title: Ranolazine ameliorates postresuscitation electrical instability and myocardial dysfunction and improves survival with good neurologic recovery in a rat model of cardiac arrest.
abstract: BACKGROUND
  During ischemia, enhancement of the "late Na+ current" (I(NaL)) contributes to intracellular Ca2+ overload. Dysregulation of intracellular Ca2+ homeostasis plays a critical role in the pathophysiology of cardiac arrest and cardiopulmonary resuscitation (CPR), leading to ventricular arrhythmias and left ventricle (LV) dysfunction.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the effects of the I(NaL) blocker ranolazine on outcome of CPR in a rat model. We hypothesized that ranolazine might reduce postresuscitation arrhythmias and improve survival and recovery.
  
  
  METHODS
  Eighteen rats were assigned to receive intravenous ranolazine 10 mg/kg or vehicle. Ventricular fibrillation was induced and untreated for 8 minutes. CPR then was performed for 8 minutes. ECG and arterial and right atrial pressures were monitored up to 3 hours after CPR. After resuscitation, LV function was monitored by echocardiography, and 72-hour survival with neurologic recovery was evaluated. Plasma was obtained for biomarkers of heart and brain injury.
  
  
  RESULTS
  All animals in the ranolazine group were resuscitated and survived up to 72 hours, whereas 72% in the vehicle group were resuscitated but 54% survived. The period of postresuscitation arrhythmia with hemodynamic instability was shorter in the ranolazine group compared to vehicle group (P < .02). Seventy-two hours after resuscitation, LV systolic and diastolic functions were better in the ranolazine group compared to vehicle (P < .05). Full neurologic recovery was observed in all ranolazine animals, whereas neurologic impairment persisted in the vehicle group (P < .02).
  
  
  CONCLUSIONS
  In this model, ranolazine pretreatment reduced postresuscitation electrical and hemodynamic instability and improved 72-hour postresuscitation LV function and survival with good neurologic recovery.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fumagalli
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Russo
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Staszewsky
authors.affiliation: School of Biomedical Engineering, Third Military Medical University and Chongqing University, Chongqing, China.
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Endocrininology Laboratory, Luigi Sacco Hospital, Milan, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Letizia
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Serge
authors.initials: S
authors.lastname: Masson
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Novelli
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi Milano-Bicocca, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Canovi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Veglianese
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi Milano-Bicocca, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy. Electronic address: gristag@gmail.com.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ristagno
mesh_terms: D000083:Acetanilides / Q000627:therapeutic use*; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016887:Cardiopulmonary Resuscitation; D002490:Central Nervous System / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006323:Heart Arrest / Q000503:physiopathology* / Q000628:therapy; D010879:Piperazines / Q000627:therapeutic use*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine
keywords: Cardiac arrest; Late Na(+) current blockade; Myocardial dysfunction; Neurologic recovery; Outcome; Postresuscitation