Ibudilast, a Phosphodiesterase Inhibitor and Toll-Like Receptor-4 Antagonist, Improves Hemorrhagic Shock and Reperfusion-Induced Left Ventricular Dysfunction by Reducing Myocardial Tumor Necrosis Factor α

Objectives: Rapid loss of blood volume causes ischemic injury to myocardial cells and impairs cardiac function. Subsequent reperfusion, although necessary to revitalize stunned tissues, can induce production of reactive oxygen species and inflammation, causing further tissue damages and weakening cardiac function. Ibudilast, a Toll-like receptor-4 (TLR4) antagonist and an inhibitor of phosphodiesterase-4, possesses antioxidative and anti-inflammatory capacities. In this study, we aim to examine the protective efficacy of ibudilast against hemorrhagic shock and reperfusion (HSR)-induced myocardial injury and cardiac dysfunction.

Methods: Studies were conducted on male Sprague-Dawley rats in 3 groups: sham-operated, HSR with, and HSR without pretreatment of ibudilast. Hemorrhagic shock was induced by withdrawing blood from the femoral artery until the mean aortic pressure dropped to around 40 mm Hg; reperfusion was conducted by replenishing blood after 120 minutes of hemorrhagic shock, and the observation continued for another 240 minutes. The left ventricular (LV) contractility, diastolic suction capacity, and ventricular stiffness were evaluated using simultaneous LV pressure, and volume was recorded during a temporary inferior vena cava constriction at the end of reperfusion. Ibudilast (10 mg/kg) was administered intraperitoneally 3 days and 20 minutes prior to HSR. Serum creatine kinase myocardial band (CK-MB) was examined at the end of both HSR, and serum CK-MB, myocardial TLR4 protein expression, and malondialdehyde (MDA) and tumor necrosis factor (TNF)-α levels at the end of reperfusion.

Results: HSR induced an increase in serum CK-MB. Subsequent reperfusion further increased serum CK-MB, upregulated myocardial TLR4 protein expression, and increased tissue levels MDA and TNF-α vs the sham (P < .05). HSR reduced LV contractility, prolonged LV relaxation time, and increased LV diastolic stiffness. Ibudilast pretreatment attenuated HSR-induced TLR4 protein expression, reduced myocardial MDA and TNF-α levels, and protected against cardiac dysfunction.

Conclusions: Ibudilast pretreatment reduced myocardial TLR4 expression, decreased MDA and TNF-α levels, and protected against HSR-induced decrease in LV contractility, prolonged LV relaxation time, and increased diastolic stiffness.