ATP: the red blood cell link to NO and local control of the pulmonary circulation

Abstract

Recently, we reported that rabbit red blood cells (RBCs) were required for the expression of nitric oxide (NO) activity on pulmonary vascular resistance (PVR) in rabbit lungs. Here, we investigate the hypothesis that RBCs participate in the regulation of PVR via release of ATP in response to mechanical deformation that, in turn, evokes vascular NO synthesis. We found that rabbit and human RBCs, but not dog RBCs, release ATP in response to mechanical deformation. To determine the contribution of this ATP to NO synthesis and PVR, we compared the effects of human and dog RBCs on pressure-flow relationships in isolated rabbit lungs. In the presence of human RBCs, NG-nitro-L-arginine methyl ester (100 microM) produced a shift in the pressure-flow relationship consistent with a reduction in vascular caliber. NG-nitro-L-arginine methyl ester had no effect in lungs perfused with dog RBCs. These results suggest a unique mechanism for the control of PVR in rabbits and humans whereby release of ATP by RBCs in response to mechanical deformation leads to stimulation of NO synthesis that, in turn, modulates the PVR.

The Age-Old Tale of Skeletal Muscle Vasodilation: New Ideas Regarding Erythrocyte Dysfunction and Intravascular ATP in Human Physiology

“…We openly acknowledge this limitation in our manuscript and are working to develop a selective antagonist. However, with respect to hypoxic vasodilation in resistance vessels, a number of important observations support our data: (1) perfusion of isolated resistance vessels with a buffer lacking erythrocytes fails to elicit vasodilation when extraluminal oxygen tension is reduced 11 ; (2) perfusion of isolated skeletal muscle resistance vessels with erythrocytes not capable of releasing ATP does not elicit vasodilation in response to this stimulus 12,13 ; (3) rescuing low O 2 -induced ATP release from diseased erythrocytes restores vasodilation when extraluminal oxygen tension is reduced. 12 These studies to date have not been performed within contracting muscle, and although this would be technically difficult, is certainly an area in need of future investigation.…”

Cell-Free and Erythrocytic S -Nitrosohemoglobin Inhibits Human Platelet Aggregation

“…The answer may also lie in the vascular endothelium. Indeed, Sprague et al 29 recently found that human RBCs release ATP in response to mechanical deformation; this ATP evokes the release of NO, thereby lowering pulmonary vascular resistance. Endothelial activation in this manner should attenuate platelet aggregation.…”

Role of A2A‐adenosine receptor activation for ATP‐mediated coronary vasodilation in guinea‐pig isolated heart

“…ATP can be released from endothelium in response to increases in shear stress (Bodin et al, 1991) and from perivascular nerve terminals (Ralevic & Burnstock, 1998;Burnstock & Kennedy, 1986). In¯ammatory mediators, ischaemia, and damage to blood vessels also cause ATP release from endothelial cells, neutrophils, cardiomyocytes, erythrocytes and platelets (Borst & Schrader, 1991;Born & Kratzer, 1984;Bodin & Burnstock, 1998;Pearson & Gordon, 1985;Yang et al, 1994;Bergfeld & Forrester, 1992;Gordon, 1986;Ralevic & Burnstock, 1991;1998;Sprague et al, 1996;Olsson & Pearson, 1990). ATP is rapidly broken down to adenosine by endothelial ectonucleotidases (Pearson & Gordon, 1985).…”