scholarly journals Theoretical model of metabolic blood flow regulation: roles of ATP release by red blood cells and conducted responses

2008 ◽  
Vol 295 (4) ◽  
pp. H1562-H1571 ◽  
Author(s):  
Julia C. Arciero ◽  
Brian E. Carlson ◽  
Timothy W. Secomb
Keyword(s):  
Theoretical Model ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Muscle Mechanics ◽  
Atp Release ◽  
Oxygen Demand ◽  
Flow Regulation ◽  
Response Signal ◽  
Arteriolar Tone ◽  
Conducted Response

A proposed mechanism for metabolic flow regulation involves the saturation-dependent release of ATP by red blood cells, which triggers an upstream conducted response signal and arteriolar vasodilation. To analyze this mechanism, a theoretical model is used to simulate the variation of oxygen and ATP levels along a flow pathway of seven representative segments, including two vasoactive arteriolar segments. The conducted response signal is defined by integrating the ATP concentration along the vascular pathway, assuming exponential decay of the signal in the upstream direction with a length constant of ∼1 cm. Arteriolar tone depends on the conducted metabolic signal and on local wall shear stress and wall tension. Arteriolar diameters are calculated based on vascular smooth muscle mechanics. The model predicts that conducted responses stimulated by ATP release in venules and propagated to arterioles can account for increases in perfusion in response to increased oxygen demand that are consistent with experimental findings at low to moderate oxygen consumption rates. Myogenic and shear-dependent responses are found to act in opposition to this mechanism of metabolic flow regulation.

scholarly journals Theoretical comparison of wall-derived and erythrocyte-derived mechanisms for metabolic flow regulation in heterogeneous microvascular networks

2012 ◽  
Vol 302 (10) ◽  
pp. H1945-H1952 ◽  
Author(s):  
Tuhin K. Roy ◽  
Axel R. Pries ◽  
Timothy W. Secomb
Keyword(s):  
Blood Flow ◽  
Metabolic Regulation ◽  
Muscle Mechanics ◽  
Oxygen Demand ◽  
Flow Regulation ◽  
Oxygen Deficit ◽  
Low Flow ◽  
Microvascular Networks ◽  
Metabolic Signal ◽  
Arteriolar Tone

The objective of this study is to compare the effectiveness of metabolic signals derived from erythrocytes and derived from the vessel wall for regulating blood flow in heterogeneous microvascular networks. A theoretical model is used to simulate blood flow, mass transport, and vascular responses. The model accounts for myogenic, shear-dependent, and metabolic flow regulation. Metabolic signals are assumed to be propagated upstream along vessel walls via a conducted response. Arteriolar tone is assumed to depend on the conducted metabolic signal as well as local wall shear stress and wall tension, and arteriolar diameters are calculated based on vascular smooth muscle mechanics. The model shows that under certain conditions metabolic regulation based on wall-derived signals can be more effective in matching perfusion to local oxygen demand relative to regulation based on erythrocyte-derived signals, resulting in higher extraction and lower oxygen deficit. The lower effectiveness of the erythrocyte-derived signal is shown to result in part from the unequal partition of hematocrit at diverging bifurcations, such that low-flow vessels tend to receive a reduced hematocrit and thereby experience a reduced erythrocyte-derived metabolic signal. The model simulations predict that metabolic signals independent of erythrocytes may play an important role in local metabolic regulation of vascular tone and flow distribution in heterogeneous microvessel networks.

scholarly journals Inhibition of Rho Kinase by Y27632 Increases Low Oxygen Tension‐Induced ATP Release from Human Red Blood Cells (RBCs)

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Kelly Thuet ◽  
Elizabeth Bowles ◽  
Meera Sridharan ◽  
Shaquria Adderley ◽  
Randy Sprague ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Oxygen Tension ◽  
Blood Cells ◽  
Atp Release ◽  
Rho Kinase ◽  
Low Oxygen ◽  
Human Red Blood Cells ◽  
Low Oxygen Tension

ATP Release from Red Blood Cells Is Regulated by a Negative Feedback Pathway where ADP Acts on P2Y13 Receptors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1576-1576
Author(s):  
Martin L. Olsson ◽  
Lingwei Wang ◽  
Goran Olivecrona ◽  
Matthias Gotberg ◽  
Stefan Amisten ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Negative Feedback ◽  
Blood Cells ◽  
Atp Release ◽  
Pig Model ◽  
Coronary Vein ◽  
Human Red Blood Cells ◽  
Adp Receptor ◽  
Tissue Circulation ◽  
Feedback Pathway

Abstract Background: Red blood cells regulate tissue circulation and O2 delivery by releasing the vasodilator adenosine triphosphate (ATP) in response to hypoxia. When released extracellularly, ATP is rapidly degraded to adenosine diphosphate (ADP) in the circulation by ectonucleotidases. ATP and ADP activate subtypes of the large P2 receptor family (15 subtypes). Here we show that ADP acting on P2Y13 receptors on red blood cells serves as a negative feedback pathway for the inhibition of ATP release. Methods: mRNA was quantified with real-time PCR. Western blot was used to detect P2 receptors with available antibodies. cAMP levels were determined with an enzyme immunoassay. ATP release was measured in incubated red blood cells using microdialysis and a luciferase assay. In a pig model, catheters were inserted through the carotid artery to place a catheter in the left coronary artery, and through the jugular vein to place a microdialysis probe in the coronary vein. 2-MeSADP was injected in the artery and ATP levels were measured in the coronary vein. Results: mRNA of the ADP receptor P2Y13 was highly expressed in human red blood cells and reticulocytes, whilst other ADP receptors were not (Fig.1). Figure Figure The stable ADP analogue 2-MeSADP decreased ATP release from red blood cells by inhibition of cAMP. The P2Y12 and P2Y13 receptor antagonist AR-C67085 (30 mM), but not the P2Y1 blocker MRS2179, inhibited the effects of 2-MeSADP. At doses where AR-C67085 only blocks P2Y12 (100 nM), it had no effect. AR-C67085 and the nucleotidase apyrase increased cAMP per se, indicating a constant cAMP inhibitory effect of endogenous extracellular ADP. 2-MeSADP reduced plasma ATP concentrations in an in vivo pig model. Furthermore, a missense polymorphism in the coding region of P2Y13 has been found that is in total disequilibrium with 5 polymorphisms in P2Y12 (the important ADP receptor in platelets) forming a haplotype that could contribute to vascular disease. Conclusion: Our results show that P2Y13 is selectively expressed in human red blood cells. The ATP degradation product ADP inhibited ATP release by acting on this receptor. This negative feedback system could be important in the control of plasma ATP levels and tissue circulation. Because blood consists of approximately 40% red blood cells, containing a 1000-fold higher ATP concentration than plasma (mM vs. uM), even a minor release of ATP from the high intracellular concentrations could have major circulatory effects. A negative system may therefore be of great physiological importance to mitigate ATP release. In addition, this finding could be of interest for efforts to preserve intracellular ATP in red blood cells during storage.

Deformation-induced ATP release from red blood cells requires CFTR activity

1998 ◽  
Vol 275 (5) ◽  
pp. H1726-H1732 ◽  
Author(s):  
Randy S. Sprague ◽  
Mary L. Ellsworth ◽  
Alan H. Stephenson ◽  
Mary E. Kleinhenz ◽  
Andrew J. Lonigro
Keyword(s):  
Cystic Fibrosis ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Atp Release ◽  
Chronic Obstructive Lung Disease ◽  
Mechanical Deformation ◽  
Chronic Obstructive ◽  
Healthy Humans ◽  
Human Red Blood Cells ◽  
Human Rbcs

Recently, it was reported that rabbit and human red blood cells (RBCs) release ATP in response to mechanical deformation. Here we investigate the hypothesis that the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP binding cassette, is required for deformation-induced ATP release from RBCs. Incubation of rabbit RBCs with either of two inhibitors of CFTR activity, glibenclamide (10 μM) or niflumic acid (20 μM), resulted in inhibition of deformation-induced ATP release. To demonstrate the contribution of CFTR to deformation-induced ATP release from human RBCs, cells from healthy humans, patients with cystic fibrosis (CF), or patients with chronic obstructive lung disease (COPD) unrelated to CF were studied. RBCs of healthy humans and COPD patients released ATP in response to mechanical deformation. In contrast, deformation of RBCs from patients with CF did not result in ATP release. We conclude that deformation-induced ATP release from rabbit and human RBCs requires CFTR activity, suggesting a previously unrecognized role for CFTR in the regulation of vascular resistance.

scholarly journals Fall in the ATP levels in the red blood cells in ApoE-LDLR double-deficient mice model prior to atherosclerosis development

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
F C Alcicek ◽  
T Mohaissen ◽  
K Bulat ◽  
E Szczesny-Malysiak ◽  
J Dybas ◽  
...  
Keyword(s):  
Blood Flow ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Matched Control ◽  
Complete Blood Count ◽  
Atp Release ◽  
Animal Testing ◽  
Mice Model ◽  
Intracellular Atp ◽  
Atp Levels

Abstract Background It was previously reported that red blood cells (RBCs) regulate blood flow via RBC-derived ATP [1]. Nevertheless, to the best of our knowledge, no study was performed to characterize possible alterations in RBC ATP levels in ApoE/LDLR−/− mice [2] which constitute a reliable model of human atherosclerosis, displaying distinct erythropathy [3]. Interestingly, young ApoE/LDLR−/− mice display higher exercise capacity and higher O2 carrying capacity of RBCs, as compared to their age-matched control [3,4]. However, it is not known whether increased exerise capacity in ApoE/LDLR−/− mice is linked to altered ATP release from RBCs. It was previously reported that prostacyclin analogs, known atheroprotective agents, which preserve vascular endothelium functions in various diseases [5,6], induce ATP release from human RBCs [1,7]. Purpose To characterize intra- and extra-cellular ATP levels in RBCs isolated from ApoE/LDLR−/− mice in comparison to control mice. Methods All experiments were conducted according to the Guidelines for Animal Care and Treatment of the EU and to the Local Ethical Committee on Animal Testing at our University. For experiments, 8- and 24-week-old C57BL/6 control mice (N=4–6 and N=5–8, respectively) and ApoE/LDLR−/− mice (N=4–7 and N=4–5, respectively) were used. The complete blood count, RBC morphology, biochemistry of blood plasma, RBC deformability, and RBC phosphatidylserine exposure were assessed. The intra- and extra-cellular ATP levels and ATP release from RBCs due to administration of iloprost (100 nM, 1 μM, 10 μm) were studied. Results Intracellular ATP level in RBCs isolated from 8-week-old ApoE/LDLR−/− mice was considerably lower as compared to their age-matched control (7.72±0.77 and 21.23±3.40 pmoles/1x106 RBCs, respectively). In 24-week-old mice, intracellular ATP in RBCs was low not only in ApoE/LDLR−/− mice but also in control mice (8.70±1.30 and 6.27±0.96 pmoles/1x106 RBCs, respectively). Basal extracellular ATP released from RBCs over 30 min incubation was 400 times lower than corresponding intracellular level, and mirrored intracellular ATP levels in all studied groups. Iloprost (100 nM–10 μM) did not produce robust ATP release in any of the studied groups, with only some effects when the highest concentration was used (10 μM). Conclusion(s) Hypercholesterolemia-dependent changes in young ApoE/LDLR−/− mice prior to atherosclerotic plaque development may induce a severe fall in intracellular ATP levels in the RBCs that might be linked to a possible diversion of glycolysis to 2,3-DPG to increase oxygen delivery, and might contribute to the alterations in RBC-dependent regulation of blood flow in ApoE/LDLR−/−. Further studies are required to mechanistically explain these findings. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1) National Science Centre, Poland2) the Innovation Incubator 4.0 project funded by the Ministry of Science and Higher Education, Poland

scholarly journals Liposomal Delivery of a Phosphodiesterase 5 Inhibitor Enhances Prostacyclin-Mediated Adenosine Triphosphate Release from Human Red Blood Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4803-4803
Author(s):  
Elizabeth Bowles ◽  
Randy Sprague ◽  
Nuran Ercal
Keyword(s):  
Side Effects ◽  
Red Blood Cells ◽  
Adenosine Triphosphate ◽  
Blood Cells ◽  
Conflicts Of Interest ◽  
Pde5 Inhibitor ◽  
Atp Release ◽  
Pde5 Inhibitors ◽  
Phosphodiesterase 5 ◽  
Human Rbcs

Abstract Pulmonary arterial hypertension (PAH) is characterized by high pulmonary vascular resistance (PVR) and right heart failure. Red blood cells (RBCs) of PAH patients fail to release the vasodilator, adenosine triphosphate (ATP), when deformed as would occur when traversing the lung. Such a defect could contribute to increased PVR. However, RBCs of PAH patients do release ATP in response to prostacyclin (PGI2) analogs and this is augmented by phosphodiesterase 5 (PDE5) inhibitors. Current PAH treatment includes PGI2 analogs and PDE5 inhibitors alone or in combination. Unfortunately, these drugs can have untoward side effects. Encapsulation of drugs within liposomes (small lipid-membraned vesicles) that can be targeted to RBCs has been shown to increase effectiveness and tolerability of some medications. The objective of this study was to determine if encapsulation of the PDE5 inhibitor zaprinast (ZAP) within liposomes is an effective means to deliver this class of drugs to human RBCs and if this approach would augment ATP release stimulated by the PGI2 analog UT-15c. Human RBCs were isolated and incubated with either blank liposomes (n=10), liposomes containing ZAP (n=9) or liposomes containing the PDE3 inhibitor, cilosatzol (CILO, n=10). RBCs (20% hematocrit) were then treated with UT-15c (1 µM). ATP release was measured before and 5, 10, and 15 min after the addition of UT-15c. In the presence of empty liposomes, the dose of UT-15c used did not stimulate ATP release. However, UT-15c did stimulate ATP release from RBCs pretreated with ZAP encapsulated by liposomes (P<0.01). The average time for maximal release was 9 ± 1 min. In contrast, when exposed to liposomes containing CILO, there was no ATP release following UT-15c administration. These studies demonstrate that the selective delivery of a PDE5 inhibitor to human RBCs potentiates UT-15c induced ATP release. Moreover the findings are consistent with the hypothesis that directed delivery of this class of drugs to PAH RBCs could be a new and important method to augment PGI2 analog-induced ATP release from these cells. Such an approach could significantly limit side effects of both drugs without compromise of their therapeutic effectiveness in PAH. Disclosures No relevant conflicts of interest to declare.

Red blood cell regulation of microvascular tone through adenosine triphosphate

2000 ◽  
Vol 278 (4) ◽  
pp. H1294-H1298 ◽  
Author(s):  
Hans H. Dietrich ◽  
Mary L. Ellsworth ◽  
Randy S. Sprague ◽  
Ralph G. Dacey
Keyword(s):  
Blood Flow ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Tissue Perfusion ◽  
Vessel Diameter ◽  
Flow Regulation ◽  
Vascular Control ◽  
Cerebral Arterioles

The matching of blood flow with metabolic need requires a mechanism for sensing the needs of the tissue and communicating that need to the arterioles, the ultimate controllers of tissue perfusion. Despite significant strides in our understanding of blood flow regulation, the identity of the O2 sensor has remained elusive. Recently, the red blood cell, the Hb-containing O2carrier, has been implicated as a potential O2 sensor and contributor to this vascular control by virtue of its concomitant carriage of millimolar amounts of ATP, which it is able to release when exposed to a low-O2 environment. To evaluate this possibility, we exposed perfused cerebral arterioles to low extraluminal O2 in the absence and presence of red blood cells or 6% dextran and determined both vessel diameter and ATP in the vessel effluent. Only when the vessels were perfused with red blood cells did the vessels dilate in response to low extraluminal O2. In addition, this response was accompanied by a significant increase in vessel effluent ATP. These findings support the hypothesis that the red blood cell itself serves a role in determining O2 supply to tissue.

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