Exercising skeletal muscle blood flow in humans responds to reduction in arterial oxyhaemoglobin, but not to altered free oxygen

1. We hypothesised that reducing arterial oxyhaemoglobin (O(2)Hb(a)) with c arbon monoxide (CO) in both normoxia and hyperoxia, or acute hypoxia would cause similar compensatory increases in human skeletal muscle blood flow an d vascular conductance during submaximal exercise, despite vast differences in arterial free oxygen partial pressure (P-a,P-O2). 2. Seven healthy males completed four 5 min one-legged knee-extensor exerci se bouts in the semi-supine position (30 +/- 3 W, mean +/- S.E.M.), separat ed by similar to1 h Of rest, under the following conditions: (a) normoxia ( O(2)Hb(a) = 195 ml l(-1); P-a,P-O2 = 105 mmHg); (b) hypoxia (163 ml l(-1); 47 mmHg); (c) CO + normoxia (18% COHb(a); 159 ml l(-1); 119 mmHg); and (d) CO + hyperoxia (19% COHb(a); 158 ml l(-1); 538 mmHg). 3. CO + normoxia, CO + hyperoxia and systemic hypoxia resulted in a 29-44% higher leg blood flow and leg vascular conductance compared to normoxia (P < 0.05), without altering blood pH, blood acid-base balance or net leg lact ate release. 4. Leg blood flow and leg vascular conductance increased in association wit h reduced O(2)Hb(a) (r(2) = 0.92-0.95; P < 0.05), yet were unrelated to alt ered P-a,P-O2. This association was further substantiated in two subsequent studies with graded increases in COHb(a) (n = 4) and NO synthase blockade (n = 2) in the presence of normal P-a,P-O2. 5. The elevated leg blood flow with CO + normoxia and CO + hyperoxia allowe d a similar to 17% greater O-2 delivery (P < 0.05) to exercising muscles, c ompensating for the lower leg O-2 extraction (61%) compared to normoxia and hypoxia (69%; P < 0.05), and thereby maintaining leg oxygen uptake constan t. 6. The compensatory increases in skeletal muscle blood flow and vascular co nductance during exercise with both a CO load and systemic hypoxia are inde pendent of pronounced alterations in P-a,P-O2 (47-538 mmHg), but are closel y associated with reductions in O(2)Hb(a). These results suggest a pivotal role of O-2 bound to haemoglobin in increasing skeletal muscle vasodilatati on during exercise in humans.