The antiarrhythmic peptide analog ZP123 prevents atrial conduction slowing during metabolic stress.
OBJECTIVE
As atrial conduction slowing is important in the pathogenesis of atrial reentry arrhythmias, a drug that increases atrial conduction or prevents atrial conduction slowing could serve to prevent atrial reentry arrhythmias. In this study, we investigated whether the novel stable antiarrhythmic peptide analog, ZP123, was able to prevent atrial conduction slowing.


METHODS
We examined the effect of ZP123 on metabolic stress-induced changes in conduction velocity (CV) and on dynamic CV restitution in isolated left atria from male Sprague-Dawley rats. We performed binding of ZP123 to a broad panel of 80 different cardiac and noncardiac ion channels and receptors and examined the effect of ZP123 on HERG channel conductance.


RESULTS
ZP123 dose-dependently prevented metabolic stress-induced atrial CV slowing at doses ranging from 1 nM to 10 microM. ZP123 did not affect CV during physiological conditions nor did it affect dynamic CV restitution. ZP123 had no effect on atrial contractility. ZP123 showed no or low affinity binding to all ion channels and receptors examined. ZP123 had no effects on HERG channel activity in concentrations that affected atrial conduction. The concentration of ZP123 giving maximal effect on atrial conduction (100 nM) inhibited the outward K(+)-current by 2.7 +/- 0.1%.


CONCLUSIONS
ZP123 has no effects on atrial conduction during physiological conditions, but it selectively prevents atrial conduction slowing during metabolic stress.
Haugan
Ketil
K
Zealand Pharma A/S, DK-2600 Glostrup, Denmark. kha@zp.dk
Olsen
Kristine Boisen
KB
Hartvig
Line
L
Petersen
Jørgen Søberg
JS
Holstein-Rathlou
Niels-Henrik
NH
Hennan
James K
JK
Nielsen
Morten Schak
MS
D000818:Animals; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007473:Ion Channels; D009842:Oligopeptides; C029579:antiarrhythmic peptide; C477643:rotigaptide