The effects of torbafylline on blood flow, pO2 and function of rat ischaemic skeletal muscle

Blood flow at rest and during contractions (measured with labelled microspheres), red cell flux (assessed by laser-Doppler flowmetry), surface pO2, lactate accumulation and release, the development of fatigue during acute muscle contractions, and performance in chronic experiments (running wheel) were estimated in rat hind limb muscles during unilateral acute occlusion or chronic ligation of the femoral artery. The effects of torbafylline (7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)3-methylxanthine) on the above-mentioned parameters were studied after acute i.v. infusion or chronic oral gavage. Torbafylline significantly ameliorated the decreased skeletal muscle blood flow, red cell flux and surface pO2 after acute occlusion of the femoral artery, with more pronounced effects on the microcirculatory parameters, the laser-Doppler flux and pO2. Chronic ligation of the femoral artery and consequent stimulation for 45 min induced increased fatigue (fatigue index in control muscles: 70%, in ligated muscles: 78%). Three weeks oral treatment with torbafylline (25 mg/kg per day) decreased fatigue to 68%. The blood flow in ligated muscles increased to a much smaller extent than in control muscles, and this smaller increase was attenuated by torbafylline. A chronic decrease in the blood supply resulted in a significant shortening of the running time. This decrease in running time was reversed by chronic treatment with torbafylline (25 mg/kg p.o. 2 times-day for 2 weeks). This improved performance may be explained by a decreased accumulation of lactate in muscles with a limited blood supply due to an effect of torbafylline to increase the release of lactate from ischaemic muscles.