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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 0.3 μM, with increasing effect at higher concentrations, which indicated a direct negative inotropic effect upon the heart. It also decreased heart rate and coronary flow (≥ 1 μM) and prolonged PR/QRS intervals (3 μM). In mechanistic studies, ITZ inhibited the cardiac NaV channel (IC{sub 50}: 4.2 μM) 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 withmore » 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{sup 2+} channels are eliminated. The exact mechanism underlying the negative inotropy is uncertain, and requires further study. - Highlights: ► Effect of itraconazole (ITZ) was assessed in the isolated rabbit heart (IRH) assay. ► ITZ decreased ventricular contractility in IRH, indicating a direct effect. ► IC{sub 50} of ITZ on L-type I{sub Ca} was greater than 30 μM, on I{sub Na} was 4.2 μM. ► ITZ had minimal effects on mitochondrial functions. ► ITZ had minimal hits in pharmacology profiling and kinase selectivity panel.« less

Authors:
 [1]; ; ;  [1]; ;  [2]; ; ;  [1]
  1. Toxicology Science, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320 (United States)
  2. Discovery Toxicology, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320 (United States)
Publication Date:
OSTI Identifier:
22285266
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 268; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CORONARIES; ENZYMES; HEART; IN VITRO; MEMBRANES; MITOCHONDRIA; PHARMACOLOGY; RABBITS; RATS; RECEPTORS

Citation Formats

Qu, Yusheng, Fang, Mei, Gao, BaoXi, Amouzadeh, Hamid R., Li, Nianyu, Narayanan, Padma, Acton, Paul, Lawrence, Jeff, and Vargas, Hugo M. Itraconazole decreases left ventricular contractility in isolated rabbit heart: Mechanism of action. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.01.029.
Qu, Yusheng, Fang, Mei, Gao, BaoXi, Amouzadeh, Hamid R., Li, Nianyu, Narayanan, Padma, Acton, Paul, Lawrence, Jeff, & Vargas, Hugo M. Itraconazole decreases left ventricular contractility in isolated rabbit heart: Mechanism of action. United States. https://doi.org/10.1016/J.TAAP.2013.01.029
Qu, Yusheng, Fang, Mei, Gao, BaoXi, Amouzadeh, Hamid R., Li, Nianyu, Narayanan, Padma, Acton, Paul, Lawrence, Jeff, and Vargas, Hugo M. 2013. "Itraconazole decreases left ventricular contractility in isolated rabbit heart: Mechanism of action". United States. https://doi.org/10.1016/J.TAAP.2013.01.029.
@article{osti_22285266,
title = {Itraconazole decreases left ventricular contractility in isolated rabbit heart: Mechanism of action},
author = {Qu, Yusheng and Fang, Mei and Gao, BaoXi and Amouzadeh, Hamid R. and Li, Nianyu and Narayanan, Padma and Acton, Paul and Lawrence, Jeff and Vargas, Hugo M.},
abstractNote = {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 0.3 μM, with increasing effect at higher concentrations, which indicated a direct negative inotropic effect upon the heart. It also decreased heart rate and coronary flow (≥ 1 μM) and prolonged PR/QRS intervals (3 μM). In mechanistic studies, ITZ inhibited the cardiac NaV channel (IC{sub 50}: 4.2 μM) 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{sup 2+} channels are eliminated. The exact mechanism underlying the negative inotropy is uncertain, and requires further study. - Highlights: ► Effect of itraconazole (ITZ) was assessed in the isolated rabbit heart (IRH) assay. ► ITZ decreased ventricular contractility in IRH, indicating a direct effect. ► IC{sub 50} of ITZ on L-type I{sub Ca} was greater than 30 μM, on I{sub Na} was 4.2 μM. ► ITZ had minimal effects on mitochondrial functions. ► ITZ had minimal hits in pharmacology profiling and kinase selectivity panel.},
doi = {10.1016/J.TAAP.2013.01.029},
url = {https://www.osti.gov/biblio/22285266}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 268,
place = {United States},
year = {Mon Apr 15 00:00:00 EDT 2013},
month = {Mon Apr 15 00:00:00 EDT 2013}
}