Key result
LPS reduced the beating-rate of cardiomyocytes by 20.1% in vitro, indicating direct inhibition of HCN-channels, while indirectly sensitizing them to sympathetic activation in vivo.
Why the study?
Does bacterial endotoxin (LPS) interact with HCN-channels to affect pacemaker activity in cardiomyocytes and mice?
Does bacterial endotoxin (LPS) interact with HCN-channels to affect pacemaker activity in cardiomyocytes and mice?
Absolute Event Rate: 20.1% vs 24.6%
LPS interacts directly with HCN-channels to inhibit pacemaker activity while indirectly sensitizing them to sympathetic activation, which may contribute to septic autonomic dysfunction.
In critically ill patients regulation of heart-rate is often severely disturbed. Interaction of bacterial endotoxin (lipopolysaccharide, LPS) with hyperpolarization-activated cyclic nucleotide-gated cation-(HCN)-channels may interfere with heart-rate regulation. This study analyzes the effect of LPS, the HCN-channel blocker ivabradine or Ca(2+) -channel blockers (nifedipine, verapamil) on pacemaking in spontaneously beating neonatal rat cardiomyocytes (CM) in vitro. In vivo, the effect of LPS on the heart-rate of adult CD1-mice with and without autonomic blockade is analyzed telemetrically. LPS (100 ng/mL) and ivabradine (5 μg/mL) reduced the beating-rate of CM by 20.1% and 24.6%, respectively. Coincubation of CM with both, LPS and ivabradine, did not further reduce the beating-rate, indicating interaction of both compounds with HCN-channels, while coincubation with Ca(2+) -channel blockers and LPS caused additive beating-rate reduction. In CD1-mice (containing an active autonomic-nervous-system), injection of LPS (0.4 mg/kg) expectedly resulted in increased heart-rate. However, if the autonomic nervous system was blocked by propranolol and atropine, in line with the in vitro data, LPS induced a significant reduction of heart-rate, which was not additive to ivabradine. The in vivo and in vitro results indicate that LPS interacts with HCN-channels of cardiomyocytes. Thus, LPS indirectly sensitizes HCN-channels for sympathetic activation (tachycardic-effect), and in parallel directly inhibits channel activity (bradycardic-effect). Both effects may contribute to the detrimental effects of septic cardiomyopathy and septic autonomic dysfunction.
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Ebelt et al. (2015) studied Septic cardiomyopathy and autonomic dysfunction. Bacterial endotoxin (LPS) vs. Ivabradine, Ca(2+)-channel blockers, or autonomic blockade was evaluated on Beating-rate of cardiomyocytes / heart-rate. LPS reduced the beating-rate of cardiomyocytes by 20.1% in vitro, indicating direct inhibition of HCN-channels, while indirectly sensitizing them to sympathetic activation in vivo.
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