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

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.

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Vasodilator drugs and peripheral vascular disease

Drug and Therapeutics Bulletin ◽

10.1136/dtb.10.23.91 ◽

1972 ◽

Vol 10 (23) ◽

pp. 91-92

Keyword(s):

Blood Flow ◽

Vascular Disease ◽

Peripheral Vascular Disease ◽

Intermittent Claudication ◽

Placebo Effect ◽

Perfusion Pressure ◽

Symptomatic Improvement ◽

Peripheral Vascular ◽

Vasodilator Drug ◽

Local Accumulation

Many drugs are recommended for the treatment of peripheral vascular disease but evidence for their usefulness is conflicting, mainly because the drug responses are difficult to assess. For instance a symptom such as intermittent claudication may fluctuate spontaneously1 and is also particularly susceptible to a placebo effect.2 Objective criteria may also mislead, for an increase in the blood flow in the ischaemic limb during exercise does not necessarily correlate with symptomatic improvement,3 and in healthy limbs the response to a drug may be quite different from that in a diseased one. In the diseased limb, for instance, a vasodilator drug may not increase the blood flow above that already produced by the local accumulation of metabolites,4 and furthermore any drug that causes widespread dilatation in normal vessels may reduce the perfusion pressure and thus the flow to the ischaemic limb,5 or may shunt blood away from ischaemic zones towards normal areas.

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Calf Muscle Mitochondrial and Glycogenolytic Atp Synthesis in Patients with Claudication Due to Peripheral Vascular Disease Analysed Using 31P Magnetic Resonance Spectroscopy

Clinical Science ◽

10.1042/cs0890581 ◽

1995 ◽

Vol 89 (6) ◽

pp. 581-590 ◽

Cited By ~ 44

Author(s):

G. J. Kemp ◽

L. J. Hands ◽

G. Ramaswami ◽

D. J. Taylor ◽

A. Nicolaides ◽

...

Keyword(s):

Blood Flow ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Vascular Disease ◽

Peripheral Vascular Disease ◽

Muscle Blood Flow ◽

Atp Synthesis ◽

Resonance Spectroscopy ◽

Peripheral Vascular ◽

Proton Efflux

1. We set out to define abnormalities of oxidative ATP synthesis, cellular proton efflux and the efficiency of ATP usage in gastrocnemius muscle of patients with claudication due to peripheral vascular disease, using data obtained by 31P magnetic resonance spectroscopy during aerobic exercise and recovery. 2. Eleven patients with moderate claudication were studied and results were compared with 25 age-matched control subjects. Changes in pH and phosphocreatine concentration during recovery were used to calculate the maximum rate of oxidative ATP synthesis (Qmax.) and the capacity of net proton efflux. Changes in pH and phosphocreatine concentration were used to estimate rates of non-oxidative and (indirectly) oxidative ATP synthesis throughout exercise, taking account of abnormalities in proton efflux during exercise. 3. In patients with claudication, slow post-exercise phosphocreatine recovery showed a 42 ± 9% decrease in Qmax., and the slow ADP recovery was consistent with this. pH recovery was slow, showing a 77 ± 9% decrease in the capacity for proton efflux. Both abnormalities are compatible with a substantial reduction in muscle blood flow. 4. During exercise, increased phosphocreatine depletion and intracellular acidification were a consequence of impaired oxidative ATP synthesis and the consequent increase in non-oxidative ATP synthesis, compounded by reduced proton efflux. The acidification prevented an increase in ADP concentration which could otherwise partially compensate for the oxidative defect. All these abnormalities are compatible with a reduced muscle blood flow. 5. In addition, initial-exercise changes in pH and phosphocreatine concentration implied a 44 ± 5% reduction in ‘effective muscle mass’, necessitating an ATP turnover (per litre of muscle water) twice as high for given power output as in control muscle. Some of this is probably due to a localized loss of muscle fibres, but the rest appears to reflect reduced metabolic efficiency of the muscle. This is not a direct consequence of reduced blood flow, and may be related to change in muscle fibre type.

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