title: Itraconazole decreases left ventricular contractility in isolated rabbit heart: mechanism of action.
abstract: Itraconazole (ITZ) is an approved antifungal agent that carries a "black box warning" in its label regarding a risk of negative cardiac inotropy based on clinical findings. Since the mechanism of the negative inotropic effect is unknown, we performed a variety of preclinical and mechanistic studies to explore the pharmacological profile of ITZ and understand the negative inotropic mechanism. ITZ was evaluated in: (1) an isolated rabbit heart (IRH) preparation using Langendorff retrograde perfusion; (2) ion channel studies; (3) a rat heart mitochondrial function profiling screen; (4) a mitochondrial membrane potential (MMP) assay; (5) in vitro pharmacology profiling assays (148 receptors, ion channels, transporters, and enzymes); and (6) a kinase selectivity panel (451 kinases). In the IRH, ITZ decreased cardiac contractility (>30%) at 0.3μM, with increasing effect at higher concentrations, which indicated a direct negative inotropic effect upon the heart. It also decreased heart rate and coronary flow (≥1μM) and prolonged PR/QRS intervals (3μM). In mechanistic studies, ITZ inhibited the cardiac NaV channel (IC50: 4.2μM) and was devoid of any functional inhibitory effect at the remaining pharmacological targets. Lastly, ITZ did not affect MMP, nor interfere with mitochondrial enzymes or processes involved with fuel substrate utilization or energy formation. Overall, the cardiovascular and mechanistic data suggest that ITZ-induced negative inotropy is a direct effect on the heart, in addition, the potential involvement of mitochondria function and L-type Ca(2+) channels are eliminated. The exact mechanism underlying the negative inotropy is uncertain, and requires further study.
authors: Toxicology Science, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. yqu@amgen.com
authors: Yusheng
authors: Y
authors: Qu
authors: Mei
authors: M
authors: Fang
authors: BaoXi
authors: B
authors: Gao
authors: Hamid R
authors: HR
authors: Amouzadeh
authors: Nianyu
authors: N
authors: Li
authors: Padma
authors: P
authors: Narayanan
authors: Paul
authors: P
authors: Acton
authors: Jeff
authors: J
authors: Lawrence
authors: Hugo M
authors: HM
authors: Vargas
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D003864:Depression, Chemical; D005260:Female; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D017964:Itraconazole / Q000494:pharmacology*; D048671:MAP Kinase Kinase 5 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000935:Antifungal Agents; D007473:Ion Channels; D017964:Itraconazole; D048671:MAP Kinase Kinase 5; C482565:Map2k5 protein, rat