Drug effects on function in the ferret ischemic hindlimb

Abstract

In this article a new model of peripheral occlusive arterial disease is described. The lower hindlimb of an anesthetized ferret was fixed to a holder, the distal end of the Achilles tendon attached to an isometric force transducer, and a passive preload of 100 g was applied to the muscle preparation. The hindlimb was stimulated to contract isometrically via supramaximal electrical stimulation of the sciatic nerve. During the initial period, when femoral blood pressure equaled aortic blood pressure, net contractile force peaked within 1 or 2 min (372 ± 24g, n = 20) and gradually declined to about 85% of peak over 20 min. Following 60 min of ischemia (induced by partial occlusion of the abdominal aorta), when blood pressure in the contralateral femoral artery was about 45 mm Hg, the 15-min area under the force-time curve (AUC) was 33.2 ± 2.5% (n = 4) of the initial value. To validate the utility of this model in the search for treatment of peripheral vascular diseases, two drugs were tested. Pentoxifylline, which is clinically effective, attenuated the loss of function observed during ischemia in a dose-related manner, but nifedipine, which is without clinical benefit, had no effect at a dose that was extremely hypotensive. Because femoral perfusion pressure was controlled, systemic hemodynamic effects of test compounds are minimized as potential mechanisms of action, simplifying the evaluation of novel pharmacotherapy for treatment of ischemic diseases.