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J Physiol 572.1 (2006) pp 295–305

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Erythrocytes and the regulation of human skeletal muscle blood flow and oxygen delivery: role of erythrocyte count and oxygenation state of haemoglobin
Jos´ Gonz´ lez-Alonso1,3 , Stefan P. Mortensen1 , Ellen A. Dawson1,2 , Niels H. Secher1,2 e a and Rasmus Damsgaard1
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The Copenhagen Muscle Research Centre, 2 Department of Anaesthesia,Rigshospitalet, University of Copenhagen, Denmark Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge, Middlesex UB8 3PH, UK

Blood flow to dynamically contracting myocytes is regulated to match O2 delivery to metabolic demand. The red blood cell (RBC) itself functions as an O2 sensor, contributing to the control of O2 delivery by releasing the vasodilators ATP andS-nitrosohaemoglobin with the offloading of O2 from the haemoglobin molecule. Whether RBC number is sensed remains unknown. To investigate the role of RBC number, in isolation and in combination with alterations in blood oxygenation, on muscle and systemic perfusion, we measured local and central haemodynamics during one-legged knee-extensor exercise (∼50% peak power) in 10 healthy males under conditions ofnormocythaemia (control), anaemia, anaemia + plasma volume expansion (PVX), anaemia + PVX + hypoxia, polycythaemia, polycythaemia + hyperoxia and polycythaemia + hypoxia, which changed either RBC count alone or both RBC count and oxyhaemoglobin. Leg blood flow (LBF), cardiac output (Q) and vascular conductance did not change with either anaemia or polycythaemia alone. However, LBF increased with anaemia+ PVX (28 ± 4%) and anaemia + PVX + hypoxia (46 ± 6%) and decreased with polycythaemia + hyperoxia (18 ± 5%). LBF and Q with anaemia + PVX + hypoxia (8.0 ± 0.5 and 15.8 ± 0.7 l min−1 , respectively) equalled those during maximal knee-extensor exercise. Collectively, LBF and vascular conductance were intimately related to leg arterial–venous (a–v) O2 difference (r 2 = 0.89–0.93; P < 0.001),suggesting a pivotal role of blood O2 gradients in muscle microcirculatory control. The systemic circulation accommodated to the changes in muscle perfusion. Our results indicate that, when coping with severe haematological challenges, local regulation of skeletal muscle blood flow and O2 delivery primarily senses alterations in the oxygenation state of haemoglobin and, to a lesser extent, alterations inthe number of RBCs and haemoglobin molecules.
(Received 2 November 2005; accepted after revision 23 January 2006; first published online 26 January 2006) Corresponding author J. Gonz´ lez-Alonso: Centre for Sports Medicine and Human Performance, Brunel University, a Uxbridge, Middlesex UB8 3PH, UK. Email: j.gonzalez-alonso@brunel.ac.uk

Blood flow to dynamically contracting myocytes is regulatedto match O2 delivery to metabolic demand. This complex regulatory process is classically thought to integrate metabolic, myogenic and neural signals that are either released into the vascular lumen or accumulate in the muscle interstitial space as a result of the enhanced myocyte metabolism (Laughlin et al. 1996). Recently, the idea has been advanced that signals released from the circulatingerythrocytes in association with the offloading of O2 from the haemoglobin molecule contribute to the local regulation of blood flow and ultimately O2 delivery in the microcirculation (Ellsworth et al. 1995; Stamler et al. 1997; Gonz´ lez-Alonso et al. 2002). Support for this theory a is found in both in vitro and in vivo reports demonstrating
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that: (1) red blood cells (RBCs) release thevasodilators ATP and S-nitrosohaemoglobin (SNO-Hb) when exposed to hypoxia (Bergfeld & Forrester, 1992; Ellsworth et al. 1995; Jia et al. 1996; Stamler et al. 1997; McMahon et al. 2002; (2) perfusion of the isolated arterioles with a buffer or dextran solution, instead of RBCs, does not increase vessel diameter and affluent ATP with exposure to low PO2 (Dietrich et al. 2000); (3) alterations in blood O2...