Faculty Collaboration Database

Cardioprotective effects of monophosphoryl lipid A, a novel endotoxin analogue, in the dog. Cardiovasc Res 1993 May;27(5):832-8

Date

05/01/1993

Pubmed ID

8394211

DOI

10.1093/cvr/27.5.832

Scopus ID

2-s2.0-85047677864 (requires institutional sign-in at Scopus site)   81 Citations

Abstract

OBJECTIVE: The major objective of the present study was to determine the effects of a new endotoxin analogue, monophosphoryl lipid A (MLA), on myocardial infarct size in dogs. A second aim was to determine if potential cardioprotective effects of MLA might be mediated via an enhancement of antioxidant defence mechanisms.

METHODS: Barbiturate anaesthetised dogs were subjected to 60 min left circumflex coronary artery occlusion followed by 5 h reperfusion. Either of two different doses of MLA (30 and 100 micrograms.kg-1) or an equivalent volume of vehicle were given intravenously 24 h prior to the infarct experiments. Transmural myocardial blood flow was measured at 30 min of occlusion by the radioactive microsphere technique and infarct size was determined at the end of 5 h of reperfusion by triphenyltetrazolium staining. Tissue catalase and myeloperoxidase activities were measured at 5 h of reperfusion as indices of antioxidant activity and neutrophil infiltration, respectively.

RESULTS: There were no significant differences between groups in systemic haemodynamic variables, myocardial oxygen demand, ischaemic bed size, or coronary and collateral blood flow to the ischaemic region. However, administration of MLA produced a marked dose dependent reduction in myocardial infarct size: 19.8(SEM 3.7)% and 14.1(2.5)%, respectively, v 32.7(2.9)% in the vehicle control group, p < 0.05. Pretreatment with either 30 or 100 micrograms.kg-1 of MLA resulted in small increases in tissue catalase activity in the non-ischaemic region of the heart: 0.169(0.033) and 0.197(0.013) K.g-1, respectively, v 0.136(0.013) K.g-1 tissue in the control; however, the increases were not statistically significant by ANOVA. Myeloperoxidase activity in the border zone immediately adjacent to the infarct was markedly decreased in both MLA treated groups: MLA 30 micrograms.kg-1, 2.69(0.82); MLA 100 micrograms.kg-1, 2.49(0.47), v control group, 5.81(1.20) units.g-1 tissue; p < 0.05.

CONCLUSIONS: These data are the first to show a marked cardioprotective effect of a lipid A derivative of endotoxin in an in vivo model of myocardial infarction. Although the mechanism responsible for the reduction in infarct size by MLA is unknown, a reduction in neutrophil migration at the site of ongoing tissue injury, the border zone, may be partially responsible.

Author List

Yao Z, Auchampach JA, Pieper GM, Gross GJ

Author

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Catalase
Disease Models, Animal
Dogs
Endotoxins
Female
Heart
Lipid A
Male
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Peroxidase