Selective type III phosphodiesterase inhibition prevents elevated compartment pressure after ischemia/reperfusion injury

Background: A new synthetic cyclic adenosine monophosphate phosphodiesterase inhibitor, cilostazol, has been shown to inhibit platelet aggregation and act synergistically with endogenous prostaglandin I₂ to enhance smooth-muscle cell vasodilitation. The effect of cilostazol in ischemia/reperfusion injury-induced compartment syndrome was investigated. Methods: Sixteen rabbits underwent femoral artery occlusion after ligation of branches from the terminal aorta to the femoral artery. After 7 hours of ischemia, reperfusion was established with heparinized polyethylene shunts. Experimental animals (n = 8) received cilostazol (3.0 mg/kg) and control animals (n = 8) received normal saline as an intravenous infusion 10 minutes before shunt placement. During reperfusion, anterior compartment pressure was continuously monitored in the left lower extremity, and femoral artery blood flow was measured by laser Doppler fluorometry. To quantitate skeletal muscle oxidative metabolism and viability, triphenyltetrazolium chloride (TTC) reduction (micrograms of TTC per milligram of protein) of tibialis anterior muscle from the right lower extremity was measured at femoral artery occlusion, 7 hours of ischemia, and 2 hours of reperfusion. To assess tissue edema, dry/wet weight ratios were also determined at these intervals. Data were expressed as means ± SE. Comparisons within groups were performed by analysis of variance, and comparisons between groups with two-tailed unpaired t tests. Results: At 2 hours of reperfusion, the difference between controls and cilostazol-treated animals was extremely significant (p = 0.0008). Preischemia and 2-hour reperfusion TTC and dry/wet weight ratios were not significantly different within or between experimental groups, nor was femoral artery blood flow during reperfusion. Conclusion: Cilostazol inhibits the increase in compartment pressure central to the development of the compartment syndrome. The mechanism appears to be independent of altered tissue permeability or oxidative metabolism.