title: Cellular mechanisms underlying the effects of milrinone and cilostazol to suppress arrhythmogenesis associated with Brugada syndrome.
abstract: BACKGROUND
  Brugada syndrome is an inherited disease associated with vulnerability to ventricular tachycardia and sudden cardiac death in young adults. Milrinone and cilostazol, oral phosphodiesterase (PDE) type III inhibitors, have been shown to increase L-type calcium channel current (ICa) and modestly increase heart rate by elevating the level of intracellular cyclic adenosine monophosphate.
  
  
  OBJECTIVE
  To examine the effectiveness of these PDE inhibitors to suppress arrhythmogenesis in an experimental model of Brugada syndrome.
  
  
  METHODS
  Action potential (AP) and electrocardiographic recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (5 μM) and Ca(2+) channel blocker verapamil (2 μM) were used to pharmacologically mimic Brugada phenotype.
  
  
  RESULTS
  The combination induced all-or-none repolarization at some epicardial sites but not others, leading to ST-segment elevation as well as an increase in both epicardial and transmural dispersion of repolarization. Under these conditions, phase 2 reentry developed as the epicardial AP dome propagated from sites where it was maintained to sites at which it was lost, generating closely coupled extrasystoles and ventricular tachycardia. The addition of the PDE inhibitor milrinone (2.5 μM) or cilostazol (5-10 μM) to the coronary perfusate restored the epicardial AP dome, reduced dispersion, and abolished phase 2 reentry-induced extrasystoles and ventricular tachycardia.
  
  
  CONCLUSIONS
  Our study identifies milrinone as a more potent alternative to cilostazol for reversing the repolarization defects responsible for the electrocardiographic and arrhythmic manifestations of Brugada syndrome. Both drugs normalize ST-segment elevation and suppress arrhythmogenesis in experimental models of Brugada syndrome.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York; Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Szél
authors.forename: István
authors.initials: I
authors.lastname: Koncz
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D053840:Brugada Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D000077407:Cilostazol; D004195:Disease Models, Animal; D004285:Dogs; D004359:Drug Therapy, Combination; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D020105:Milrinone / Q000494:pharmacology*; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D020105:Milrinone; D000077407:Cilostazol
keywords: AP; BrS; Brugada syndrome; Cardiac arrhythmias; ECG; EDR; Electrophysiology; Endo; Epi; I(CA); I(to); L-type calcium channel current; NI; NM; PDE; Pharmacology; Phosphodiesterase inhibitor; RV; Sudden cardiac death; TDR; VF; VT; action potential; cAMP; cyclic adenosine monophosphate; electrocardiogram/electrocardiographic; endocardial; epicardial; epicardial dispersion of repolarization; notch index; notch magnitude; phosphodiesterase; right ventricle/ventricular; transient outward current; transmural dispersion of repolarization; ventricular fibrillation; ventricular tachycardia
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