Abstract
Coronary vascular resistance is regulated by a variety of factors including arterial pressure, myocardial metabolism, autonomic nervous system as well as arterial O2 tension (hypoxia). Progressive hypoxemia results in graded coronary vasodilation that is significantly more pronounced when arterial O2 tension falls below 40 mmHg. Microvascular studies have demonstrated that O2 has direct effects on vascular smooth muscle likely mediated by O2 sensors located in vessels < 15 ΰm diameter. Recent data indicates that hypoxia-induced inhibition of the pentose phosphate pathway and the subsequent decreases in NADPH and intracellular Ca2+ represent an important O2 sensing mechanism in vascular smooth muscle. However, in vivo experiments suggest direct microvascular effects of O2 contribute little to hypoxic coronary vasodilation. The vasodilation is mediated, in part, by local vasoactive metabolites produced in proportion to the degree of hypoxemia, reflex-mediated increases in myocardial metabolism and diminished myocardial tissue oxygenation. In particular, production of adenosine has been shown to increase exponentially with the degree of hypoxia and blockade or degradation of adenosine markedly impairs hypoxia-induced coronary vasodilation. Other investigations support the role of endothelial derived relaxing factors (nitric oxide, prostacyclin) in control of coronary blood flow during hypoxia. Additionally, reductions in PO2 hyperpolarize coronary vascular smooth muscle via K+ ATP channels which represent important “end effectors” that significantly contribute to hypoxic coronary vasodilation. Taken together, these data indicate that the coronary vascular response to hypoxia depends on metabolic and endothelial vasodilatory factors that are produced in proportion to the degree of hypoxemia and that function through mechanisms depending on K +ATP channels.
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References
Audibert G, Saunier CG, Siat J, Hartemann D and Lambert J. Effect of the inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester, on cerebral and myocardial blood flows during hypoxia in the awake dog. Anesth Analg81:945-951, 1995.
Bache RJ, Dai XZ, Schwartz JS and Homans DC. Role of adenosine in coronary vasodilation during exercise. Circ Res62:846-853, 1988.
Bergfeld GR and Forrester T. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res26:40- 47, 1992.
Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol204:317-322, 1963.
Berne RM. Regulation of coronary blood flow. Physiol Rev44:1-29, 1964.
Berne RM, Blackmon JR and Gardner TH. Hypoxemia and coronary blood flow. J Clin Invest36:1101-1106, 1957.
Bristow MR, Anderson FL, Port JD, Skerl L, Hershberger RE, Larrabee P, O’Connell JB, Renlund DG, Volkman K, Murray J. Differences in betaadrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation84:1024-1039, 1991.
Brown IP, Thompson CI and Belloni FL. Role of nitric oxide in hypoxic coronary vasodilatation in isolated perfused guinea pig heart. Am J Physiol264: H821-H829, 1993.
Busse R, Forstermann U, Matsuda H and Pohl U. The role of prostaglandins in the endothelium-mediated vasodilatory response to hypoxia. Pflugers Arch401:77-83, 1984.
Coburn RF, Ploegmakers F, Gondrie P and Abboud R. Myocardial myoglobin oxygen tension. Am J Physiol224:870-876, 1973.
Dart C and Standen NB. Activation of ATP-dependent K+ channels by hypoxia in smooth muscle cells isolated from the pig coronary artery. J Physiol483 ( Pt 1):29- 39, 1995.
Daut J, Maier-Rudolph W, von BN, Mehrke G, Gunther K and Goedel-Meinen L. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science247:1341-1344, 1990.
Deussen A, Borst M, Kroll K and Schrader J. Formation of S-adenosylhomocysteine in the heart. II: A sensitive index for regional myocardial underperfusion. Circ Res 63:250-261, 1988.
Deussen A, Borst M and Schrader J. Formation of S-adenosylhomocysteine in the heart. I: An index of free intracellular adenosine. Circ Res63:240-249, 1988.
Deussen A, Brand M, Pexa A and Weichsel J. Metabolic coronary flow regulation- Current concepts. Basic Res Cardiol101:453-464, 2006.
Dietrich HH, Ellsworth ML, Sprague RS and Dacey RG, Jr. Red blood cell regulation of microvascular tone through adenosine triphosphate. Am J Physiol Heart Circ Physiol278: H1294-H1298, 2000.
Doherty JU and Liang CS. Arterial hypoxemia in awake dogs. Role of the sympathetic nervous system in mediating the systemic hemodynamic and regional blood flow responses. J Lab Clin Med104:665-677, 1984.
Downey HF, Crystal GJ, Bockman EL and Bashour FA. Nonischemic myocardial hypoxia: coronary dilation without increased tissue adenosine. Am J Physiol243: H512-H516, 1982.
Downey HF, Grice DP and Jones CE. Systemic hypoxia activates a coronary vasoconstrictor reflex response that is blocked by prazosin. J Cardiovasc Pharmacol 18:657-664, 1991.
Downey HF, Murakami H and Kim SJ. Control of coronary vascular tone during altered myocardial oxygen demand and during altered myocardial oxygen. Hypoxia Medical J3:120-127, 1998.
Duncker DJ and Merkus D. Acute adaptations of the coronary circulation to exercise. Cell Biochem Biophys43:17-35, 2005.
Duncker DJ, van Zon NS, Ishibashi Y and Bache RJ. Role of K+ ATP channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow. J Clin Invest97:996-1009, 1996.
Duza T and Sarelius IH. Conducted dilations initiated by purines in arterioles are endothelium dependent and require endothelial Ca2+. Am J Physiol Heart Circ Physiol285: H26-H37, 2003.
Ellsworth ML. The red blood cell as an oxygen sensor: what is the evidence? Acta Physiol Scand168:551-559, 2000.
Ellsworth ML, Forrester T, Ellis CG and Dietrich HH. The erythrocyte as a regulator of vascular tone. Am J Physiol269: H2155-H2161, 1995.
Erickson HH and Stone HL. Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia. Aerosp Med43:422- 428, 1972.
Farias M, III, Gorman MW, Savage MV and Feigl EO. Plasma ATP during exercise: possible role in regulation of coronary blood flow. Am J Physiol Heart Circ Physiol 288: H1586-H1590, 2005.
Feigl EO. Coronary physiology. Physiol Rev63:1-205, 1983.
Feigl EO. Berne’s adenosine hypothesis of coronary blood flow control. Am J Physiol Heart Circ Physiol287: H1891-H1894, 2004.
Feinberg H, Gerola A, Katz LN and Boyd E. Effect of hypoxia on cardiac oxygen consumption and coronary flow. Am J Physiol195:593-600, 1958.
Feletou M and Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol291: H985-1002, 2006.
Folle LE and Viado DM. Cardiovascular effects of anoxia and the influence of a new beta adrenergic receptor blocking drug. J Pharmacol Exp Ther149:79-90, 1965.
Gauthier-Rein KM, Bizub DM, Lombard JH and Rusch NJ. Hypoxia-induced hyperpolarization is not associated with vasodilation of bovine coronary resistance arteries. Am J Physiol272: H1462-H1469, 1997.
Gewirtz H, Olsson RA and Most AS. Role of adenosine in mediating the coronary vasodilative response to acute hypoxia. Cardiovasc Res21:81-89, 1987.
Gorman MW, Ogimoto K, Savage MV, Jacobson KA and Feigl EO. Nucleotide coronary vasodilation in guinea pig hearts. Am J Physiol Heart Circ Physiol285: H1040-H1047, 2003.
Gorman MW, Tune JD, Richmond KN and Feigl EO. Feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol89:1892-1902, 2000.
Gremels H and Starling EH. On the influence of hydrogen ion concentration and of anoxaemia upon the heart volume. J Physiol61:297-304, 1926.
Grser T and Rubanyi GM. Different mechanisms of hypoxic relaxation in canine coronary arteries and rat abdominal aortas. J Cardiovasc Pharmacol20 Suppl 12: S117-S119, 1992.
Gupte SA, Arshad M, Viola S, Kaminski PM, Ungvari Z, Rabbani G, Koller A and Wolin MS. Pentose phosphate pathway coordinates multiple redox-controlled relaxing mechanisms in bovine coronary arteries. Am J Physiol Heart Circ Physiol 285: H2316-H2326, 2003.
Gupte SA and Wolin MS. Hypoxia promotes relaxation of bovine coronary arteries through lowering cytosolic NADPH. Am J Physiol Heart Circ Physiol290: H2228- H2238, 2006.
He MX and Downey HF. Downregulation of ventricular contractile function during early ischemia is flow but not pressure dependent. Am J Physiol275: H1520-H1523, 1998.
He MX, Wang S and Downey HF. Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia. Am J Physiol272: H1333- H1341, 1997.
Herrmann SC and Feigl EO. Adrenergic blockade blunts adenosine concentration and coronary vasodilation during hypoxia. Circ Res70:1203-1216, 1992.
Hilton R and Eichholtz F. The influence of chemical factors on the coronary circulation. J Physiol59:413-425, 1925.
Huang AH and Feigl EO. Adrenergic coronary vasoconstriction helps maintain uniform transmural blood flow distribution during exercise. Circ Res62:286-298, 1988.
Jackson WF. Arteriolar oxygen reactivity: where is the sensor? Am J Physiol253: H1120-H1126, 1987.
Jackson WF. Ion channels and vascular tone. Hypertension35:173-178, 2000.
Jackson WF and Duling BR. The oxygen sensitivity of hamster cheek pouch arterioles. In vitro and in situ studies. Circ Res53:515-525, 1983.
Jiang C and Collins P. Inhibition of hypoxia-induced relaxation of rabbit isolated coronary arteries by NG-monomethyl-L-arginine but not glibenclamide. Br J Pharmacol111:711-716, 1994.
Jimenez AH, Tanner MA, Caldwell WM and Myers PR. Effects of oxygen tension on flow-induced vasodilation in porcine coronary resistance arterioles. Microvasc Res 51:365-377, 1996.
Justice JM, Tanner MA and Myers PR. Endothelial cell regulation of nitric oxide production during hypoxia in coronary microvessels and epicardial arteries. J Cell Physiol182:359-365, 2000.
Kalsner S. The effect of hypoxia on prostaglandin output and on tone in isolated coronary arteries. Can J Physiol Pharmacol55:882-887, 1977.
Kalsner S. Prostaglandin mediated relaxation of coronary artery strips under hypoxia. Prostaglandins Med1:231-239, 1978.
Kalsner S. Hypoxic relaxation in functionally intact cattle coronary artery segments involves K+ ATP channels. J Pharmacol Exp Ther275:1219-1226, 1995.
Kamekura I, Okumura K, Matsui H, Murase K, Mokuno S, Toki Y, Nakashima Y and Ito T. Mechanisms of hypoxic coronary vasodilatation in isolated perfused rat hearts. J Cardiovasc Pharmacol33:836-842, 1999.
Kerkhof CJ, Van Der Linden PJ and Sipkema P. Role of myocardium and endothelium in coronary vascular smooth muscle responses to hypoxia. Am J Physiol Heart Circ Physiol282: H1296-H1303, 2002.
Kuo L and Chancellor JD. Adenosine potentiates flow-induced dilation of coronary arterioles by activating KATP channels in endothelium. Am J Physiol269: H541- H549, 1995.
Larsen BT and Gutterman DD. Hypoxia, coronary dilation, and the pentose phosphate pathway. Am J Physiol Heart Circ Physiol290: H2169-H2171, 2006.
Laxson DD, Homans DC and Bache RJ. Inhibition of adenosine-mediated coronary vasodilation exacerbates myocardial ischemia during exercise. Am J Physiol265: H1471-H1477, 1993.
Lee JC, Halloran KH, Taylor JF and Downing SE. Coronary flow and myocardial metabolism in newborn lambs: effects of hypoxia and acidemia. Am J Physiol224:1381-1387, 1973.
Lee SC, Mallet RT, Shizukuda Y, Williams AG, Jr. and Downey HF. Canine coronary vasodepressor responses to hypoxia are attenuated but not abolished by 8-phenyltheophylline. Am J Physiol262: H955-H960, 1992.
Lee YH, Kim JT and Kang BS. Mechanisms of relaxation of coronary artery by hypoxia. Yonsei Med J39:252-260, 1998.
Liu Q and Flavahan NA. Hypoxic dilatation of porcine small coronary arteries: role of endothelium and KATP-channels. Br J Pharmacol120:728-734, 1997.
Lynch FM, Austin C, Heagerty AM and Izzard AS. Adenosine and hypoxic dilation of rat coronary small arteries: roles of the ATP-sensitive potassium channel, endothelium, and nitric oxide. Am J Physiol Heart Circ Physiol290: H1145-H1150, 2006.
Martinez RR, Setty S, Zong P, Tune JD and Downey HF. Nitric oxide contributes to right coronary vasodilation during systemic hypoxia. Am J Physiol Heart Circ Physiol288: H1139-H1146, 2005.
Merkus D, Haitsma DB, Fung TY, Assen YJ, Verdouw PD and Duncker DJ. Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways. Am J Physiol Heart Circ Physiol285: H424-H433, 2003.
Merrill GF, Downey HF and Jones CE. Adenosine deaminase attenuates canine coronary vasodilation during systemic hypoxia. Am J Physiol250: H579-H583, 1986.
Merrill GF, Downey HF, Yonekura S, Watanabe N and Jones CE. Adenosine deaminase attenuates canine coronary vasodilatation during regional non-ischaemic myocardial hypoxia. Cardiovasc Res22:345-350, 1988.
Miura H, Wachtel RE, Loberiza FR, Jr., Saito T, Miura M, Nicolosi AC and Gutterman DD. Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels. Circ Res92:151-158, 2003.
Miyashiro JK and Feigl EO. Feedforward control of coronary blood flow via coronary beta-receptor stimulation. Circ Res73:252-263, 1993.
Myers PR, Muller JM and Tanner MA. Effects of oxygen tension on endothelium dependent responses in canine coronary microvessels. Cardiovasc Res25:885-894, 1991.
Nakamura Y, Takahashi M, Takei F, Matsumura N, Scholkens B and Sasamoto H. The change in coronary vascular resistance during acute induced hypoxemia–with special reference to coronary vascular reserve. Cardiologia54:91-103, 1969.
Nakhostine N and Lamontagne D. Adenosine contributes to hypoxia-induced vasodilation through ATP-sensitive K+ channel activation. Am J Physiol265: H1289-H1293, 1993.
Nakhostine N and Lamontagne D. Contribution of prostaglandins in hypoxia-induced vasodilation in isolated rabbit hearts. Relation to adenosine and KATP channels. Pflugers Arch428:526-532, 1994.
Nakhostine N, Laurent CE, Nadeau R, Cardinal R and Lamontagne D. Hypoxiainduced release of prostaglandins: mechanisms and sources of production in coronary resistance vessels of the isolated rabbit heart. Can J Physiol Pharmacol73:1742-1749, 1995.
Okada T. Hypoxia-induced change in prostanoids production and coronary flow in isolated rat heart. J Mol Cell Cardiol23:939-948, 1991.
Park KH, Rubin LE, Gross SS and Levi R. Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites. Circ Res71:992-1001, 1992.
Powers ER and Powell WJ, Jr. Effect of arterial hypoxia on myocardial oxygen consumption. Circ Res33:749-756, 1973.
Roberts AM, Messina EJ and Kaley G. Prostacyclin (PGI2) mediates hypoxic relaxation of bovine coronary arterial strips. Prostaglandins21:555-569, 1981.
Rogers PA, Dick GM, Knudson JD, Focardi M, Bratz IN, Swafford AN, Jr., Saitoh S, Tune JD and Chilian WM. H2O2-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K+ channels. Am J Physiol Heart Circ Physiol291: H2473-H2482, 2006.
Ross J, Jr. Myocardial perfusion-contraction matching. Implications for coronary heart disease and hibernation. Circulation83:1076-1083, 1991.
Saitoh S, Zhang C, Tune JD, Potter B, Kiyooka T, Rogers PA, Knudson JD, Dick GM, Swafford A and Chilian WM. Hydrogen peroxide: a feed-forward dilator that couples myocardial metabolism to coronary blood flow. Arterioscler Thromb Vasc Biol26:2614-2621, 2006.
Schrader J and Bardenheuer H. Assessment of vasoactive metabolites released from the isolated guinea pig during heart hypoxia and beta-adrenergic stimulation. Basic Res Cardiol76:365-368, 1981.
Stepp DW, Kroll K and Feigl EO. K+ATP channels and adenosine are not necessary for coronary autoregulation. Am J Physiol273: H1299-H1308, 1997.
Stowe DF. Heart bioassay of effluent of isolated, perfused guinea pig hearts to examine the role of metabolites regulating coronary flow during hypoxia. Basic Res Cardiol76:359-364, 1981.
Stumpe T and Schrader J. Phosphorylation potential, adenosine formation, and critical PO2 in stimulated rat cardiomyocytes. Am J Physiol273: H756-H766, 1997.
Tune JD, Gorman MW and Feigl EO. Matching coronary blood flow to myocardial oxygen consumption. J Appl Physiol97:404-415, 2004.
Tune JD, Richmond KN, Gorman MW and Feigl EO. Control of coronary blood flow during exercise. Exp Biol Med (Maywood )227:238-250, 2002.
Tune JD, Richmond KN, Gorman MW, Olsson RA and Feigl EO. Adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise. Am J Physiol Heart Circ Physiol278: H74-H84, 2000.
Van Wylen DG, Williams AG, Jr. and Downey HF. Interstitial purine metabolites and lactate during regional myocardial hypoxia. Cardiovasc Res27:1498-1503, 1993.
Vance JP, Parratt JR and Ledingham IM. The effects of hypoxia on myocardial blood flow and oxygen consumption: negative role of beta adrenoreceptors. Clin Sci41:257-273, 1971.
Vane JR, Anggard EE and Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med323:27-36, 1990.
Vanhoutte PM. Endothelial control of vasomotor function: from health to coronary disease. Circ J67:572-575, 2003.
von BN, Cyrys S, Dischner A and Daut J. Hypoxic vasodilatation in isolated, perfused guinea-pig heart: an analysis of the underlying mechanisms. J Physiol442:297-319, 1991.
Walley KR, Becker CJ, Hogan RA, Teplinsky K and Wood LD. Progressive hypoxemia limits left ventricular oxygen consumption and contractility. Circ Res63:849-859, 1988.
Wei HM, Kang YH and Merrill GF. Coronary vasodilation during global myocardial hypoxia: effects of adenosine deaminase. Am J Physiol254: H1004-H1009, 1988.
Xu XP, Pollock JS, Tanner MA and Myers PR. Hypoxia activates nitric oxide synthase and stimulates nitric oxide production in porcine coronary resistance arteriolar endothelial cells. Cardiovasc Res30:841-847, 1995.
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Tune, J.D. (2007). Control of Coronary Blood Flow During Hypoxemia. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia and the Circulation. Advances in Experimental Medicine and Biology, vol 618. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-75434-5_3
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