title: The anti-ischemic mechanism of action of ranolazine in stable ischemic heart disease.
abstract: OBJECTIVE
  The purpose of this explanatory analysis was to investigate the relationship between ST-segment depression and the rate-pressure product (RPP) during exercise to determine whether ranolazine's mechanism of action was related to a reduction in myocardial oxygen demand or preservation of myocardial oxygen supply.
  
  
  BACKGROUND
  In patients with stable ischemic heart disease, ranolazine increases exercise duration and reduces maximal ST-segment depression while exerting minimal effects on heart rate and blood pressure, although its mechanism of action during exercise has not been investigated.
  
  
  METHODS
  Patients with stable ischemic heart disease (n = 191) were randomly allocated to a 4-period, double-blind, balanced Latin square crossover study to receive placebo, and ranolazine 500, 1,000, and 1,500 mg twice daily (bid) for 1 week each. Exercise treadmill tests were performed at baseline and at the end of each treatment period. The RPP and ST-segment depression were assessed before starting exercise, at each stage of exercise, and at maximal exercise.
  
  
  RESULTS
  Compared with placebo, ranolazine produced a dose-dependent reduction in ST-segment depression that became more marked as exercise-induced ischemia became more pronounced, associated with clinically minor decreases in heart rate and blood pressure. At 12-min exercise, the amount of ST-segment depression compared with placebo and controlled for RPP was reduced by 22.3% on ranolazine 500 mg bid (p = 0.137), by 35.4% on 1,000 mg bid (p = 0.005), and by 45.8% on 1,500 mg bid (p < 0.001).
  
  
  CONCLUSIONS
  The progressive magnitude of ischemia reduction on ranolazine was proportionally more substantial than the minor reductions in heart rate or RPP, suggesting that ranolazine's beneficial mechanism of action is most likely primarily due to an improvement in regional coronary blood flow in areas of myocardial ischemia.
authors.affiliation: Cardiovascular Division, Brigham & Women’s Hospital, Boston, Massachusetts 02115, USA. pstone@partners.org.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Stone
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Chaitman
authors.forename: Karen
authors.initials: K
authors.lastname: Stocke
authors.forename: Junko
authors.initials: J
authors.lastname: Sano
authors.forename: Arthur
authors.initials: A
authors.lastname: DeVault
authors.forename: Gary G
authors.initials: GG
authors.lastname: Koch
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005080:Exercise Test; D005260:Female; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage*; D000069458:Ranolazine; D013997:Time Factors
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D000069458:Ranolazine