Bosentan the mixed endothelin-A- and -B-receptor antagonist suppresses intrapericardial endothelin-1-induced ventricular arrhythmias.
In earlier studies severe ventricular arrhythmias developed during intrapericardial (i.p.) endothelin-1 (ET-1) infusion. Monophasic action potential duration (MAPD90) increase and significant ST segment elevation preceded the onset of arrhythmias. The aim of this study was to test the antiarrhythmic and anti-ischemic efficacy of the mixed endothelin-A- and -B- (ETA/B) receptor antagonist bosentan (BOS) on ET-1-induced arrhythmias on six mongrel dogs. Ten minutes after an intravenous bolus dose of BOS (10 mg/kg), ET-1 (33 pmol/kg/min) was given into the pericardial space for 30min (BOS group). Six control dogs received only ET-1 infusion (control group). Mean arterial blood pressure (MAP), cardiac output, electrocardiograph (ECG), right and left ventricular endo- and epicardial (RVEND, RVEP, LVEND, LVEP) MAPD90s were recorded. MAP and cardiac output did not change significantly in the BOS group. Significant MAPD90 prolongation was found in all investigated regions of the control group (ET start vs ET 20 min: LVEP, 174 +/- 3 vs 208 +/- 10*; RVEND, 206 +/- 9 vs 241 +/- 12* ms, *p < 0.05), while significant MAPD90 alterations were not observed in the BOS group (basic vs ET 20 min: RVEP, 189 +/- 5 vs 196 +/- 5; LVEP, 199 +/- 5 vs 199 +/- 4; RVEND, 194 +/- 5 vs 195 +/- 6; LVEND, 209 +/- 3 vs 213 +/- 5 ms). Early after depolarizations (EADs) were observed in three control dogs. Severe ventricular arrhythmias [incessant nonsustained ventricular tachycardias (nsVTs) in all cases, sustained VTs (sVTs) in four, ventricular fibrillation (VF) in two instances] were present in the control group, whereas nsVTs were observed only in two dogs in the BOS group. ST segment elevation was more pronounced in the control group than in the BOS group (1.01 +/- 0.2 vs 0.41 +/- 0.07 mV, p < 0.05). In summary, bosentan effectively inhibits intrapericardial ET- 1-induced ventricular arrhythmias, moreover it may have a protective effect against epimyocardial ischemia.
Horkay
F
F
Department of Cardiovascular Surgery, Semmelweis Medical University, Budapest, Hungary. ferenc.horkay@excite.com
Gellér
L
L
Kiss
O
O
Szabó
T
T
Vagó
H
H
Kékesi
V
V
Juhász-Nagy
A
A
Merkely
B
B
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D000077300:Bosentan