Direct inhibition, but indirect sensitization of pacemaker activity to sympathetic tone by the interaction of endotoxin with HCN-channels

Clin Exp Pharmacol Physiol. 2015 Aug;42(8):874-80. doi: 10.1111/1440-1681.12415.

Abstract

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.

Keywords: HCN-channels; autonomic blockade; beating-rate; endotoxin; gene deficient mice; heart cells; heart-rate; ivabradine; neonatal rat cardiomyocytes; sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • Heart Rate / drug effects
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism*
  • Ivabradine
  • Lipopolysaccharides / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mice
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Rats
  • Sympathetic Nervous System / drug effects*
  • Sympathetic Nervous System / physiology*
  • Sympathetic Nervous System / physiopathology
  • Tachycardia / chemically induced
  • Tachycardia / metabolism
  • Tachycardia / physiopathology

Substances

  • Benzazepines
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Lipopolysaccharides
  • Ivabradine