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Title: Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo

Abstract

Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100 μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24 h. In this in vivo rat study (0.5 mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48 h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70 kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linkedmore » with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices. - Highlights: • Human response to isoproterenol induced cardiac injury evaluated in heart slices. • Isoproterenol altered apoptosis, energy, inflammation and remodeling pathways. • Human model verified by comparison to rat heart slices and rat heart in vivo. • Human and rat respond to isoproterenol at similar concentrations in vitro.« less

Authors:
; ; ;  [1];  [2];  [1]
  1. Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612 (United States)
  2. Vitron Inc., Tucson, AZ (United States)
Publication Date:
OSTI Identifier:
22285582
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 274; 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)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; ATP; COLLAGEN; FIBROSIS; GENES; GROWTH FACTORS; HEART; IN VIVO; INFLAMMATION; INJURIES; NECROSIS; NITRIC OXIDE; RATS

Citation Formats

Herrmann, Julia E., Heale, Jason, Bieraugel, Mike, Ramos, Meg, Fisher, Robyn L., and Vickers, Alison E.M., E-mail: vickers_alison@allergan.com. Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2013.11.011.
Herrmann, Julia E., Heale, Jason, Bieraugel, Mike, Ramos, Meg, Fisher, Robyn L., & Vickers, Alison E.M., E-mail: vickers_alison@allergan.com. Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. United States. doi:10.1016/J.TAAP.2013.11.011.
Herrmann, Julia E., Heale, Jason, Bieraugel, Mike, Ramos, Meg, Fisher, Robyn L., and Vickers, Alison E.M., E-mail: vickers_alison@allergan.com. 2014. "Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo". United States. doi:10.1016/J.TAAP.2013.11.011.
@article{osti_22285582,
title = {Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo},
author = {Herrmann, Julia E. and Heale, Jason and Bieraugel, Mike and Ramos, Meg and Fisher, Robyn L. and Vickers, Alison E.M., E-mail: vickers_alison@allergan.com},
abstractNote = {Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100 μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24 h. In this in vivo rat study (0.5 mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48 h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70 kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices. - Highlights: • Human response to isoproterenol induced cardiac injury evaluated in heart slices. • Isoproterenol altered apoptosis, energy, inflammation and remodeling pathways. • Human model verified by comparison to rat heart slices and rat heart in vivo. • Human and rat respond to isoproterenol at similar concentrations in vitro.},
doi = {10.1016/J.TAAP.2013.11.011},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 274,
place = {United States},
year = 2014,
month = 1
}
  • Isoproterenol, a potent B-adrenergic receptor agonist, has been known to produce infarct-like myocardial lesions in rats characterized by swelling of endoplasmic reticulum. The swelling of this system is interpreted as an influx of large amount of extracellular fluid into myocardial cells by disturbances of the electrolyte metabolism. Isoproterenol is employed clinically as a bronchodilator in respiratory disorders and as a stimulant in heart block and cardiogenic shocks. In spite of its clinical use, possible drug-chemical interactions leading to adverse health effects are obvious when individuals on a regular isoproterenol treatment are exposed to an environmental contaminant such as methyl mercury.more » Consumption of fish and fish products is by far the most significant route of exposure to environmental mercury. In spite of such a possibility, little is know about isoproterenol-methyl mercury interaction. The present study forms the first of this kind to report such interactions and their effects on cardiac membrane bound enzymes such as Na/sup +/ -K/sup +/ and Ca/sup 2 +/-ATPases. Since Na/sup +/-K/sup +/ATPase has been implicated in uptake and release processes of catecholamines, the effects were also studied on /sup 3/H-dopamine uptake by sarcoplasmic reticulum. As a prelude to these proposed long-term chronic studies with non-lethal doses in the present report only single and sub-lethal doses were used for a shorter (48h) duration.« less
  • The tumor promoter 12-O-tetradecanoylphorbol-13-acetate and the antileukemic agent mezerein are diterpene esters of plant origin with certain structural similarities. Both compounds, when applied topically to mouse skin, were equipotent on a molar basis in inducing hyperplasia, inflammation, and ornithine decarboxylase activity, as well as in reducing cyclic adenosine 3':5-monophosphate accumulation in response to ..beta..-adrenergic stimulation. In contrast, mezerein was much less effective as a tumor promoter; the phorbol ester at 8.5 nmol/application yielded 78-fold more tumors than did 8.5 nmol mezerein per application to similarly initiated SENCAR mice. The superiority of the phorbol ester was nearly as great in CD-1more » mice. These results suggest that although the induction of hyperplasia and ornithine decarboxylase activity may be necessary components of the carcinogenic process, they are not sufficient; 12-O-tetradecanoylphorbol-13-acetate must accomplish an essential event not accomplished by mezerein.« less
  • IL 1 and IL 6 share a number of biological activities, including induction of fever, neutrophilia and acute phase response, and IL 1 induces IL 6 production by fibroblasts and macrophages. Therefore, it was proposed that IL 6 mediates many of the activities of IL 1. To test this hypothesis in vivo, we assessed induction of IL 6 following IL 1 alpha administration to mice and tested IL 6 for radioprotection and induction of early (CSF) and late (fibrinogen and SAA) acute phase reactants. IL 1 alpha given to mice ip induced, in a dose dependent manner, detectable IL 6more » in circulation, with maximal titers at 2-4 hrs. However, unlike IL 1 which is 10-1000 ng/mouse of human recombinant IL 6 did not result in increased survival of mice following lethal irradiation. In fact, such treatment given 20 hrs before LD50/30 doses of radiation resulted in reduced survival of mice. However, IL 6 augmented the radioprotective effect of IL 1. IL 1 in doses above 10 ng/mouse induced within 2 to 6 hrs a dose dependent increase in CSF in circulation, but IL 6 did not induce detectable levels of CSF at 2, 6 and 20 hrs after administration. Administration of IL 6 to mice produced a dose dependent increase in circulating fibrinogen and SAA. Similarly, administration of IL 1 resulted in much greater increases in levels of fibrinogen and SAA. Therefore, IL 1 is a more effective inducer of fibrinogen and SAA in mice than is IL 6. Although definitive conclusions concerning the relative roles for IL 1 and IL 6 in vivo will await availability of anti IL 1 and anti-IL 6 antibodies, our data do not support the suggestion that the above IL 1 effects can be attributed solely to IL 6.« less
  • Extraneuronal accumulation of isoproterenol in atria and ventricle of perfused rat heart was investigated. Rat hearts were perfused with various concentrations of /sup 3/H-isoproterenol for 30 min in the absence and the presence of catechol-O-methyltransferase (COMT) inhibitor (tropolone). When COMT was intact, the accumulation of /sup 3/H-isoproterenol in both atria and ventricle after perfusion with low concentration of /sup 3/H-isopreterenol was less than that of perfusing concentration; the tissue/medium ratio (T/M) of isoproterenol for atria was lower than that for ventricle. The T/M of isoproterenol after perfusion with 10 and 20 ..mu..mol/1 of /sup 3/H-isoproterenol were 0.94 and 1.76 formore » atria and 3.25 and 2.95 for ventricle, respectively. When COMT was inhibited by tropolone, the T/M increased 6.3 - 9.0 folds for atria and 5.1 - 6.7 folds for ventricle after perfusion with /sup 3/H-isoproterenol. From these results, it was concluded that both atria and ventricle of the rat heart have an extraneuronal O-methylating system as reported in rat whole heart, and was suggested that there might be different capacities of extraneuronal uptake and COMT between them. 10 references, 1 figure.« less