The effects of RSR13 on microvascular PO2 kinetics and muscle contractile performance in the rat arterial ligation model of peripheral arterial disease

Exercise intolerance and claudication are symptomatic of peripheral arterial disease. There is a close relationship between muscle O₂ delivery, microvascular oxygen partial pressure (PmvO₂) and contractile performance. We therefore hypothesized that a reduction of hemoglobin-oxygen affinity via RSR13 would maintain a higher PmvO₂ and enhance blood-muscle O₂ transport and contractile function. In male Wistar rats we created hindlimb ischemia via right side iliac artery ligation (AL). The contralateral (left) muscle served as control (CONT). Seven days after AL, phosphorescence quenching techniques were used to measure PmvO₂ at rest and during contractions (electrical stimulation) in tibialis anterior muscle (TA) under saline (n = 10) or RSR13 (n =10) conditions. RSR13 at rest increased TA PmvO₂ in CONT (13.9 to 19.3 torr, P < 0.05) and AL (9.0 to 9.9 torr, P < 0.05). Furthermore RSR13 extended maintenance of the initial TA force (i.e. improved contractile performance) such that force was not decreased significantly until contraction 240 versus 150 in CONT and 80 versus 20 in AL. This improved muscle endurance with RSR 13 was accompanied by a greater PmvO₂ (PmvO₂ decrease from baseline) (CONT: 7.4 to 11.2, AL: 6.9 to 8.6 torr, both P < 0.05). Whereas RSR13 did not alter the kinetics profile of PmvO₂ (i.e. mean response time) substantially during contractions, muscle force was elevated and the ratio of muscle force-to-PmvO₂ increased. In conclusion, reduction of hemoglobin-oxygen affinity via RSR13 in AL increased PmvO₂ and improved muscle contractile performance most likely via enhanced blood-muscle O₂ diffusion.

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