title: A phosphodiesterase 3 inhibitor, K-134, improves hindlimb skeletal muscle circulation in rat models of peripheral arterial disease.
abstract: OBJECTIVE
  Cilostazol is a phosphodiesterase (PDE)3 inhibitor used to treat peripheral arterial disease with intermittent claudication, as there is clinical evidence that it improves treadmill exercise capacity. However, details of the mechanism underlying this enhanced walking capacity remain to be elucidated.
  
  
  METHODS
  Based on the hypothesis that PDE3 inhibitors improve peripheral microcirculation in the hindlimbs via vascular smooth muscle relaxation and antiplatelet effects, we examined the effects of a more potent and selective PDE3 inhibitor, K-134, in rat models of peripheral arterial disease (PAD).
  
  
  RESULTS
  In a hindlimb ischemia model established by bilateral femoral artery occlusion, oral administration of K-134 for 27 days significantly increased blood flow in hindlimb skeletal muscle after exercise induced by electrical stimulation of the sciatic nerve. Moreover, K-134 enlarged the luminal area of intramuscular arteries and prevented rarefaction of capillary density in the gastrocnemius muscle. These effects were observed without pre-administration on the day following the last administration, suggesting that vasodilatory, antiplatelet and angiogenic activities of K-134 were indirectly responsible for the long-term beneficial effects. In fact, K-134 dose-dependently induced relaxation of rat femoral arteries in vitro, and inhibited rat platelet aggregation ex vivo. Interestingly, in a laurate-induced peripheral vascular injury model, oral administration of K-134 for 6 days prevented progression of hindlimb necrosis.
  
  
  CONCLUSIONS
  These findings suggest that the beneficial effects of PDE3 inhibitors on walking capacity are due to increased hindlimb skeletal muscle blood flow via intramuscular artery enlargement, and that K-134 is a promising drug for PAD associated with platelet hyperaggregability.
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd., Tokyo, Japan. touyakuyoshida@yahoo.co.jp
authors.forename: Hideo
authors.initials: H
authors.lastname: Yoshida
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Itoh
authors.forename: Takuya
authors.initials: T
authors.lastname: Hara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kondo
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Akimune
authors.initials: A
authors.lastname: Asanuma
authors.forename: Sohei
authors.initials: S
authors.lastname: Tanabe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb; D007850:Lauric Acids; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D009336:Necrosis; D058729:Peripheral Arterial Disease / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D057772:Vascular System Injuries / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D007850:Lauric Acids; D058987:Phosphodiesterase 3 Inhibitors; D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; D014665:Vasodilator Agents; C030358:lauric acid; D014508:Urea; C116725:OPC 33509