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 (nZ10) were pretreated with Monophosphoryl lipid A (350 mg/kg) or vehicle (nZ9). 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 (74G 4v s 51G5 mmHg, 3340G172 vs 2240G156 mmHg/s, respectively, P!0.01). dP/dt fall was significantly lower in the MLA group (2630G225 v 1580G210 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 (1.3G0.1 vs 0.5G0.03, P!0.05) but remained constant after ischemia and reperfusion (1.3G0.1 and 1.4G0.03, PZ0.2), while further increase was observed in the control group (from 1.0G0.1 to 1.4G0.1, P!0.05). Tumor necrosis factor-alpha protein content from heart effluent in the control group was increased during reperfusion (79G30 and 200G 22 pg/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. Conclusion: 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.