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Direct inhibition, but indirect sensitization of pacemaker activity to sympathetic tone by the interaction of endotoxin with HCN ‐channels
Author(s) -
Ebelt Henning,
Geißler Isabel,
Ruccius Sara,
Otto Volker,
Hoffmann Sophie,
Korth Heinrich,
Klöckner Udo,
Zhang Ying,
Li Yi,
Grossmann Claudia,
Rueckschloss Uwe,
Gekle Michael,
Stieber Juliane,
Frantz Stefan,
Werdan Karl,
MüllerWerdan Ursula,
Loppnow Harald
Publication year - 2015
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12415
Subject(s) - ivabradine , heart rate , nifedipine , chemistry , pharmacology , propranolol , atropine , verapamil , endocrinology , channel blocker , in vivo , medicine , potassium channel blocker , sinoatrial node , potassium channel , calcium , blood pressure , biology , microbiology and biotechnology
Summary 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 CD 1‐mice with and without autonomic blockade is analyzed telemetrically. LPS (100 ng/mL) and ivabradine (5 μ g/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 CD 1‐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.