Figure 7. Schematic diagram illustrating how erythrocyte-derived ATP contributes to the local regulation of O₂ supply to active skeletal muscle.

The red blood cells contribute to the regulation of the local processes matching O₂ supply and demand, in part by releasing the vasodilator and sympatholytic substance ATP into the vascular lumen. In vivo in exercising limb muscle, ATP is released from red blood cells in response to several metabolic and mechanical stimuli, including reduced oxyhaemoglobin, , and pH and augmented blood temperature, mechanical deformation of RBCs and elevated shear stress. The released ATP binds to vascular endothelial P₂Y purinergic receptors expressed in the endothelium of microvessels and smooth muscle cells of human limbs. In so doing, it induces profound local and conducted vasodilatation by stimulating endothelial NO, prostaglandins, EDHF production and possibly other endothelial vasoactive signals, while also modulating α₁- and α₂-adrenergic vasoconstrictor influences of increases in muscle sympathetic nerve activity (MSNA) during exercise.