Pharmacological preconditioning with monophosphoryl lipid A improves post ischemic diastolic function and modifies TNF-alpha synthesis.
OBJECTIVE
Pharmacologic preconditioning represents an attractive myocardial protection strategy. Tumor necrosis factor-alpha plays an important role in myocardial ischemia-reperfusion injury. We aimed to determine the effect of Monophosphoryl lipid A-induced delayed preconditioning on diastolic and systolic left ventricular function and tumor necrosis factor-alpha synthesis during ischemia and reperfusion.


METHODS
Rats (n=10) were pretreated with Monophosphoryl lipid A (350 microg/kg) or vehicle (n=9). Twenty-four hours later, the hearts were isolated and perfused on a Langendorff apparatus. Hemodynamic measurements, tumor necrosis factor-alpha mRNA expression and protein content were studied after stabilization (baseline), after 35 min of global ischemia and at 40 min of reperfusion.


RESULTS
Left ventricular developed pressure and peak rate of left ventricular developed pressure (dP/dt) rise were comparable between the animals in the control and Monophosphoryl lipid A treated groups during baseline but were higher in Monophosphoryl lipid A group at reperfusion (74+/-4 vs 51+/-5 mmHg, 3340+/-172 vs 2240+/-156 mmHg/s, respectively, P<0.01). dP/dt fall was significantly lower in the MLA group (2630+/-225v 1580+/-210 mmHg/s, P<0.01) at 40 min of reperfusion as well as end diastolic pressure. Baseline tumor necrosis factor-alpha mRNA (expressed as arbitrary densitometry units) were higher in the Monophosphoryl lipid A group (1.3+/-0.1 vs 0.5+/-0.03, P<0.05) but remained constant after ischemia and reperfusion (1.3+/-0.1 and 1.4+/-0.03, P=0.2), while further increase was observed in the control group (from 1.0+/-0.1 to 1.4+/-0.1, P<0.05). Tumor necrosis factor-alpha protein content from heart effluent in the control group was increased during reperfusion (79+/-30 and 200+/-22pg/ml, P<0.05) but was undetectable in the Monophosphoryl lipid A group. Marked TNF-alpha immunostaining of left ventricular tissue was observed only in the control group but no TNF-alpha staining was evident in the Monophosphoryl lipid A treated group at 40 min of reperfusion.


CONCLUSIONS
Monophosphoryl lipid A-induced preconditioning renders the heart more tolerant to ischemia-reperfusion in terms of left ventricular diastolic and systolic function, and prevents tumor necrosis factor-alpha production during ischemia, through aborting the translation phase of tumor necrosis factor-alpha synthesis.
Sharony
Ram
R
Department of Cardiothoracic Surgery, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, 6 Witzman St., Tel Aviv 64239, Israel. sharonyn@netvision.net.il
Frolkis
Inna
I
Froylich
Dvir
D
Wildhirt
Stephan M
SM
Shapira
Itzhak
I
Reichart
Bruno
B
Nesher
Nahum
N
Uretzky
Gideon
G
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects
D008050:Lipid A; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C048436:monophosphoryl lipid A