ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs.
BACKGROUND
The aim of this study was to determine if the stable antiarrhythmic peptide (AAP) analogue ZP123 increases gap junctional intercellular conductance and prevents reentrant ventricular tachycardia (VT) during coronary artery occlusion.


RESULTS
Voltage clamp experiments demonstrated that 10 nM ZP123 improved gap junctional intercellular conductance by 69% +/- 20% in pairs of guinea pig ventricular myocytes. VT was induced by programmed stimulation in alpha-chloralose anaesthetized open chest dogs 1 to 4 hours after coronary artery occlusion. Three-dimensional activation mapping was done using six bipolar electrograms on each of 23 multipolar needles in the risk zone. When VT was reproducibly induced, dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (intravenous bolus followed by 30-min infusion per dose). Attempts to induce VT were repeated in each infusion period. Mass spectrometry was used to measure ZP123 plasma concentrations. Twenty-six dogs with reentrant VT were included. ZP123 significantly prevented reentrant VT at all plasma concentrations vs saline: 1.0 +/- 0.2 nM: 6/12 vs 0/12; 7.7 +/- 0.6 nM: 7/13 vs 1/12; and 69.2 +/- 5.4 nM: 9/13 vs 1/13. The preventive effect of ZP123 on reentrant VT was closely correlated to reversal of functional, unidirectional conduction block. ZP123 did not affect effective refractory period, surface ECG parameters, mean arterial pressure, or infarct size.


CONCLUSIONS
The stable AAP analogue ZP123 increased gap junctional intercellular conductance and specifically prevented the induction of reentrant VT during ischemia in a broad dose range without proarrhythmic or hemodynamic side effects. ZP123 is a promising candidate for use in preventing ischemia-induced VT.
Xing
Dezhi
D
Department of Internal Medicine, University of Iowa College of Medicine and VA Medical Center, Iowa City, Iowa 52242, USA.
Kjølbye
Anne Louise
AL
Nielsen
Morten S
MS
Petersen
Jørgen S
JS
Harlow
Kenneth W
KW
Holstein-Rathlou
Niels-Henrik
NH
Martins
James B
JB
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D017629:Gap Junctions / Q000187:drug effects*; D006327:Heart Block / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015994:Incidence; D007262:Infusions, Intravenous; D008297:Male; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015203:Reproducibility of Results; D013223:Statistics as Topic; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*
D009842:Oligopeptides; C029579:antiarrhythmic peptide; C477643:rotigaptide