title: Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats.
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.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, R.O.C., Taiwan.|Department of Pharmacology, National Defense Medical Center, Taipei, R.O.C., Taiwan.
authors.forename: Chih-Chin
authors.initials: CC
authors.lastname: Shih
authors.affiliation: Department of Surgery, Chi Mei Medical Center, Tainan, R.O.C., Taiwan.
authors.forename: Hiong-Ping
authors.initials: HP
authors.lastname: Hii
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, R.O.C., Taiwan.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Tsao
authors.affiliation: Department of Physiology, National Defense Medical Center, Taipei, R.O.C., Taiwan.|Departments of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, R.O.C., Taiwan.|Departments of Health Management for Elderly Society, Kang-Ning Junior College of Medical Care and Management, Taipei, R.O.C., Taiwan.
authors.forename: Shiu-Jen
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, R.O.C., Taiwan.
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, R.O.C., Taiwan.
authors.forename: Mei-Hui
authors.initials: MH
authors.lastname: Liao
authors.affiliation: Department of Pharmacology, National Defense Medical Center, Taipei, R.O.C., Taiwan.
authors.forename: Chin-Chen
authors.initials: CC
authors.lastname: Wu
mesh_terms: D000138:Acidosis / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D001639:Bicarbonates / Q000097:blood; D015415:Biomarkers; D003404:Creatinine / Q000097:blood; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D004353:Drug Evaluation, Preclinical; D004573:Electrolytes / Q000097:blood; D019446:Endotoxemia / Q000150:complications; D004731:Endotoxins / Q000633:toxicity*; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D011342:Procainamide / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012206:Rhabdomyolysis / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D013481:Superoxides / Q000032:analysis; D013610:Tachycardia / Q000188:drug therapy / Q000209:etiology; D000097584:DNA Methyltransferase 3B
chemical_list: D001639:Bicarbonates; D015415:Biomarkers; D003404:Creatinine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004573:Electrolytes; D004731:Endotoxins; D006830:Hydralazine; D015850:Interleukin-6; D011342:Procainamide; D013481:Superoxides; D000097584:DNA Methyltransferase 3B; C044101:endotoxin, Escherichia coli; C000619382:Dnmt1 protein, rat