The ET(A) receptor antagonist LU 135252 has no electrophysiological or anti-arrhythmic effects during myocardial ischaemia/reperfusion in dogs.
The anti-arrhythmic effects of ET(A) receptor antagonists during myocardial ischaemia and reperfusion remain controversial. Moreover, the electrophysiological mechanism has not yet been identified. The aim of this study was to investigate the potential anti-arrhythmic and electrophysiological effects of the ET(A) receptor antagonist LU 135252 (LU) during myocardial ischaemia and reperfusion in a canine model. A bolus of LU (1 mg/kg; n=10) or saline (control; n=10) was injected into the left anterior descending coronary artery before ligation of this vessel for 30 min, which was followed by a 90-min reperfusion period. LU bolus administration (0.5 mg/kg) was repeated every 30 min. There were no differences in mean arterial blood pressure or coronary blood flow between the two groups. The determined left ventricular ischaemic mass was 25.5+/-1.8% and 27.8+/-2.2% of the total left ventricular mass in the control and LU groups respectively. The total incidence of ventricular fibrillation during ischaemia and reperfusion was 40% in the control and 50% in the LU group (not significantly different). The incidence of non-sustained and sustained ventricular tachycardias during ischaemia, reperfusion and over the whole period (ischaemia plus reperfusion) in the control group was 50%, 50% and 70% respectively, and that in the LU group was 80%, 70% and 100% respectively (no significant differences between groups). The number of ventricular premature beats was not decreased by LU during either ischaemia or reperfusion [median (25th-75th percentile): ischaemia, 20 (13-37) and 56 (32-130) for LU and control groups respectively; reperfusion, 15 (2-21) and 39 (7-74) respectively; ischaemia+reperfusion, 16 (4-35) and 43 (10-82) respectively; no significant differences between groups]. During ischaemia, the monophasic action potential duration at 90% repolarization (MAPD(90)) decreased significantly, while during reperfusion a significant prolongation of MAPD(90) was observed in the left anterior descending region that was similar in the two groups. In conclusion, LU did not affect repolarization changes and did not have anti-arrhythmic effects during either ischaemia or reperfusion in this model.
Department of Cardiovascular Surgery, Semmelweis University Budapest, Városmajor u. 68, H-1122 Budapest, Hungary. vagoh@kkt.sote.hu
Hajnalka
H
Vágó
Pál
P
Soós
Endre
E
Zima
László
L
Gellér
Violetta
V
Kékesi
Terézia
T
Andrási
Tamás
T
Szabó
Alexander
A
Juhász-Nagy
Béla
B
Merkely
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D023421:Models, Animal; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan