Combination of Cilostazol and <smlcap>L</smlcap>-Carnitine Improves Walking Performance in Peripheral Arterial Disease Model Rats

Cilostazol and <smlcap>L</smlcap>-carnitine have been used as a first-line drug and supplement, respectively, in patients with peripheral arterial disease with intermittent claudication. In this study, the effect of the combination of cilostazol and <smlcap>L</smlcap>-carnitine has been investigated in rats with unilateral hindlimb ischemia. For 28 days, cilostazol and <smlcap>L</smlcap>-carnitine were administrated separately or as a combination. The distance walked before gait disturbance developed was measured using a treadmill for 5 days a week. The capillary density of the ischemic hindlimb was evaluated by immunohistochemical staining at days 7, 14, 21, and 28. Angiogenic gene expression was measured by real-time RT-PCR at days 7 and 28. The greatest increase in the distance was observed in the combination therapy group when compared to the other groups. The capillary density in the adductor muscles of rats treated with cilostazol alone and combination therapy increased at day 28. Angiopoietin-2/Angiopoietin-1 expression ratios were higher, suggesting the promotion of angiogenesis, with cilostazol alone and combination therapy at day 7. This is the first study to show functional improvement of the hind limb following combination therapy with cilostazol and <smlcap>L</smlcap>-carnitine in experimental animals. This study also revealed that cilostazol promotes angiogenesis, and <smlcap>L</smlcap>-carnitine additively contributes to functional improvement via a non-angiogenic mechanism.