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

Abstract

We hypothesised that reducing arterial oxyhaemoglobin (O2Hba) with carbon monoxide (CO) in both normoxia and hyperoxia, or acute hypoxia would cause similar compensatory increases in human skeletal muscle blood flow and vascular conductance during submaximal exercise, despite vast differences in arterial free oxygen partial pressure (Pa,O2). Seven healthy males completed four 5 min one-legged knee-extensor exercise bouts in the semi-supine position (30 +/- 3 W, mean +/- S.E.M.), separated by approximately 1 h of rest, under the following conditions: (a) normoxia (O2Hba = 195 ml l-1; Pa,O2 = 105 mmHg); (b) hypoxia (163 ml l-1; 47 mmHg); (c) CO + normoxia (18% COHba; 159 ml l-1; 119 mmHg); and (d) CO + hyperoxia (19% COHba; 158 ml l-1; 538 mmHg). 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 lactate release. Leg blood flow and leg vascular conductance increased in association with reduced O2Hba (r2 = 0.92-0.95; P < 0.05), yet were unrelated to altered Pa,O2. This association was further substantiated in two subsequent studies with graded increases in COHba (n = 4) and NO synthase blockade (n = 2) in the presence of normal Pa,O2. The elevated leg blood flow with CO + normoxia and CO + hyperoxia allowed a approximately 17% greater O2 delivery (P < 0.05) to exercising muscles, compensating for the lower leg O2 extraction (61%) compared to normoxia and hypoxia (69%; P < 0.05), and thereby maintaining leg oxygen uptake constant. The compensatory increases in skeletal muscle blood flow and vascular conductance during exercise with both a CO load and systemic hypoxia are independent of pronounced alterations in Pa,O2 (47-538 mmHg), but are closely associated with reductions in O2Hba. These results suggest a pivotal role of O2 bound to haemoglobin in increasing skeletal muscle vasodilatation during exercise in humans.

Figures

Figure 1. Schematic diagram of the experimental set-up

The apparatus consists of a closed-circuit respiratory system and an ergometer for knee-extensor exercise (Anderson & Saltin, 1985). The closed-circuit system comprised a 4 l custom-made chamber containing CO2 absorber, a 10 l reservoir, a two-way breathing valve and two hoses connecting the chamber and the breathing valve. The inspiratory gas in the reservoir was adjusted using gas regulators connected to two tanks containing 11% O2 in N2 and 100% O2, while being monitored on-line with a Medgraphics CPX/D metabolic cart. This set-up provides the opportunity to study the systemic (e.g. cardiac output, heart rate, ventilation) and the local regulation of skeletal muscle blood flow while using CO to manipulate the O2 bound to haemoglobin and varying the inspiratory fraction of O2 to alter the O2 dissolved in the blood.

Figure 2. Blood flow and blood pressure responses to submaximal one-legged knee-extensor exercise with normoxia, hypoxia and CO breathing combined with normoxia and hyperoxia

A, leg blood flow. B, mean arterial blood pressure. C, leg vascular conductance. *Significantly higher than normoxia (P < 0.05).

Figure 3. Oxygen parameters measured during submaximal one-legged knee-extensor exercise with normoxia, hypoxia and CO breathing combined with normoxia and hyperoxia

A, leg femoral arterial-to-venous oxygen difference (a-vO2 diff). B, leg oxygen delivery. C, leg oxygen extraction. D, leg oxygen uptake (VO2). *Significantly different from normoxia (P < 0.05).

Figure 7. Effect of NO synthase blockade on skeletal muscle haemodynamics during submaximal one-legged knee-extensor exercise when exposed to systemic hypoxia and CO combined with normoxia

A, leg blood flow. B, mean arterial blood pressure. C, leg vascular conductance. Two subjects underwent this follow-up study showing no effect of NO synthase blockade on skeletal muscle haemodynamics. Data from one of the subjects are depicted.

Figure 4. Relationship between leg blood flow and arterial blood oxygen

A, rise in leg blood flow with reduced oxyhaemoglobin concentration induced by hypoxia and carbon monoxide inhalation under normoxic and hyperoxic conditions. B, lack of relationship between the rise in leg blood flow and the alterations in arterial PO2. C, rise in leg blood flow with reduced arterial oxygen content.

Figure 5. Relationship between leg vascular conductance and arterial blood oxygen

A, rise in leg vascular conductance with reduced oxyhaemoglobin concentration induced by hypoxia and carbon monoxide inhalation under normoxic and hyperoxic conditions. B, lack of relationship between the rise in leg vascular conductance and the alterations in arterial PO2. C, rise in leg vascular conductance with reduced arterial oxygen content.

Figure 6. Effect of graded reductions in arterial oxyhaemoglobin on skeletal muscle haemodynamics during submaximal one-legged knee-extensor exercise

A, leg blood flow. B, mean arterial blood pressure. C, leg vascular conductance. The progressive reductions in arterial oxyhaemoglobin (O2Hb) were produced by graded increases in carboxyhaemoglobin (COHb), i.e. 1.8 ± 0.1, 9.1 ± 0.6 and 15.7 ± 0.8% COHb, when Pa,O2 was maintained between 113 and 117 mmHg. Data are means ±s.e. for 4 subjects.