Effects of dual endothelin receptor blockade on sympathetic activation and arrhythmogenesis during acute myocardial infarction in rats.
The effects of dual (ETA and ETB) endothelin receptor blockade on ventricular arrhythmogenesis during acute myocardial infarction are not well defined. We randomly allocated Wistar rats to bosentan (100 mg/kg daily, n=24), a dual endothelin receptor antagonist, or vehicle (n=23). After 7 days of treatment, myocardial infarction was induced by permanent coronary ligation. Ventricular tachyarrhythmias were evaluated for 24 h following ligation, using a miniature telemetry electrocardiogram recorder. Action potential duration was measured from monophasic epicardial recordings and sympathetic activation was assessed by heart rate variability and catecholamine serum level measurements. Compared to controls (1012+/-185 s), bosentan (59+/-24 s) markedly decreased (P<0.00001) the total duration of ventricular tachyarrhythmias during the delayed (1-24 h) phase post-ligation, with a modest effect during the early (0-1 h) phase (132+/-38 s, versus 43+/-18 s, respectively, P=0.053). Treatment did not affect infarct size or total mortality. Action potential duration at 90% repolarization prolonged in controls (from 93.1+/-4.7 ms to 117.6+/-6.9 ms), displaying increased temporal dispersion (from 4.14+/-0.45 ms to 10.42+/-2.51 ms, both P<0.001), but was preserved in treated animals. Bosentan decreased norepinephrine, but increased epinephrine levels 24 h post-ligation. Low frequency spectra of heart rate variability, an index of net sympathetic tone, were lower in bosentan-treated rats. Dual endothelin-1 receptor blockade decreases ventricular tachyarrhythmias during myocardial infarction without reperfusion, by preventing repolarization inhomogeneity. Diverse treatment effects on sympathetic activation may ameliorate the antiarrhythmic action.
Department of Cardiology, University of Ioannina, 1 Stavrou Niarxou Avenue, 45110 Ioannina, Greece. thkolet@cc.uoi.gr
Theofilos M
TM
Kolettis
Giannis G
GG
Baltogiannis
Dimitrios G
DG
Tsalikakis
Alexandros T
AT
Tzallas
Maria G
MG
Agelaki
Andreas
A
Fotopoulos
Dimitrios I
DI
Fotiadis
Zenon S
ZS
Kyriakides
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D004562:Electrocardiography; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D004837:Epinephrine / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy*; D009638:Norepinephrine / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000209:etiology; D013686:Telemetry; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000209:etiology
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan; D009638:Norepinephrine; D004837:Epinephrine