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Updated: Oct 28, 2025
Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System
Published on: May 22, 2018
In cardiac muscle cells, both adrenergic agonists and antagonists induce reactive oxygen species from NOX2 but
Anamika Prasad1, Amena Mahmood2, Richa Gupta1
1School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India.
Abstract:
In cardiac muscle cells adrenergic agonists stimulate the generation of reactive oxygen species, followed by redox signaling. We postulated that the antagonists would attenuate such reactive oxygen species generation by the agonists. H9c2 cardiac myoblasts, neonatal rat cardiac myocytes, and HEK293 cells expressing β1/β2 adrenoceptors were stimulated with several agonists and antagonists. All the agonists and antagonists independently generated reactive oxygen species; but its generation was minimum whenever an agonists was added together with an antagonist. We monitored the Ca++ signaling in the treated cells and obtained similar results. In all treatment sets, superoxide and H2O2 were generated in the mitochondria and the cytosol respectively. NOX2 inhibitor gp91ds-tat blocked reactive oxygen species generation by both the agonists and the antagonists. The level of p47phox subunit of NOX2 rapidly increased upon treatment, and it translocated to the plasma membrane, confirming NOX2 activation. Inhibitor studies showed that the activation of NOX2 involves ERK, PI3K, and tyrosine kinases. Recombinant promoter-reporter assays showed that reactive oxygen species generated by both the agonists and antagonists modulated downstream gene expression. Mice injected with the β-adrenergic agonist isoproterenol and fed with the antagonist metoprolol showed a robust induction of p47phox in the heart. We conclude that both the agonism and antagonism of adrenoceptors initiate redox signaling but when added together, they mutually counteract each other's effects. Our study thus highlights the importance of reactive oxygen species in adrenoceptor agonism and antagonism with relevance to the therapeutic use of the β blockers.
Insights
Both beta-adrenergic agonists and antagonists generate reactive oxygen species (ROS) in cardiac cells. When combined, they counteract each other
Area of Science:
- Cardiovascular Physiology
- Cellular Redox Signaling
- Pharmacology
Background:
- Adrenergic agonists stimulate reactive oxygen species (ROS) generation in cardiac cells, initiating redox signaling pathways.
- The role of adrenergic antagonists in modulating agonist-induced ROS generation and subsequent signaling was investigated.
Purpose of the Study:
- To investigate the effects of adrenergic agonists and antagonists on reactive oxygen species (ROS) generation in cardiac cells.
- To elucidate the underlying mechanisms of NOX2 activation and its role in adrenoceptor-mediated redox signaling.
- To assess the impact of combined agonist and antagonist treatment on ROS production and downstream gene expression.
Main Methods:
- Experiments were conducted on H9c2 cardiac myoblasts, neonatal rat cardiac myocytes, and HEK293 cells expressing β1/β2 adrenoceptors.
- Cells were stimulated with various adrenergic agonists and antagonists, and ROS generation was measured.
- NOX2 activation, p47phox translocation, Ca++ signaling, and downstream gene expression were analyzed using inhibitors and reporter assays. In vivo studies in mice were also performed.
Main Results:
- Both adrenergic agonists and antagonists independently generated ROS, with minimal generation observed when used together.
- NOX2 activation, involving p47phox translocation, was confirmed as the source of ROS, and its activation was dependent on ERK, PI3K, and tyrosine kinases.
- ROS modulated downstream gene expression, and in vivo studies showed p47phox induction in the heart upon combined agonist and antagonist administration.
Conclusions:
- Both adrenoceptor agonism and antagonism initiate redox signaling, but their combined application leads to mutual counteraction of ROS generation.
- This study highlights the critical role of ROS in adrenoceptor agonism and antagonism.
- Findings have implications for the therapeutic use of beta-blockers, suggesting a complex interplay in their effects on cardiac redox signaling.
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