Direct inhibition, but indirect sensitization of pacemaker activity to sympathetic tone by the interaction of endotoxin with HCN-channels.
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.
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Henning
H
Ebelt
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Isabel
I
Geißler
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Sara
S
Ruccius
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Volker
V
Otto
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Sophie
S
Hoffmann
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Heinrich
H
Korth
Julius-Bernstein-Institute of Physiology, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
Udo
U
Klöckner
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Ying
Y
Zhang
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Yi
Y
Li
Julius-Bernstein-Institute of Physiology, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
Claudia
C
Grossmann
Julius-Bernstein-Institute of Physiology, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
Uwe
U
Rueckschloss
Julius-Bernstein-Institute of Physiology, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
Michael
M
Gekle
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen, Erlangen, Germany.
Juliane
J
Stieber
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Stefan
S
Frantz
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Karl
K
Werdan
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.|Chair of Geriatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Ursula
U
Müller-Werdan
Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Harald
H
Loppnow
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism*; D000077550:Ivabradine; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology* / Q000503:physiopathology; D013610:Tachycardia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
D001552:Benzazepines; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008070:Lipopolysaccharides; D000077550:Ivabradine
HCN-channels; autonomic blockade; beating-rate; endotoxin; gene deficient mice; heart cells; heart-rate; ivabradine; neonatal rat cardiomyocytes; sepsis