A method for evaluating drug effects on intermittent claudication using a treadmill in rats with unilateral hindlimb artery occlusion.
BACKGROUND
We have developed an in vivo experimental model for evaluating peripheral arterial insufficiency and predicting the efficacy of drugs on intermittent claudication (IC). We found that rats that had been running normally on a treadmill developed a gait disturbance when a hindlimb artery was unilaterally occluded. We hypothesized that the distance run before gait disturbance developed (DGD) in rats with occlusion of a hindlimb artery might be an appropriate index of the severity of peripheral insufficiency, and that the model might serve as a test bed for evaluating drug efficacy. To prove this hypothesis, we examined whether DGD was determined by severity of hindlimb ischemia. Furthermore, we also examined whether cilostazol, which has been proved to have ameliorative effects in patients with IC, increased DGD.


METHODS
To vary the severity of ischemia, either the superficial femoral artery, the distal portion of the iliac artery, or the proximal portion of iliac artery was unilaterally occluded. After a recovery period, these rats were subjected to a treadmill test (15 m/min and 15% incline) to determine DGD and examine the effect of cilostazol on DGD.


RESULTS
DGD was the longest and shortest in rats with superficial femoral artery and proximal portion of iliac artery occlusion, respectively. Intermediate DGD was observed in rats with distal portion of iliac artery occlusion. These data suggest that DGD is correlated with the severity of hindlimb ischemia. Two weeks or longer administration of cilostazol 30 and 100 mg/kg twice a day evoked a significant increase in DGD.


CONCLUSIONS
Peripheral arterial insufficiency and its modulation by drugs can be evaluated in rats with unilateral hindlimb artery occlusion, on a treadmill, by measuring DGD.
Orito
Kensuke
K
Research Institute of Pharmacological and Therapeutical Development, First Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima 771-0192, Japan.
Kishi
Masami
M
Fujiki
Hiroyuki
H
Nakazawa
Toru
T
Imaizumi
Takashi
T
Kimura
Yukio
Y
Mori
Toyoki
T
Kambe
Toshimi
T
D000818:Animals; D000077407:Cilostazol; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005080:Exercise Test / Q000379:methods*; D005263:Femoral Artery / Q000503:physiopathology; D006614:Hindlimb / Q000098:blood supply; D007383:Intermittent Claudication / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007511:Ischemia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
D013777:Tetrazoles; D014665:Vasodilator Agents; D000077407:Cilostazol