The effects of RSR13 on microvascular Po2 kinetics and muscle contractile performance in the rat arterial ligation model of peripheral arterial disease

Abstract

Exercise intolerance and claudication are symptomatic of peripheral arterial disease. There is a close relationship between muscle O2 delivery, microvascular oxygen partial pressure (P mvO2), and contractile performance. We therefore hypothesized that a reduction of hemoglobin-oxygen affinity via RSR13 would maintain a higher P mvO2 and enhance blood-muscle O2 transport and contractile function. In male Wistar rats (12 wk of age), 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 P mvO2 at rest and during contractions (electrical stimulation; 1 Hz, 300 s) in tibialis anterior muscle (TA) under saline ( n = 10) or RSR13 ( n = 10) conditions. RSR13 at rest increased TA P mvO2 in CONT (13.9 ± 1.6 to 19.3 ± 1.9 Torr, P < 0.05) and AL (9.0 ± 0.5 to 9.9 ± 0.7 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 vs. 150 in CONT and 80 vs. 20 in AL. This improved muscle endurance with RSR13 was accompanied by a greater ΔP mvO2 (P mvO2 decrease from baseline) (CONT, 7.4 ± 1.0 to 11.2 ± 1.3; AL, 6.9 ± 0.5 to 8.6 ± 0.6 Torr, both P < 0.05). Whereas RSR13 did not alter the kinetics profile of P mvO2 (i.e., mean response time) substantially during contractions, muscle force was elevated, and the ratio of muscle force to P mvO2 increased. In conclusion, reduction of hemoglobin-oxygen affinity via RSR13 in AL increased P mvO2 and improved muscle contractile performance most likely via enhanced blood-muscle O2 diffusion. NEW & NOTEWORTHY This is the first investigation to examine the effect of RSR13 (erythrocyte allosteric effector) on skeletal muscle microvascular oxygen partial pressure kinetics and contractile function using an arterial ligation model of peripheral arterial disease in experimental animals. The present results provide strong support for the concept that reducing hemoglobin-O2 affinity via RSR13 improved tibialis anterior muscle contractile performance most likely via enhanced blood-muscle O2 diffusion.