K-134, a phosphodiesterase 3 inhibitor, improves gait disturbance and hindlimb blood flow impairment in rat peripheral artery disease models.
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 30 mg/kg significantly prolonged walking distance. These results suggest that K-134 may be useful for treating intermittent claudication.
Tokyo New Drug Research Laboratories, Kowa Company, Ltd., 2-17-43, Higashimurayama, Tokyo 189-0022, Japan. y-sasaki@kowa.co.jp
Yusuke
Y
Sasaki
Hideo
H
Suzuki
Shinsuke
S
Itoh
Hideo
H
Yoshida
Shoichi
S
Kondo
Keisuke
K
Inoue
Sohei
S
Tanabe
D000818:Animals; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply* / Q000187:drug effects; D007794:Lameness, Animal / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D058729:Peripheral Arterial Disease / Q000188:drug therapy* / Q000201:enzymology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D058987:Phosphodiesterase 3 Inhibitors; D011804:Quinolines; D014508:Urea; C116725:OPC 33509