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Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats
Chih-Chin Shih1,2, Hiong-Ping Hii3, Cheng-Ming Tsao4
1Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, R.O.C., Taiwan.
Abstract:
Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.
Insights
Procainamide, an antiarrhythmic drug, treats rhabdomyolysis by inhibiting DNA methyltransferase 1 (DNMT1) and reducing inflammation. This study shows procainamide improves muscle damage, kidney function, and metabolic issues in rats with lipopolysaccharide-induced rhabdomyolysis.
Area of Science:
- Biochemistry
- Pharmacology
- Pathophysiology
Background:
- Systemic inflammation predisposes to skeletal muscle damage and rhabdomyolysis.
- Aberrant DNA methylation is implicated in excessive inflammatory responses.
- Procainamide inhibits DNA methyltransferase 1 (DNMT1), a key enzyme in DNA methylation.
Purpose of the Study:
- To investigate the therapeutic effects of procainamide on lipopolysaccharide (LPS)-induced rhabdomyolysis in rats.
- To explore the role of DNMT1 and interleukin-6 (IL-6) in the pathophysiology of rhabdomyolysis.
Main Methods:
- Rhabdomyolysis was induced in rats using LPS infusion.
- Procainamide (50 mg/kg) or hydralazine was administered.
- Hemodynamics, muscle injury, kidney function, blood parameters, and IL-6 levels were assessed.
- Lung tissue was analyzed for superoxide production, neutrophil infiltration, and DNMT expression.
Main Results:
- LPS-induced rhabdomyolysis in rats mimicked human clinical syndromes, including acute kidney injury and metabolic disturbances.
- Procainamide treatment inhibited DNMT1 overexpression and reduced plasma IL-6 levels.
- Procainamide improved muscle damage, renal dysfunction, electrolyte imbalances, acidosis, hypotension, and hypoglycemia.
- Hydralazine also demonstrated protective effects against muscle damage, renal dysfunction, and hypoglycemia.
Conclusions:
- Procainamide exhibits therapeutic effects in endotoxin-induced rhabdomyolysis.
- These effects are likely mediated by the suppression of DNMT1 and pro-inflammatory cytokines like IL-6.
- Targeting DNA methylation pathways presents a potential therapeutic strategy for rhabdomyolysis.
