title: Ketamine-induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol.
abstract: OBJECTIVE
  Growing evidence suggests that long-term abuse of ketamine does harm the heart and increases the risk of sudden death. The present study was performed to explore the cardiotoxicity of ketamine and the protective effects of metoprolol.
  
  
  METHODS
  Rats and rabbits were divided into control, ketamine, metoprolol alone and ketamine plus metoprolol groups. Ketamine (40 mg·kg(-1) ·day(-1), i.p.) and metoprolol (20 mg·kg(-1) ·day(-1), p.o.) were administered continuously for 12 weeks in rats and 8 weeks in rabbits. Cardiac function, electrophysiological disturbances, cardiac collagen, cardiomyocte apoptosis and the remodelling-related proteins were evaluated.
  
  
  RESULTS
  Rabbits treated with ketamine showed decreased left ventricular ejection fraction, slowed ventricular conduction velocity and increased susceptibility to ventricular arrhythmia. Metoprolol prevented these pathophysiological alterations. In ketamine-treated rats, cardiac collagen volume fraction and apoptotic cell number were higher than those of control animals; these effects were prevented by co-administration of metoprolol. Consistently, the expressions of poly (ADP-ribose) polymerases-1, apoptosis-inducing factor and NF-κB-light-chain-enhancer of activated B cells were all increased after ketamine treatment and sharply reduced after metoprolol administration. Moreover, ketamine enhanced sympathetic sprouting, manifested as increased growth-associated protein 43 and tyrosine TH expression. These effects of ketamine were prevented by metoprolol.
  
  
  CONCLUSIONS
  Chronic treatment with ketamine caused significant ventricular myocardial apoptosis, fibrosis and sympathetic sprouting, which altered the electrophysiological properties of the heart and increased its susceptibility to malignant arrhythmia that may lead to sudden cardiac death. Metoprolol prevented the cardiotoxicity of ketamine, indicating a promising new therapeutic strategy.
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: Y
authors: Y
authors: Li
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: J
authors: J
authors: Shi
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: B F
authors: BF
authors: Yang
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: L
authors: L
authors: Liu
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: C L
authors: CL
authors: Han
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: W M
authors: WM
authors: Li
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: D L
authors: DL
authors: Dong
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: Z W
authors: ZW
authors: Pan
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: G Z
authors: GZ
authors: Liu
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: J Q
authors: JQ
authors: Geng
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: L
authors: L
authors: Sheng
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: X Y
authors: XY
authors: Tan
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: D H
authors: DH
authors: Sun
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: Z H
authors: ZH
authors: Gong
authors: Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
authors: Y T
authors: YT
authors: Gong
mesh_terms: D000700:Analgesics / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013287:Illicit Drugs / Q000009:adverse effects*; D007649:Ketamine / Q000009:adverse effects*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C494831:Aifm1 protein, rat; D000700:Analgesics; D051033:Apoptosis Inducing Factor; D013287:Illicit Drugs; D016328:NF-kappa B; D020011:Protective Agents; D007649:Ketamine; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008790:Metoprolol