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Interaction of bacterial endotoxin (lipopolysaccharide, <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>) with hyperpolarization\u2010activated cyclic nucleotide\u2010gated cation\u2010(<jats:styled-content style=\"fixed-case\">HCN<\/jats:styled-content>)\u2010channels may interfere with heart\u2010rate regulation. This study analyzes the effect of <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content>, the <jats:styled-content style=\"fixed-case\">HCN<\/jats:styled-content>\u2010channel blocker ivabradine or Ca<jats:sup>2+<\/jats:sup>\u2010channel blockers (nifedipine, verapamil) on pacemaking in spontaneously beating neonatal rat cardiomyocytes (<jats:styled-content style=\"fixed-case\">CM<\/jats:styled-content>) <jats:italic>in\u00a0vitro<\/jats:italic>. <jats:italic>In vivo<\/jats:italic>, the effect of <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> on the heart\u2010rate of adult <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>1\u2010mice with and without autonomic blockade is analyzed telemetrically. <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> (100\u00a0ng\/mL) and ivabradine (5\u00a0<jats:italic>\u03bc<\/jats:italic>g\/mL) reduced the beating\u2010rate of <jats:styled-content style=\"fixed-case\">CM<\/jats:styled-content> by 20.1% and 24.6%, respectively. Coincubation of <jats:styled-content style=\"fixed-case\">CM<\/jats:styled-content> with both, <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> and ivabradine, did not further reduce the beating\u2010rate, indicating interaction of both compounds with <jats:styled-content style=\"fixed-case\">HCN<\/jats:styled-content>\u2010channels, while coincubation with Ca<jats:sup>2+<\/jats:sup>\u2010channel blockers and <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> caused additive beating\u2010rate reduction. In <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>1\u2010mice (containing an active autonomic\u2010nervous\u2010system), injection of <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> (0.4\u00a0mg\/kg) expectedly resulted in increased heart\u2010rate. However, if the autonomic nervous system was blocked by propranolol and atropine, in line with the <jats:italic>in\u00a0vitro<\/jats:italic> data, <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> induced a significant reduction of heart\u2010rate, which was not additive to ivabradine. The <jats:italic>in\u00a0vivo<\/jats:italic> and <jats:italic>in\u00a0vitro<\/jats:italic> results indicate that LPS interacts with <jats:styled-content style=\"fixed-case\">HCN<\/jats:styled-content>\u2010channels of cardiomyocytes. Thus, <jats:styled-content style=\"fixed-case\">LPS<\/jats:styled-content> indirectly sensitizes <jats:styled-content style=\"fixed-case\">HCN<\/jats:styled-content>\u2010channels for sympathetic activation (tachycardic\u2010effect), and in parallel directly inhibits channel activity (bradycardic\u2010effect). Both effects may contribute to the detrimental effects of septic cardiomyopathy and septic autonomic dysfunction.<\/jats:p>","DOI":"10.1111\/1440-1681.12415","type":"journal-article","created":{"date-parts":[[2015,4,30]],"date-time":"2015-04-30T11:32:09Z","timestamp":1430393529000},"page":"874-880","source":"Crossref","is-referenced-by-count":10,"title":["Direct inhibition, but indirect sensitization of pacemaker activity to sympathetic tone by the interaction of endotoxin with <scp>HCN<\/scp>\u2010channels"],"prefix":"10.1111","volume":"42","author":[{"given":"Henning","family":"Ebelt","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III Martin Luther University Halle\u2010Wittenberg Halle (Saale) Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Gei\u00dfler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III Martin Luther University Halle\u2010Wittenberg Halle (Saale) 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