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Correlation between cardiac oxidative stress and myocardial pathology due to acute and chronic norepinephrine
Margherita Neri1, Daniela Cerretani, Anna Ida Fiaschi
1Department of Forensic Pathology, University of Foggia, Italy.
Background:
To investigate the cardiotoxic role of reactive oxygen species (ROS) and of products derived from catecholamines auto-oxidation, we studied: (1) the response of antioxidant cardiac cellular defence systems to oxidative stress induced by norepinephrine (NE) administration, (2) the effect of NE administration on cardiac beta1-adrenergic receptors by means of receptor binding assay, (3) the cellular morphological alterations related to the biologically cross-talk between the NE administration and cytokines [tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), interleukins IL6, IL8, IL10].
Methods And Results:
A total of 195 male rats was used in the experiment. All animals underwent electrocardiogram (EKG) before being sacrificed. The results obtained show that NE administration influences the antioxidant cellular defence system significantly increasing glutathione peroxidase (GPx) activity, glutathione reductase (GR) and superoxide dismutase (SOD). The oxidized glutathione (GSH/GSSG) ratio significantly decreases and malondialdehyde (MDA) levels increase showing a state of lipoperoxidation of cardiac tissue. We describe a significant apoptotic process randomly sparse in the damaged myocardium and the effect of ROS on the NE-mediated TNF-alpha, MCP-1, and IL6, IL8, IL10 production.
Conclusions:
Our results support the hypothesis that catecholamines may induce oxidative damage through reactive intermediates resulting from their auto-oxidation, irrespective of their interaction with adrenergic receptors, thus representing an important factor in the pathogenesis of catecholamines-induced cardiotoxicity. The rise of the cardioinhibitory cytokines may be interpreted as the adaptive response of jeopardized myocardium with respect to the cardiac dysfunction resulting from NE injection.
Insights
Norepinephrine (NE) induces cardiotoxicity via reactive oxygen species (ROS) and catecholamine auto-oxidation products, independent of adrenergic receptors. This oxidative damage contributes to heart dysfunction and triggers an adaptive cytokine response.
Area of Science:
- Cardiology
- Toxicology
- Biochemistry
Background:
- Investigating the cardiotoxic effects of reactive oxygen species (ROS) and catecholamine auto-oxidation products.
- Examining antioxidant defense systems' response to norepinephrine (NE)-induced oxidative stress.
- Assessing NE's impact on cardiac beta1-adrenergic receptors and cellular morphology.
Purpose of the Study:
- To elucidate the role of ROS and catecholamine auto-oxidation in cardiotoxicity.
- To understand the interplay between NE, oxidative stress, and cardiac cytokine production.
- To determine if NE-induced cardiotoxicity is mediated through adrenergic receptors.
Main Methods:
- Utilized 195 male rats, electrocardiograms (EKG), and biochemical assays.
- Measured antioxidant enzyme activities (GPx, GR, SOD), glutathione redox state (GSH/GSSG), and malondialdehyde (MDA) levels.
- Analyzed NE-mediated effects on cytokines (TNF-alpha, MCP-1, IL6, IL8, IL10) and observed cellular morphology.
Main Results:
- NE administration significantly increased antioxidant enzyme activity and lipoperoxidation (MDA levels).
- Observed a decreased GSH/GSSG ratio, indicating oxidative stress, and apoptotic processes in the myocardium.
- Demonstrated NE-induced production of TNF-alpha, MCP-1, IL6, IL8, and IL10, influenced by ROS.
Conclusions:
- Catecholamines induce oxidative damage via auto-oxidation intermediates, contributing to cardiotoxicity independently of adrenergic receptor interaction.
- The observed increase in cardioinhibitory cytokines represents an adaptive response to NE-induced myocardial dysfunction.
- Findings highlight a novel mechanism in catecholamine-induced cardiotoxicity involving ROS and cytokine signaling.
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