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Journal of Pharmacology and Therapeutic Research
Volume 1 Issue 1
Clinical Pharmacy 2017
Notes:
Page 55
December 07-09, 2017 | Rome, Italy
7
th
World Congress on
Clinical Pharmacy and Pharmacy Practice
Cellular and ionic mechanisms underlying
effects of Cilostazol, Milrinone and
Isoproterenol to suppress Arrhythmogenesis
in an experimental model of early
repolarization syndrome
Hector Barajas-Martinez
1
, Bence Patocskai
1,2
, István Koncz
1,2
, Zsolt
Gurabi
1,2
, Charles Antzelevitch
3
and
Dan Hu
1
1
Masonic Medical Research Laboratory, USA
2
University of Szeged, Hungary
3
Lankenau Institute for Medical Research, USA
Background:
Early repolarization syndrome (ERS) is
associated with polymorphic ventricular tachycardia
(PVT) and ventricular fibrillation (VF), leading to sudden
cardiac death.
Objective:
The present study tests the hypothesis that
the Ito-blocking effect of phosphodiesterase-3 (PDE-
3) inhibitors plays a role in reversing repolarization
heterogeneities responsible for arrhythmogenesis in
experimental models of ERS.
Methods & Results:
Transmembrane action potentials
(AP) were simultaneously recorded from epicardial and
endocardial regions of coronary-perfused canine left-
ventricular (LV) wedge preparations, together with a
transmural pseudo-ECG. The Ito-agonist NS5806 (7-15
μM) and ICa-blocker verapamil (2-3 uM) were used to
induce an ER pattern and PVT. Following stable induction
of arrhythmogenesis, the PDE-3 inhibitors Cilostazol and
Milrinone or Isoproterenol were added to the coronary
perfusate. All were effective in restoring the AP dome
in the LV epicardium, thus abolishing the repolarization
defects responsible for phase-2-reentry (P2R) and PVT.
Arrhythmic activity was suppressed in 7/8 preparations by
Cilostazol (10 µM), 6/7 by milrinone (2.5 µM) and 7/8 by
isoproterenol (0.1-1 µM). Using voltage clamp techniques
applied to LV epicardial myocytes, both Cilostazol (10
µM) and milrinone (2.5 µM) were found to reduce Ito by
44.4% and 40.4%, respectively, in addition to their effects
to augment ICa.
Conclusions:
Our findings suggest that PDE-3 inhibitors
exert an ameliorative effect in the setting of ERS by
producing an inward shift in the balance of current in the
early phases of the epicardial AP via inhibition of Ito as well
as augmentation of ICa, thus reversing the repolarization
defects underlying development of P2R and VT/VF.
barajash@mmrl.eduJ Pharmacol Ther Res 2017