Experimental Models of Chronic Lower Extremity Arterial Occlusive Disease: Lessons for Drug Development

Abstract

Peripheral vascular disease is the result of chronic vascular insufficiency. As the vascular insufficiency of the lower limbs progressively deteriorates, the condition progresses from intermittent claudication (pain upon exercise) to pain at rest and gangrene. In very severe cases amputation of the leg may be necessary. Whilst dieting, cessation of smoking and physical exercise all beneficially affect the progression of the disorder, the available drug therapy is of limited benefit. Very effective pharmacological agents capable of alleviating the symptoms of chronic peripheral vascular disease have not been developed. In order to mimic the vascular insufficiency of intermittent claudication, an animal model was developed in rats. This involves short-term and long-term 6–10 weeks ligation of the femoral artery of the rat. As demonstrated using measurements of hindlimb skeletal muscle, blood flow, pO₂, metabolism and function, a model of intermittent claudication was produced. Using this model, the beneficial effects of physical training was demonstrated. Physical training induced an increase in blood flow and a greater capacity for aerobic metabolism in the partially ischaemic skeletal muscle. The effect of vasodilators has also been examined in this model; in contrast to agents such as Ca²⁺ antagonists, K⁺ channel openers appear to improve nutritional blood flow and metabolism in the afflicted skeletal muscle. This model can also be utilized to demonstrate the effects of haemorrheological interventions and of agents modulating muscle metabolism. However, additional effort is required to develop models for the evaluation of efficacy of antiatherothrombotic drugs.