Endothelin-A-receptor antagonist LU 135.252 Inhibits the formation of ventricular arrhythmias caused by intrapericardial infusion of endothelin-1

O. Kiss, L. Gellér, B. Merkely, T. Szabo, M. Raschack, L. Seres, E. Zima, A. Juhász-Nagy, F. Horkay

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Abstract

Intrapericardial endothelin-1 (ET-1) infusion causes dose-dependent severe ventricular arrhythmias. We examined the effects of the endothelin-A- (ET(A)) 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 20 min: 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 afterdepolarization (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.

Original languageEnglish
JournalJournal of Cardiovascular Pharmacology
Volume36
Issue number5 SUPPL. 1
DOIs
Publication statusPublished - 2000

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Endothelin-1
Cardiac Arrhythmias
Arterial Pressure
Control Groups
Ventricular Tachycardia
Cardiac Output
Action Potentials
Dogs
Pericardium
Ventricular Fibrillation
Endothelin A Receptor Antagonists
Electrocardiography
Thorax

Keywords

  • Endothelin (ET)
  • LU 135.252 (LU)
  • Monophasic action potential duration (MAPD)
  • Ventricular arrhythmia

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

@article{2d588f3e907e452c8f13443e3974fb9a,
title = "Endothelin-A-receptor antagonist LU 135.252 Inhibits the formation of ventricular arrhythmias caused by intrapericardial infusion of endothelin-1",
abstract = "Intrapericardial endothelin-1 (ET-1) infusion causes dose-dependent severe ventricular arrhythmias. We examined the effects of the endothelin-A- (ET(A)) 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 20 min: 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 afterdepolarization (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.",
keywords = "Endothelin (ET), LU 135.252 (LU), Monophasic action potential duration (MAPD), Ventricular arrhythmia",
author = "O. Kiss and L. Gell{\'e}r and B. Merkely and T. Szabo and M. Raschack and L. Seres and E. Zima and A. Juh{\'a}sz-Nagy and F. Horkay",
year = "2000",
doi = "10.1097/00005344-200000006-00001",
language = "English",
volume = "36",
journal = "Journal of Cardiovascular Pharmacology",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",
number = "5 SUPPL. 1",

}

TY - JOUR

T1 - Endothelin-A-receptor antagonist LU 135.252 Inhibits the formation of ventricular arrhythmias caused by intrapericardial infusion of endothelin-1

AU - Kiss, O.

AU - Gellér, L.

AU - Merkely, B.

AU - Szabo, T.

AU - Raschack, M.

AU - Seres, L.

AU - Zima, E.

AU - Juhász-Nagy, A.

AU - Horkay, F.

PY - 2000

Y1 - 2000

N2 - Intrapericardial endothelin-1 (ET-1) infusion causes dose-dependent severe ventricular arrhythmias. We examined the effects of the endothelin-A- (ET(A)) 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 20 min: 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 afterdepolarization (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.

AB - Intrapericardial endothelin-1 (ET-1) infusion causes dose-dependent severe ventricular arrhythmias. We examined the effects of the endothelin-A- (ET(A)) 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 20 min: 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 afterdepolarization (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.

KW - Endothelin (ET)

KW - LU 135.252 (LU)

KW - Monophasic action potential duration (MAPD)

KW - Ventricular arrhythmia

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U2 - 10.1097/00005344-200000006-00001

DO - 10.1097/00005344-200000006-00001

M3 - Article

C2 - 11078408

AN - SCOPUS:0033744183

VL - 36

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

IS - 5 SUPPL. 1

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