title: Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action.
abstract: Midazolam is a short-acting benzodiazepine that is widely used in anesthesia. Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking. Using the double-electrode voltage clamp technique, we studied pharmacological effects of midazolam on heterologously expressed Kv1.5 channels underlying atrial repolarizing current I(Kur). Midazolam dose-dependently inhibited Kv1.5 current, yielding an IC50 of 17 μM in an HEK cell line and an IC50 of 104 μM in Xenopus oocytes. We further showed that midazolam did not affect the half-maximal activation voltage of Kv1.5 channels. However, a small negative shift of the inactivation curve could be observed. Midazolam acted as a typical open-channel inhibitor with rapid onset of block and without frequency dependence of block. Taken together, midazolam is an open channel inhibitor of cardiac Kv1.5 channels. These data add to the current understanding of the pharmacological profile of midazolam.
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Vonderlin
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Fathima
authors.initials: F
authors.lastname: Fischer
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany ; German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zitron
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Seyler
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherer
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany ; German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany ; German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
mesh_terms: D000777:Anesthetics / Q000008:administration & dosage / Q000494:pharmacology*; D004553:Electric Conductivity; D057809:HEK293 Cells; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*
chemical_list: D000777:Anesthetics; D051666:Kv1.5 Potassium Channel; D008874:Midazolam; D011188:Potassium
keywords: anesthetics; pharmacology; potassium channels