affected by LPS. Lipid A, which constitutes the endotoxic principle of LPS, was not responsible for these changes. However, O-antigen, part of the polysaccharide moiety of LPS, seems to be indispensable for the interaction of LPS and hHCN2. Similar observations were made in murine SAN cells and in HEK293 cells expressing hHCN4.

Conclusions: 

Our results provide new insight into mechanisms by which LPS modulates the activity of HCN channels. Most observed alterations are supposed to slow down diastolic depolarization of pacemaker cells and hence reduce HRV and the frequency of the heart beat.