Key Takeaways & Executive Findings
- •• Arsenic exposure significantly impairs myocardial perfusion and induces cardiac dysfunction in rats, as evidenced by reduced WIS and WIS × PI on myocardial contrast echocardiography. • Dantrolene treatment, particularly at high dose, effectively mitigates arsenic-induced myocardial injury and improves cardiac perfusion parameters. • The cardioprotective mechanism of dantrolene is attributed to its stabilization of RyR2, preventing pathological calcium leakage in cardiac myocytes. • These findings suggest dantrolene as a potential therapeutic agent for arsenic cardiotoxicity, warranting further clinical investigation.
Abstract
Arsenic, a toxic metalloid, exists in organic or inorganic states within the Earth’s seawater, river water, soil, atmosphere, food sources, and diverse biological tissues [1]. It poses a threat to the health of hundreds of millions of people globally [2]. Arsenic exposure has toxic effects on the cardiovascular system of organisms, thus endangering human health [3]. Research has indicated that the harmful effect of arsenic exposure on the heart is associated with abnormal calcium handling in myocardial cells [4]. The cardiac ryanodine receptor type 2 (RyR2) is a primary channel involved in the surface of the endoplasmic reticulum in cardiac myocytes that regulates the release of Ca2+ during the systolic phase [5]. The integrity of its function is crucial for maintaining calcium homeostasis in cardiac myocytes. However, when myocardial tissue is damaged and undergoes pathological changes, the spatial structure of the RyR2 protein becomes unstable and becomes excessively activated, thereby triggering Ca2+ leakage [6]. Dantrolene (Dan), which serves as a stabilizer of RyR1, is frequently employed in clinical settings for the treatment of malignant hyperpyrexia and relieves spastic muscle tension [7]. Previous studies have demonstrated that dantrolene also has a stabilizing effect on RyR2 [8]. Research has shown that dantrolene can prevent calcium leakage in myocardial cells by stabilizing the tertiary structure of the RyR2 protein and thereby inhibiting the pathological hyperactivity of RyR2 [9]. Therefore, this study hypothesizes that dantrolene, by virtue of this stabilizing effect, can alleviate myocardial injury caused by arsenic exposure to some extent and plays a role in protecting cardiac function. For this purpose, we established an arsenic exposure model and a Dan intervention arsenic exposure model to verify the protective effect of Dan on the myocardial tissue and cardiac function of arsenic-exposed rats.
1. Introduction
Arsenic, a toxic metalloid, exists in organic or inorganic states within the Earth’s seawater, river water, soil, atmosphere, food sources, and diverse biological tissues [1]. It poses a threat to the health of hundreds of millions of people globally [2]. Arsenic exposure has toxic effects on the cardiovascular system of organisms, thus endangering human health [3]. Research has indicated that the harmful effect of arsenic exposure on the heart is associated with abnormal calcium handling in myocardial cells [4].
The cardiac ryanodine receptor type 2 (RyR2) is a primary channel involved in the surface of the endoplasmic reticulum in cardiac myocytes that regulates the release of Ca2+ during the systolic phase [5]. The integrity of its function is crucial for maintaining calcium homeostasis in cardiac myocytes. However, when myocardial tissue is damaged and undergoes pathological changes, the spatial structure of the RyR2 protein becomes unstable and becomes excessively activated, thereby triggering Ca2+ leakage [6]. Dantrolene (Dan), which serves as a stabilizer of RyR1, is frequently employed in clinical settings for the treatment of malignant hyperpyrexia and relieves spastic muscle tension [7]. Previous studies have demonstrated that dantrolene also has a stabilizing effect on RyR2 [8]. Research has shown that dantrolene can prevent calcium leakage in myocardial cells by stabilizing the tertiary structure of the RyR2 protein and thereby inhibiting the pathological hyperactivity of RyR2 [9]. Therefore, this study hypothesizes that dantrolene, by virtue of this stabilizing effect, can alleviate myocardial injury caused by arsenic exposure to some extent and plays a role in protecting cardiac function.
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Chuncui Chen, Ruoxi Chen, Xueting Guo, Lei Huang, Kuican Liu, Wenrong Shi, Caiyun Zhang, Kunxuan Liu, Huan Liu, Shanshan Dong, Guilin Lu, Wenjuan Qin (2026). Investigation of the cardioprotective potential of dantrolene in mitigating arsenic-induced cardiac dysfunction in rats. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025193
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that dantrolene can mitigate arsenic-induced cardiac dysfunction in rats by stabilizing RyR2 and preventing calcium leakage, thereby improving myocardial perfusion.
How was cardiac function assessed in the rats?
Cardiac function was assessed using myocardial contrast echocardiography (MCE) to measure parameters such as peak intensity (PI), wash-in slope (WIS), WIS × PI, and area under the curve (AUC), along with serum markers of myocardial injury.
What is the significance of RyR2 in arsenic cardiotoxicity?
Arsenic exposure leads to abnormal calcium handling in cardiac myocytes, partly due to instability and hyperactivity of RyR2, which causes calcium leakage and contributes to myocardial injury.
What doses of dantrolene were used in this study?
Rats received dantrolene at doses of 5 mg/kg/day (low-dose) and 10 mg/kg/day (high-dose) for 7 consecutive days after arsenic exposure.
What are the clinical implications of this research?
The findings suggest that dantrolene, already used clinically for malignant hyperthermia, could be repurposed as a therapeutic agent to protect against arsenic-induced cardiac damage, though further studies are needed.
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