Endothelin-A-receptor antagonist LU 135.252 inhibits the formation of ventricular arrhythmias caused by intrapericardial infusion of endothelin-1.
Intrapericardial endothelin-1 (ET-1) infusion causes dose-dependent severe ventricular arrhythmias. We examined the effects of the endothelin-A- (ETA) receptor antagonist LU 135.252 (LU) on ET-1-induced arrhythmias on six open-chest mongrel dogs. Ten minutes after an intravenous bolus of LU (5 mg/kg), ET- 1 (33 pmol/kg/min) was given into the pericardial space for 30 min (LU group). Six dogs received ET-1 infusion without LU treatment (control group). Mean arterial blood pressure (MAP), cardiac output, electrocardiograph (ECG), right ventricular endocardial and epicardial (RVEND, RVEP), and left ventricular endocardial and epicardial (LVEND, LVEP) monophasic action potential durations (MAPDs) were recorded. No significant changes were observed in MAP and cardiac output. MAPD90s did not change significantly in the LU group (basic vs ET 20min: RVEP, 186 +/-7 vs 190 +/- 7; LVEP, 189 +/- 8 vs 201 +/- 11; RVEND, 191 +/- 10 vs 192 +/- 9; LVEND, 199 +/- 11 vs 203 +/- 11 ms), while 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). No early after depolarization (EAD) was observed in the LU group, while EADs occurred in three controls. In the LU group, we have not found any significant arrhythmias except nonsustained ventricular tachycardias (nsVTs) in one animal. In the control group incessant nsVTs were observed in six, sustained VTs (sVTs) in four and ventricular fibrillation (VF) in two instances. Significant ST-elevation was observed in all animals in the LU and control groups (LU: 6.7 +/- 2.1 mV; control: 10.1 +/- 2.0 mV, p = NS). In conclusion, the arrhythmogenic action and the main electrophysiological effects of pericardial ET-1 infusion, MAPD prolongation and EAD formation, are inhibited by LU. However, LU could not prevent the ischemic changes resulting from ET-1 infusion.
Kiss
O
O
Department of Cardiovascular Surgery, Semmelweis Medical University, Budapest, Hungary. kissors@hotmail.com
Gellér
L
L
Merkely
B
B
Szabó
T
T
Raschack
M
M
Seres
L
L
Zima
E
E
Juhász-Nagy
A
A
Horkay
F
F
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D006439:Hemodynamics / Q000187:drug effects; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan