Pharmacological characterization of the new stable antiarrhythmic peptide analog Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2 (ZP123): in vivo and in vitro studies.
Antiarrhythmic peptides (AAPs) are a group of compounds with antiarrhythmic properties; however, their use has been hampered by very low plasma stability. The aim of this study was to compare the in vitro and in vivo stability of our new stable AAP analog Ac-d-Tyr-d-Pro-d-Hyp-Gly-d-Ala-Gly-NH2 (ZP123) with the previously described AAP analog AAP10. Moreover, the effect of the two compounds was examined in a murine in vivo model of ouabain-induced second degree AV-block, and the effect on dispersion of action potential duration (APD dispersion) was studied during hypokalemic-ischemia in isolated perfused rabbit hearts. The in vitro t1/2 of ZP123 in rat and human plasma was about 1,700 times longer than t1/2 of AAP10. Due to rapid elimination, it was not possible to obtain an in vivo pharmacokinetic characterization of AAP10; however, calculations suggested that the clearance of ZP123 was at least 140 times slower than for AAP10. AAP10 and ZP123 produced a dose-dependent delay in onset of ouabain-induced AV-block in mice at doses of 10-11 to 10-7 mol/kg i.v. ZP123 and 10-11 to 10-6 mol/kg i.v. AAP10. Maximal efficacy of ZP123 was reached at a 10-fold lower dose (10-8 mol/kg i.v.) than with AAP10. In the isolated rabbit hearts, ZP123 and AAP10 had no effect on dispersion during control conditions. The increased APD dispersion during hypokalemic ischemia is considered a major arrhythmic substrate and only ZP123 prevented the increase in APD dispersion. In conclusion, ZP123 is a new potent AAP analog with improved stability.
Kjølbye
Anne Louise
AL
Department of Pharmacology, Zealand Pharma A/S, Smedeland, Denmark. alk@zp.dk
Knudsen
Carsten Boye
CB
Jepsen
Trine
T
Larsen
Bjarne Due
BD
Petersen
Jorgen Søberg
JS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics*; D004355:Drug Stability; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013997:Time Factors
C090806:AAP 10; D000889:Anti-Arrhythmia Agents; D009842:Oligopeptides; C477643:rotigaptide