Electrophysiologic effects of the new I(Ks)-blocking agent chromanol 293b in the postinfarction canine heart. Preserved positive use-dependence and preferential prolongation of refractoriness in the infarct zone.
OBJECTIVE
Aim of the present study was to investigate site- and rate dependent effects of the IKs-blocking agent chromanol 293b on conduction and refractoriness in normal, infarcted, and transitional regions of in-situ canine hearts.


METHODS
In five dogs with subacute myocardial infarction, three-dimensional mapping was performed after insertion of 6 x 6 needle electrodes in the left ventricle. Before and after application of chromanol 293b (10 mg/kg), activation patterns and local refractory periods (ERPs) at pacing intervals of 300, 500 and 850 ms were obtained for the surviving epicardial muscle layer of the infarct zone (IZ) and for epi-, endo-, and midmyocardial muscle layers of both the normal zone (NZ) and the border zone (BZ) separating normal and infarcted areas.


RESULTS
At baseline, both the NZ and the BZ exhibited uniform ERPs throughout the ventricular wall. Epicardial ERPs were longer in the IZ than in the NZ, and intermediate in the BZ. Chromanol 293b did not affect total activation times. However, at fast heart rates regional areas of slow conduction occurred. Chromanol 293b ubiquitously prolonged local ERPs, most markedly in the IZ. A preferential effect on individual muscle layers of the NZ or BZ and, thus, drug-induced transmural dispersion of ERP could not be observed. Again ubiquitously, the effect on ERP was more pronounced at faster than at slower heart rates, that is, positive use-dependent. At a basic cycle length of 300 ms, chromanol 293b prolonged local ERPs in the IZ by 46 +/- 24 %, in the BZ by 34 +/- 26%, and in the NZ by 20 +/- 17% (p < or = 0.05).


CONCLUSIONS
At least in theory, the electrophysiologic properties of chromanol 293 b, that is, preferential prolongation of refractoriness in ischemic myocardium, more pronounced at faster than at slower heart rates, but homogeneously throughout the intact ventricular wall, appear to be favorable. Whether this translates into a clinical benefit, particularly in the treatment of ischemia-related ventricular tachyarrhythmias, remains to be determined.
Bauer
A
A
Abteilung Innere Medizin III, Medizinische Universitätsklinik, Heidelberg, Germany. alexander_bauer@med.uni-heidelberg.de
Becker
R
R
Freigang
K D
KD
Senges
J C
JC
Voss
F
F
Kraft
P
P
Kuebler
W
W
Schoels
W
W
D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D004285:Dogs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D026902:Potassium Channel Blockers; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*
D002839:Chromans; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane