Erythrocyte and the Regulation of Human Skeletal Muscle Blood Flow and Oxygen Delivery

Abstract

Abstract-Blood flow to contracting skeletal muscle is tightly coupled to the oxygenation state of hemoglobin. To investigate if ATP could be a signal by which the erythrocyte contributes to the regulation of skeletal muscle blood flow and oxygen (O 2 ) delivery, we measured circulating ATP in 8 young subjects during incremental one-legged knee-extensor exercise under conditions of normoxia, hypoxia, hyperoxia, and Key Words: skeletal muscle blood flow Ⅲ erythrocytes Ⅲ oxygen sensor Ⅲ oxygen delivery T he signals regulating the rapid adjustments of skeletal muscle blood flow to exercise and altered inspiratory O 2 fraction have been the focus of more than a century of research. Recently, the idea has been advanced that optimal local circulatory adjustments to alterations in blood oxygenation and exercise require the existence of extracellular and cellular O 2 sensors coupled to signal-transduction systems, which are capable of evoking the appropriate vascular responses in contracting and resting muscle. 1-9 The extensive available evidence demonstrating that alterations in circulating O 2 are inversely related to changes in exercising skeletal muscle blood flow provides indirect support for this notion. 10 -20 To assess the primary extracellular site of O 2 sensing, this laboratory's initial approach was to elucidate whether alterations in skeletal muscle blood flow to exercise in humans were associated with either the amount of O 2 dissolved in circulating plasma or the amount of O 2 bound to hemoglobin. 16,19 Using normoxia, hypoxia, anemia, anemiaϩhypoxia, COϩnormoxia, and COϩhyperoxia as interventions, we found compelling evidence indicating that elevations in exercising muscle blood flow and vascular conductance are independent of pronounced alterations in PaO 2 (40 to 540 mm Hg) but are closely linked to the reductions in arterial oxyhemoglobin. 16,19 Our findings suggest that the main vascular O 2 sensor locus is located in the erythrocyte itself, rather than in the PO 2 sensitive regions of the endothelium or vascular smooth muscle.The red blood cell itself might be involved in the regulation of local blood flow and O 2 delivery by signaling O 2 availability in the erythrocyte. This theory is consistent with the findings from two independent groups of researchers who have demonstrated that red blood cells release ATP 3 and NO 4,5 in response to a fall in hemoglobin O 2 saturation. The release of NO from the S-nitrosohemoglobin molecule with the lowering in oxyhemoglobin is thought to induce the diffusion of the NO group to the vascular endothelium where it stimulates vessel relaxation. 4 -5 ATP in turn can induce vasodilatation by binding to P 2y -purinergic receptors located on the vascular endothelial cells to release NO-and/or endothelium-derived hyperpolarization factors, which diffuse to the vascular smooth muscle and result in vasodilatation. 3 The vasodilator potency of ATP is clearly supported by Original

Mechanisms for the control of local tissue blood flow during thermal interventions: influence of temperature‐dependent ATP release from human blood and endothelial cells

“…1995; González‐Alonso et al . 2002, 2015), is overridden during passive heating in vivo because venous O 2 saturation and tension increase drastically when O 2 delivery rises in the face of an unchanged metabolic demand. In contrast to the responses to heating, plasma [ATP] did not change with graded cooling in vivo .…”

“…1995; González‐Alonso et al . 2002, 2015; Gourine et al . 2010), because metabolic changes in response to local heating and cooling are relatively small (Barcroft & Edholm, 1943; Pearson et al .…”

Blood temperature and perfusion to exercising and non‐exercising human limbs

“…1995; González‐Alonso et al . 2002; Kalsi & González‐Alonso, 2012). ATP is an attractive mediating signal for skeletal muscle blood‐flow regulation, not only because it can act as a potent vasodilator capable of increasing leg perfusion by up to ∼8 l min −1 (Duff et al .…”

“…1954; González‐Alonso et al . 2002, 2008), but also because of its sympatholytic properties in the human limb circulation (Rosenmeier et al . 2004; Kirby et al .…”

“…During exercise in normal environmental conditions, plasma ATP also increases in the forearm and leg circulations (Forrester & Lind, 1969; Forrester, 1972; González‐Alonso et al . 2002; Mortensen et al . 2011), possibly in response to alterations in erythrocyte oxygen binding and other adjuvant metabolic, thermal and mechanical stimuli (Bergfeld & Forrester, 1992; Ellsworth et al .…”