K-134, a phosphodiesterase 3 inhibitor, improves gait disturbance and hindlimb blood flow impairment in rat peripheral artery disease models

Abstract

K-134, a phosphodiesterase 3 (PDE3) inhibitor with anti-thrombotic and anti-hyperplastic activity, is being developed for the treatment of intermittent claudication. We assessed the efficacy of K-134 against gait disturbance in two rat experimental peripheral arterial disease (PAD) models: the bilateral laurate-induced PAD model and femoral artery ligation model. In the laurate-induced peripheral arterial disease model, 1 week of repeated oral administration of K-134 significantly improved gait disturbance. Cilostazol and clopidogrel did not significantly improve gait disturbance. Repeated oral administration of K-134 and cilostazol significantly improved gait disturbance in the femoral artery ligation model. We evaluated the effects of K-134 and cilostazol treatment on hindlimb blood flow pre- and post-treadmill exercise in this model by laser Doppler perfusion imaging. Both drugs increased hindlimb blood flow both pre- and post-treadmill exercise after 1 week of treatment. After 4 weeks of drug treatment, without preceding drug administration which is supposed to exert acute effects on vessel walls, both drugs significantly increased hindlimb blood flow after exercise. Moreover, K-134 at 30mg/kg significantly prolonged walking distance. These results suggest that K-134 may be useful for treating intermittent claudication.