title: Mechanism of the negative inotropic effect of midazolam and diazepam in cultured foetal mouse cardiac myocytes.
abstract: We have investigated the effects of midazolam and diazepam on intracellular calcium (Ca2+) handling in foetal mouse ventricular myocytes using the Ca(2+)-sensitive fluorescent indicator, indo-1. We also investigated separately whether flumazenil or the L-type Ca2+ channel agonist, Bay K8644, antagonized these myocardial depressive effects. Midazolam and diazepam decreased the Ca2+ transient and beating rate in a concentration-dependent manner, and these decreases were prevented by Bay K8644. Flumazenil did not antagonize the myocardial depressive effects. In myocytes whose sarcoplasmic reticulum was inhibited by ryanodine, midazolam and diazepam had the same potent cardiodepressive effects. Midazolam and diazepam are direct cardiac depressants, which decrease the Ca2+ transient and beating rate, and the L-type Ca2+ channel is important in the negative inotropism and chronotropism caused by these drugs.
authors.affiliation: Department of Anaesthesiology, Yamanashi Medical University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nonaka
authors.forename: S
authors.initials: S
authors.lastname: Kashimoto
authors.forename: M
authors.initials: M
authors.lastname: Imamura
authors.forename: A
authors.initials: A
authors.lastname: Furuya
authors.forename: T
authors.initials: T
authors.lastname: Kumazawa
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002478:Cells, Cultured; D003864:Depression, Chemical; D003975:Diazepam / Q000494:pharmacology*; D005260:Female; D005318:Fetal Heart / Q000166:cytology / Q000378:metabolism*; D005442:Flumazenil / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006340:Heart Rate, Fetal / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008874:Midazolam / Q000494:pharmacology*; D011247:Pregnancy; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D002120:Calcium Channel Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D012433:Ryanodine; D005442:Flumazenil; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D003975:Diazepam; D008874:Midazolam; D002118:Calcium