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

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 approximately 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.

[1]  B. Folkow A critical study of some methods used in investigations on the blood circulation. , 1953, Acta physiologica Scandinavica.

[2]  A. Otis,et al.  BLOOD FLOW, BLOOD OXYGEN TENSION, OXYGEN UPTAKE, AND OXYGEN TRANSPORT IN SKELETAL MUSCLE. , 1964, The American journal of physiology.

[3]  A. Somlyo,et al.  VASCULAR SMOOTH MUSCLE , 1968 .

[4]  D. Horstman,et al.  Effects of altering O2 delivery on VO2 of isolated, working muscle. , 1976, The American journal of physiology.

[5]  H N Mayrovitz,et al.  Microvascular blood flow: evidence indicating a cubic dependence on arteriolar diameter. , 1983, The American journal of physiology.

[6]  N. Simionescu,et al.  The Cardiovascular System , 1983 .

[7]  T C Skalak,et al.  The microvasculature in skeletal muscle. I. Arteriolar network in rat spinotrapezius muscle. , 1985, Microvascular research.

[8]  Arthur C. Guyton,et al.  Handbook of Physiology—The Cardiovascular System , 1985 .

[9]  B. Saltin,et al.  Maximal perfusion of skeletal muscle in man. , 1985, The Journal of physiology.

[10]  G. Schmid-Schönbein,et al.  The microvasculature in skeletal muscle. II. Arteriolar network anatomy in normotensive and spontaneously hypertensive rats. , 1986, Microvascular research.

[11]  R. D. Hogan,et al.  Vasomotor control: functional hyperemia and beyond. , 1987, Federation proceedings.

[12]  R. Regal,et al.  Relation of blood flow to VO2, PO2, and PCO2 in dog gastrocnemius muscle. , 1988, The American journal of physiology.

[13]  M. J. Davis,et al.  Myogenic responses of isolated arterioles: test for a rate-sensitive mechanism. , 1990, The American journal of physiology.

[14]  M. J. Davis,et al.  Endothelial independence of myogenic response in isolated skeletal muscle arterioles. , 1991, The American journal of physiology.

[15]  T. Forrester,et al.  Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. , 1992, Cardiovascular research.

[16]  J. Tarbell,et al.  Mechanisms of flow-mediated signal transduction in endothelial cells: kinetics of ATP surface concentrations. , 1992, Journal of vascular research.

[17]  W Schaffartzik,et al.  Relationship between body and leg VO2 during maximal cycle ergometry. , 1992, Journal of applied physiology.

[18]  J. Barberà,et al.  Effects of training on muscle O2 transport at VO2max. , 1992, Journal of applied physiology.

[19]  D. Poole,et al.  Effect of reduced hemoglobin concentration on leg oxygen uptake during maximal exercise in humans. , 1993, Journal of applied physiology.

[20]  T. Secomb,et al.  Simulation of O2 transport in skeletal muscle: diffusive exchange between arterioles and capillaries. , 1994, The American journal of physiology.

[21]  A. Pries,et al.  Resistance to blood flow in microvessels in vivo. , 1994, Circulation research.

[22]  A. Pries,et al.  Design principles of vascular beds. , 1995, Circulation research.

[23]  B. Duling,et al.  Electromechanical coupling and the conducted vasomotor response. , 1995, The American journal of physiology.

[24]  A. Koller,et al.  Flow‐Dependent Dilation and Myogenic Constriction Interact to Establish the Resistance of Skeletal Muscle Arterioles , 1995, Microcirculation.

[25]  J. Pearson,et al.  Kinetics of extracellular ATP hydrolysis by microvascular endothelial cells from rat heart. , 1995, The Biochemical journal.

[26]  A. Pries,et al.  Biophysical aspects of blood flow in the microvasculature. , 1996, Cardiovascular research.

[27]  J. Spaan,et al.  Shear stress is not sufficient to control growth of vascular networks: a model study. , 1996, The American journal of physiology.

[28]  A. Pries,et al.  Relationship between structural and hemodynamic heterogeneity in microvascular networks. , 1996, The American journal of physiology.

[29]  M. Ellsworth,et al.  Arteriolar responses to extracellular ATP in striated muscle. , 1997, The American journal of physiology.

[30]  I. T. Demchenko,et al.  Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. , 1997, Science.

[31]  I H Sarelius,et al.  Direct coupling between blood flow and metabolism at the capillary level in striated muscle. , 1997, The American journal of physiology.

[32]  G Burnstock,et al.  Receptors for purines and pyrimidines. , 1998, Pharmacological reviews.

[33]  G. Thurston,et al.  Inhibition of nitric oxide synthesis increases venular permeability and alters endothelial actin cytoskeleton. , 1998, American journal of physiology. Heart and circulatory physiology.

[34]  J. Beach,et al.  Capillaries and arterioles are electrically coupled in hamster cheek pouch. , 1998, The American journal of physiology.

[35]  M. Ellsworth,et al.  Conducted vascular responses: communication across the capillary bed. , 1998, Microvascular research.

[36]  J. Roca,et al.  Evidence of O2 supply-dependent VO2 max in the exercise-trained human quadriceps. , 1999, Journal of applied physiology.

[37]  B. Kiens,et al.  Hyperoxia does not increase peak muscle oxygen uptake in small muscle group exercise. , 1999, Acta physiologica Scandinavica.

[38]  J. Leigh,et al.  Cellular PO2 as a determinant of maximal mitochondrial O(2) consumption in trained human skeletal muscle. , 1999, Journal of applied physiology.

[39]  G. G. Emerson,et al.  Endothelial cell pathway for conduction of hyperpolarization and vasodilation along hamster feed artery. , 2000, Circulation research.

[40]  T. Gloe,et al.  Large arterioles in the control of blood flow: role of endothelium-dependent dilation. , 2000, Acta physiologica Scandinavica.

[41]  I. Sarelius,et al.  Remote arteriolar dilations in response to muscle contraction under capillaries. , 2000, American journal of physiology. Heart and circulatory physiology.

[42]  M L Ellsworth,et al.  The red blood cell as an oxygen sensor: what is the evidence? , 2000, Acta physiologica Scandinavica.

[43]  B. Reglin,et al.  Structural adaptation of microvascular networks: functional roles of adaptive responses. , 2001, American journal of physiology. Heart and circulatory physiology.

[44]  T. Secomb,et al.  A theoretical model for oxygen transport in skeletal muscle under conditions of high oxygen demand. , 2001, Journal of applied physiology.

[45]  C G Ellis,et al.  Role of erythrocyte in regulating local O2 delivery mediated by hemoglobin oxygenation. , 2001, American journal of physiology. Heart and circulatory physiology.

[46]  B. Saltin,et al.  Erythrocyte and the Regulation of Human Skeletal Muscle Blood Flow and Oxygen Delivery: Role of Circulating ATP , 2002, Circulation research.

[47]  R. Hester,et al.  Venular-arteriolar communication in the regulation of blood flow. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[48]  D. Poole,et al.  Skeletal muscle capillary hemodynamics from rest to contractions: implications for oxygen transfer. , 2002, Journal of applied physiology.

[49]  Axel R Pries,et al.  Information Transfer in Microvascular Networks , 2002, Microcirculation.

[50]  D. Paul,et al.  Central Role of Connexin40 in the Propagation of Electrically Activated Vasodilation in Mouse Cremasteric Arterioles In Vivo , 2003, Circulation research.

[51]  A. Fuglevand,et al.  Oxygen delivery to skeletal muscle fibers: effects of microvascular unit structure and control mechanisms. , 2003, American journal of physiology. Heart and circulatory physiology.

[52]  T. Secomb,et al.  Estimation of capillary density in human skeletal muscle based on maximal oxygen consumption rates. , 2003, American journal of physiology. Heart and circulatory physiology.

[53]  S. Segal,et al.  Interaction between sympathetic nerve activation and muscle fibre contraction in resistance vessels of hamster retractor muscle , 2003, The Journal of physiology.

[54]  I. Sarelius,et al.  Conducted dilations initiated by purines in arterioles are endothelium dependent and require endothelial Ca2+. , 2003, American journal of physiology. Heart and circulatory physiology.

[55]  Iain S. Bartlett,et al.  Homocellular Conduction Along Endothelium and Smooth Muscle of Arterioles in Hamster Cheek Pouch: Unmasking an NO Wave , 2003, Circulation research.

[56]  K. Jacobson,et al.  Nucleotide coronary vasodilation in guinea pig hearts. , 2003, American journal of physiology. Heart and circulatory physiology.

[57]  P. Buehler,et al.  Oxygen sensing in the circulation: "cross talk" between red blood cells and the vasculature. , 2004, Antioxidants & redox signaling.

[58]  S. Segal,et al.  Neural control of muscle blood flow during exercise. , 2004, Journal of applied physiology.

[59]  M. L. Ellsworth,et al.  Red blood cell-derived ATP as a regulator of skeletal muscle perfusion. , 2004, Medicine and science in sports and exercise.

[60]  Timothy W. Secomb,et al.  Green's Function Methods for Analysis of Oxygen Delivery to Tissue by Microvascular Networks , 2004, Annals of Biomedical Engineering.

[61]  R. Sprague,et al.  Heterotrimeric G protein Gi is involved in a signal transduction pathway for ATP release from erythrocytes. , 2004, American journal of physiology. Heart and circulatory physiology.

[62]  E. Feigl,et al.  Plasma ATP during exercise: possible role in regulation of coronary blood flow. , 2005, American journal of physiology. Heart and circulatory physiology.

[63]  Timothy W Secomb,et al.  A Theoretical Model for the Myogenic Response Based on the Length–Tension Characteristics of Vascular Smooth Muscle , 2005, Microcirculation.

[64]  Guy Salama,et al.  Propagated Endothelial Ca2+ Waves and Arteriolar Dilation In Vivo: Measurements in Cx40BAC-GCaMP2 Transgenic Mice , 2007, Circulation research.

[65]  Chien-Chang Chen,et al.  Are voltage-dependent ion channels involved in the endothelial cell control of vasomotor tone? , 2007, American journal of physiology. Heart and circulatory physiology.

[66]  B. E. Carlson,et al.  Theoretical model of blood flow autoregulation: roles of myogenic, shear-dependent, and metabolic responses. , 2008, American journal of physiology. Heart and circulatory physiology.