Delayed protection against ventricular arrhythmias by monophosphoryl lipid-A in a canine model of ischaemia and reperfusion

A. Végh, Katalin György, Mohamed Ali Rastegar, J. Papp, J. Parratt

Research output: Contribution to journalArticle

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Abstract

Bacterial endotoxin reduces the severity of ventricular arrhythmias which occur when a coronary artery is occluded several hours later. We have now examined in anaesthetised dogs the effects on ischaemia and reperfusion- induced arrhythmias, of a non-toxic derivative component of the endotoxin molecule of the lipid-A (monophosphoryl lipid-A). This was given intravenously, in doses of 10 and 100 μg kg-1, 24 h prior to coronary artery occlusion. Arrhythmia severity was markedly reduced by monophosphoryl lipid-A. During ischaemia, ventricular premature beats were reduced from 315 ± 84 in the vehicle controls to 89 ± 60 (with the lower dose of monophosphoryl lipid-A) and 53 ± 23 (P <0.05) with the higher dose. The incidence of ventricular tachycardia was reduced from 75% to 25% (P <0.05) and 31% (P <0.05), and the number of episodes of ventricular tachycardia from 13.4 ± 4.9 per dog to 1.1 ± 1.1 (P <0.05) and 1.2 ± 0.9 (P <0.05) after doses of 10 and 100 μg kg-1, respectively. The incidence of ventricular fibrillation during occlusion and reperfusion in the control group was 96% (15/16), i.e., only 6% (1/16) dogs survived the combined ischaemia-reperfusion insult. Monophosphoryl lipid-A (100 μg kg-1) significantly reduced the incidence of occlusion-induced ventricular fibrillation (from 50% to 7%; P <0.05), and increased survival following reperfusion to 54% (P <0.05). Monophosphoryl lipid-A also significantly reduced ischaemia severity as assessed from ST-segment elevation recorded from epicardial electrodes as well as the degree of inhomogeneity of electrical activation within the ischaemia area. There were no haemodynamic differences prior to coronary occlusion between vehicle controls and monophosphoryl lipid-A-treated dogs. These results demonstrate that monophosphoryl lipid-A reduces arrhythmia severity 24 h after administration. Although the precise mechanisms are still unclear, there is some evidence that nitric oxide and prostanoids (most likely prostacyclin) may be involved because the dual inhibition of nitric oxide synthase and cyclooxygenase enzymes by administration of aminoguanidine and meclofenamate abolished the marked antiarrhythmic protection resulted from monophosphoryl lipid-A treatment 24 h previously.

Original languageEnglish
Pages (from-to)81-90
Number of pages10
JournalEuropean Journal of Pharmacology
Volume382
Issue number2
DOIs
Publication statusPublished - Oct 8 1999

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Reperfusion
Canidae
Cardiac Arrhythmias
Ischemia
Dogs
Coronary Occlusion
Ventricular Fibrillation
Ventricular Tachycardia
Endotoxins
Incidence
Coronary Vessels
Meclofenamic Acid
Lipid A
Ventricular Premature Complexes
monophosphoryl lipid A
Epoprostenol
Prostaglandin-Endoperoxide Synthases
Nitric Oxide Synthase
Prostaglandins
Nitric Oxide

Keywords

  • Aminoguanidine
  • Bacterial endotoxin
  • Ischaemia
  • Meclofenamate
  • Monophosphoryl lipid-A
  • Nitric oxide (NO)
  • Reperfusion
  • Ventricular arrhythmias

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Delayed protection against ventricular arrhythmias by monophosphoryl lipid-A in a canine model of ischaemia and reperfusion. / Végh, A.; György, Katalin; Rastegar, Mohamed Ali; Papp, J.; Parratt, J.

In: European Journal of Pharmacology, Vol. 382, No. 2, 08.10.1999, p. 81-90.

Research output: Contribution to journalArticle

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