Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Regulation of Coronary Microvascular Resistance in Health and Disease

Cuihua Zhang, Paul A Rogers, Daphne Merkus, Judy M Muller‐Delp, Christiane P Tiefenbacher, Barry Potter, Jarrod D Knudson, Petra Rocic, William M Chilian

10.1002/cphy.cp020412

Source: Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation

Originally published: 2008

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Introduction and Background
2 Endothelial and Myogenic Mechanisms of Coronary Regulation
2.1 Endothelium‐dependent vasodilation
2.2 Flow‐ or shear stress‐dependent dilation
2.3 Myogenic control mechanisms
2.4 Interaction of pressure‐ and flow‐dependent control
3 Metabolic Regulation of Coronary Microvascular Resistance
3.1 General concepts
3.2 Parallel vs. redundant pathways
3.3 Measurement of metabolic control in vivo‐myocardial oxygen balance
3.4 Measurement of metabolic control in vitro
3.5 Putative mediators of metabolic regulation
4 Neurohumoral Control
4.1 General concepts
4.2 Sympathetic control
4.3 Parasympathetic control
4.4 Non‐adrenergic, non‐cholinergic control
4.5 Humoral control
5 Pathophysiological Disturbances
5.1 Impact of microvascular disease on the heart
5.2 Pathophysiology of endothelial dysfunction
5.3 Role of vasoconstrictors
6 Summary, Conclusions, Directions
Figure 1. Figure 1.

Distribution of pressures in the coronary microcirculation of the beating heart under control conditions and during intense vasodilation with dipyridamole. Dipyridamole produced a 5 to 6‐fold increase in flow, and despite this huge increase in flow, the pressure drop across the small arteries and arterioles decreased by half. This implies that resistance decreased by 10 to 12‐fold during dypridamole‐induced vasodilation.

Adapted from Ref. 3
Figure 2. Figure 2.

Pressure diameter relations of subepicardial arterioles before (closed circle) and after (open circle) mechanical denudation of endothelium. There is no statistical difference in myogenic response before and after mechanical denudation. Lumen diameters were normalized to diameter at a pressure of 60cmH2O in presence of nitroprusside(10−4M). Average luminal diameter(d) inphysiological saline‐albumin solution at 60cmH2O is shown. Vertical bars denote mean ± SEM. *Significantly different from diameter at 60cmH2O pressure with or without endothelium.

Adapted from Ref. 23
Figure 3. Figure 3.

Example of interaction between pressure‐induced myogenic responses and flow‐dependent dilation in isolated subepicardial arterioles. (A) Myogenic constriction was inhibited by an increase in flow. (B) Myogenic dilation was potentiated by flow. (C) Flow‐induced dilation was attenuated by elevating pressure. (D) Flow‐induced dilation was potentiated by lowering pressure. With permission from Ref. 30.
Figure 4. Figure 4.

Hypothetical scheme illustrating the interaction of pressure‐. flow‐ and metabolic control mechanisms during a rise in coronary perfusion pressure during sympathetic adrenal activation. Myogenic arteriolar constriction serves to limit the increase in coronary blood flow and the rise in pressure in coronary exchange vessels, perhaps thus protecting the myocardium from edema. Each of the interactions shown may be subject to neurohumoral influences. MVO2, myocardial oxygen consumption.
Figure 5. Figure 5.

Regulation of myocardial oxygen balance during changes in myocardial oxygen consumption. (See page 12 in colour section at the back of the book)
Figure 6. Figure 6.

Effects of endothelin receptor blockade (Tezosentan: ETA/ETB; EMD 122946: ETA) on coronary oxygen extraction and venous oxygen saturation during exercise under control conditions and during endothelin receptor blockade. Note, that endothelin blockade significantly affected the relationships suggesting the during the sympathoadrenal excitation with exercise, endothelin exerts a constrictor effect on coronary blood flow.

Adapted from Ref. 221. (See page 13 in colour section at the back of the book)
Figure 7. Figure 7.

Constriction of isolated coronary arterioles exposed to supernatant from cardiac myocytes stimulated with increasing concentrations of phenylephrine. Addition of the ETa antagonist, FR 139317 to the arteriolar tissue bath abolished the constrictor response that was observed following administration of 8‐para‐sulfaphenyltheophylline (8‐PSPT) to block adenosine A1 and A2 receptors. Adminstration of the α1‐adrenergic antagonist prazosin to the isolated myocytes prevented the production of the vasoconstrictor compound by the cardiac myocytes and had no effect when administered to the vessels (not shown), indicating that α‐adrenergic coronary constriction is mediated by the production of a myocyte‐derived vasoconstrictor, and not due to direct actions on smooth muscle. With permission from Teifenbacher el al. (1998).
Figure 8. Figure 8.

Responses of coronary microvessels 50–250μm in diameter to the α‐adrenergic agonist BHT‐933 under control conditions (Di) with autoregulatory mechanisms intact (left) and during hypoperfusion at 40mm Hg (D40) to prevent autoregulatory responses (right). Percent change in diameter is plotted as a function of control diameter. Under control conditions, small arterioles dilated as seen by a positive change in diameter while large arterioles constricted. Prevention of autoregulatory responses resulted in vasoconstriction of all arterioles.

Adapted from Chilian 109
Figure 9. Figure 9.

Blockade of feedforward β‐adrenergic dilation of the coronary microcirculation reduces the myocardial oxygen supply‐to‐consumption ratio in exercising dogs. With permission from Gorman el al. (2000).
Figure 10. Figure 10.

Schematic for the regulation of NO production and the influences of atherosclerosis. risk factors, and angiotensin on NO metabolism. (See page 13 in colour section at the back of the book)
Figure 11. Figure 11.

The metabolism of L‐arginine into NO and degradation of NO into nitrites and nitrates.
Figure 12. Figure 12.

Responses of isolated coronary arterioles removed from the ischemic region after ischemia‐reperfusion. The data presented were obtained from arterioles (n = 3 to n = 5) during initial conditions after ischemia/reperfusion (I/R), during incubation with 10μmol/L MH4 (I/R + MH4), a synthetic cell‐permeable tetrahydrobiopterin, and after washout of MH4 (I/R + MH4 + Wash). Data are expressed as mean±SEM. *p < 0.05 vs. ischemia/reperfusion.

Adapted from Ref. 215
Figure 13. Figure 13.

Responses of isolated human coronary arterioles from patients with significant atherosclerosis. Results were obtained from arterioles (n = 10) during baseline conditions and after incubation with 1 μM sepiapterin to restore endogenous pools of BH4. Data are expressed as mean±SEM. *p < 0.05 vs. baseline.

Adapted from Ref. 215


Figure 1.

Distribution of pressures in the coronary microcirculation of the beating heart under control conditions and during intense vasodilation with dipyridamole. Dipyridamole produced a 5 to 6‐fold increase in flow, and despite this huge increase in flow, the pressure drop across the small arteries and arterioles decreased by half. This implies that resistance decreased by 10 to 12‐fold during dypridamole‐induced vasodilation.

Adapted from Ref. 3


Figure 2.

Pressure diameter relations of subepicardial arterioles before (closed circle) and after (open circle) mechanical denudation of endothelium. There is no statistical difference in myogenic response before and after mechanical denudation. Lumen diameters were normalized to diameter at a pressure of 60cmH2O in presence of nitroprusside(10−4M). Average luminal diameter(d) inphysiological saline‐albumin solution at 60cmH2O is shown. Vertical bars denote mean ± SEM. *Significantly different from diameter at 60cmH2O pressure with or without endothelium.

Adapted from Ref. 23


Figure 3.

Example of interaction between pressure‐induced myogenic responses and flow‐dependent dilation in isolated subepicardial arterioles. (A) Myogenic constriction was inhibited by an increase in flow. (B) Myogenic dilation was potentiated by flow. (C) Flow‐induced dilation was attenuated by elevating pressure. (D) Flow‐induced dilation was potentiated by lowering pressure. With permission from Ref. 30.



Figure 4.

Hypothetical scheme illustrating the interaction of pressure‐. flow‐ and metabolic control mechanisms during a rise in coronary perfusion pressure during sympathetic adrenal activation. Myogenic arteriolar constriction serves to limit the increase in coronary blood flow and the rise in pressure in coronary exchange vessels, perhaps thus protecting the myocardium from edema. Each of the interactions shown may be subject to neurohumoral influences. MVO2, myocardial oxygen consumption.



Figure 5.

Regulation of myocardial oxygen balance during changes in myocardial oxygen consumption. (See page 12 in colour section at the back of the book)



Figure 6.

Effects of endothelin receptor blockade (Tezosentan: ETA/ETB; EMD 122946: ETA) on coronary oxygen extraction and venous oxygen saturation during exercise under control conditions and during endothelin receptor blockade. Note, that endothelin blockade significantly affected the relationships suggesting the during the sympathoadrenal excitation with exercise, endothelin exerts a constrictor effect on coronary blood flow.

Adapted from Ref. 221. (See page 13 in colour section at the back of the book)


Figure 7.

Constriction of isolated coronary arterioles exposed to supernatant from cardiac myocytes stimulated with increasing concentrations of phenylephrine. Addition of the ETa antagonist, FR 139317 to the arteriolar tissue bath abolished the constrictor response that was observed following administration of 8‐para‐sulfaphenyltheophylline (8‐PSPT) to block adenosine A1 and A2 receptors. Adminstration of the α1‐adrenergic antagonist prazosin to the isolated myocytes prevented the production of the vasoconstrictor compound by the cardiac myocytes and had no effect when administered to the vessels (not shown), indicating that α‐adrenergic coronary constriction is mediated by the production of a myocyte‐derived vasoconstrictor, and not due to direct actions on smooth muscle. With permission from Teifenbacher el al. (1998).



Figure 8.

Responses of coronary microvessels 50–250μm in diameter to the α‐adrenergic agonist BHT‐933 under control conditions (Di) with autoregulatory mechanisms intact (left) and during hypoperfusion at 40mm Hg (D40) to prevent autoregulatory responses (right). Percent change in diameter is plotted as a function of control diameter. Under control conditions, small arterioles dilated as seen by a positive change in diameter while large arterioles constricted. Prevention of autoregulatory responses resulted in vasoconstriction of all arterioles.

Adapted from Chilian 109


Figure 9.

Blockade of feedforward β‐adrenergic dilation of the coronary microcirculation reduces the myocardial oxygen supply‐to‐consumption ratio in exercising dogs. With permission from Gorman el al. (2000).



Figure 10.

Schematic for the regulation of NO production and the influences of atherosclerosis. risk factors, and angiotensin on NO metabolism. (See page 13 in colour section at the back of the book)



Figure 11.

The metabolism of L‐arginine into NO and degradation of NO into nitrites and nitrates.



Figure 12.

Responses of isolated coronary arterioles removed from the ischemic region after ischemia‐reperfusion. The data presented were obtained from arterioles (n = 3 to n = 5) during initial conditions after ischemia/reperfusion (I/R), during incubation with 10μmol/L MH4 (I/R + MH4), a synthetic cell‐permeable tetrahydrobiopterin, and after washout of MH4 (I/R + MH4 + Wash). Data are expressed as mean±SEM. *p < 0.05 vs. ischemia/reperfusion.

Adapted from Ref. 215


Figure 13.

Responses of isolated human coronary arterioles from patients with significant atherosclerosis. Results were obtained from arterioles (n = 10) during baseline conditions and after incubation with 1 μM sepiapterin to restore endogenous pools of BH4. Data are expressed as mean±SEM. *p < 0.05 vs. baseline.

Adapted from Ref. 215
References
 1. Kuo L, Davis MJ and Chilian WM. Myogenic activity in isolated subepicardial and subendocardial coronary arterioles. Am J Physiol 255: H1558–H1562, 1988b.
 2. Kuo L, Davis MJ and Chilian WM. Endothelium‐dependent, flow‐induced dilation of isolated coronary arterioles. Am J Physiol 259: H1063–H1070, 1990c.
 3. Chilian WM, Eastham CL and Marcus ML. Microvascular distribution of coronary vascular resistance in beating left ventricle. Am J Physiol 251: H779–H788, 1986.
 4. Chilian WM. Microvascular pressures and resistances in the left ventricular subepicardium and subendocardium. Circ Res 69: 561–570, 1991b.
 5. Zhang C, Hein TW and Kuo L. Transmural difference in coronary arteriolar dilation to adenosine: effect of luminal pressure and K(ATP) channels. Am J Physiol Heart Circ Physiol 279 (6): H2612–H2619, 2000b.
 6. Bache RJ and Schwartz JS. Effect of perfusion pressure distal to a coronary stenosis on transmural myocardial blood flow. Circulation 65 (5): 928–935, 1982.
 7. Quillen JE and Harrison DG. Vasomotor properties of porcine endocardial and epicardial microvessels. Am J Physiol Heart Circ Physiol 262: H1143–H1148, 1992.
 8. Gorman MW, Tune JD, Richmond KN and Feigl EO. Feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol 89 (5): 1892–1902, 2000a.
 9. Miyashiro JK and Feigl EO. Feedforward control of coronary blood flow via coronary beta‐receptor stimulation. Circ Res 73 (2): 252–263, 1993a.
 10. Hein TW, Zhang C, Wang W and Kuo L. Heterogeneous beta2‐adrenoceptor expression and dilation in coronary arterioles across the left ventricular wall. Circulation 110 (17): 2708–2712, 2004b.
 11. Mullane KM and Pinto A. Endothelium, arachidonic acid, and coronary vascular tone. Fed Proc 46: 54–62, 1987.
 12. Quillen JE, Sellke FW, Brooks LA and Harrison DG. ischemiareperfusion impairs endothelium‐dependent relaxation of coronary microvessels but does not affect large arteries. Circulaiton 82: 586–594, 1990.
 13. Chilian WM, Kuo L, DeFily DV, Jones CJH and Davis MJ. Endothelial regulation of coronary microvascular tone under physiological and pathophysiological conditions. Eur Heart J 14 (Suppl 1): 55–59, 1993.
 14. Tschudi M, Richard V, Bühler FR and Lüscher TF. Importance of endothelium‐derived nitric oxide in porcine coronary resistance arteries. Am J Physiol 260: H13–H20, 1991b.
 15. Lamping KG, Kanatsuka H, Eastham CL, Chilian WM and Marcus ML. Nonuniform vasomotor responses of the coronary microcirculation to serotonin and vasopressin. Circ Res 65: 343–351, 1989b.
 16. Jones CJH, Kuo L, Davis MJ, Chilian WM and DeFily DV. Role of nitric oxide in the coronary microvascular responses to adenosine and increased metabolic demand. Circulaiton 91: 1807–1813, 1995b.
 17. Huang A, Sun D, Jacobson A, Carroll MA, Falck JR and Kaley G. Epoxyeicosatrienoic acids are released to mediate shear stress‐dependent hyperpolarization of arteriolar smooth muscle. Circ Res 96 (3): 376–383, 2005.
 18. Huang A, Wu Y, Sun D, Koller A and Kaley G. Effect of estrogen on flow‐induced dilation in NO deficiency: role of prostaglandins and EDHF. J Appl Physiol 91 (6): 2561–2566, 2001.
 19. Miura H, Bosnjak JJ, Ning G, Saito T, Miura M and Gutterman DD. Role for hydrogen peroxide in flow‐induced dilation of human coronary arterioles. Circ Res 92 (2): e31–e40, 2003.
 20. Nishikawa Y, Stepp DW and Chilian WM. Nitric oxide exerts feedback inhibition on EDHF‐induced coronary arteriolar dilation in vivo. Am J Physiol Heart Circ Physiol 279 (2): H459–H465, 2000.
 21. Jones CJH, Kuo L, Davis MJ and Chilian WM. Myogenic and flow‐dependent control mechanisms in the coronary microcirculation. Basic Res Cardiol 88: 2–10, 1993b.
 22. Cornelissen AJM, Dankelman J, VanBavel E and Spaan JAE. Balance between myogenic, flow‐dependent, and metabolic flow control in coronary arterial tree: a model study. Am J Physiol Heart Circ Physiol 282 (6): H2224–H2237, 2002.
 23. Kuo L, Chilian WM and Davis MJ. Coronary arteriolar myogenic response is independent of endothelium. Circ Res 66: 860–866, 1990a.
 24. Kuo L, Davis MJ and Chilian WM. Longitudinal gradients for endothelium‐dependent and ‐independent vascular responses in the coronary microcirculation. Circulation 92: 518–525, 1995a.
 25. Kuo L, Arko F, Chilian WM and Davis MJ. Nitrovasodilator‐mediated flow‐induced dilation in isolated porcine coronary venules. HFASEB J 6: A1752, 1992a.
 26. Muller JM, Chilian WM and Davis MJ. Integrin signaling transduces shear stress‐dependent vasodilation of coronary arterioles. Circ Res 80: 320–326, 1997.
 27. Koshida R, Rocic P, Saito S, Kiyooka T, Zhang C and Chilian WM. Role of focal adhesion kinase in flow‐induced dilation of coronary arterioles. Arterioscler Thromb Vasc Biol 25 (12): 2548–2553, 2005.
 28. Muller JM, Davis MJ, Kuo L and Chilian WM. Changes in coronary endothelial cell Ca2+ concentration during shear stress‐ and agonist‐induced vasodilation. Am J Physiol 276 (5 Pt 2): H1706–H1714, 1999.
 29. Stepp DW, Nishikawa Y and Chilian WM. Regulation of shear stress in the canine coronary microcirculation. Circulation 100 (14): 1555–1561, 1999.
 30. Kuo L, Chilian WM and Davis MJ. Interaction of pressure‐ and flow‐induced responses in porcine coronary resistance vessels. Am J Physiol Hear Circ Physiol 261 (6 Pt 2): H1706–H1715, 1991.
 31. Stepp DW, Merkus D, Nishikawa Y and Chilian WM. Nitric oxide limits coronary vasoconstriction by a shear stress‐dependent mechanism. Am J Physiol Heart Circ Physiol 281 (2): H796–803, 2001.
 32. DeFily DV. Control of microvascular resistance in physiological conditions and reperfusion. J Mot Cell Cardiol 30: 2547–2554, 1998.
 33. Martinez‐Lemusa LA, Wu X, Wilson E, Hill MA, Davis GE, Davis MJ and Meininger GA. Integrins as unique receptors for vascular control. J Vasc Res 40 (3): 211–233, 2003.
 34. Chilian WM and Layne SM. Coronary microvascular responses to reductions in perfusion pressure: Evidence for persistent arteriolar vasomotor tone during coronary hypoperfusion. Circ Res 66: 1227–1238, 1990.
 35. Kanatsuka H, Lamping KG, Eastham CL and Marcus ML. Heterogeneous changes in epimyocardial microvascular size during graded coronary stenosis: Evidence of the microvascular site for autoregulation. Circ Res 66: 389–396, 1990.
 36. Miller FJJ, Dellsperger KC and Gutterman DD. Myogenic constriction of human coronary arterioles. Am J Physiol 273: H257–H264, 1997.
 37. Dole WP and Nuno DW. Myocardial oxygen tension determines the degree and pressure range of coronary autoregulation. Circ Res 59 (2): 202–215, 1986.
 38. Zhang C, Hein TW and Kuo L. Transmural difference in coronary arteriolar dilation to adenosine: effect of luminal pressure and K(ATP) channels. Am J Physiol Heart Circ Physiol 279 (6): H2612–H2619, 2000a.
 39. Kuo L, Davis MJ, Cannon MS and Chilian WM. Pathophysiological consequences of atherosclerosis extend into the coronary microcirculation: Restoration of endothelium‐dependent responses by L‐arginine. Circ Res 70: 465–476, 1992b.
 40. DeFily DV and Chilian WM. Preconditioning protects coronary arteriolar endothelium from ischemia‐reperfusion injury. Am J Physiol 265 (2 Pt 2): H700–H706, 1993.
 41. Alders DJ, Groeneveld AB, de Kanter FJ and van Beek JH. Myocardial O2 consumption in porcine left ventricle is heterogeneously distributed in parallel to heterogeneous O2 delivery. Am J Physiol Heart Circ Physiol 287 (3): H1353–H1361, 2004.
 42. Ishibashi Y, Duncker DJ, Zhang J and Bache RJ. ATP‐sensitive K+ channels, adenosine, and nitric oxide‐mediated mechanisms account for coronary vasodilation during exercise. Circ Res 82 (3): 346–359, 1998.
 43. Merkus D, Duncker DJGM and Chilian WM. Metabolic Regulation of Coronary Vascular Tone‐ Role of Endothelin‐1. Am J Physiol Heart Circ Physiol 283 (5): H1915–H1921, 2002c.
 44. Berne RM and Rubio R. Regulation of coronary blood flow. Adv Cardiol 12 (0): 303–317, 1974.
 45. Olsson RA, Bunger R and Spaan JA. Coronary circulation. In: The Heart and Cardiovascular System, eds Fozzard HA, Haber E, Jennings RB, Katz AM and Morgan HE. New York: Raven Press, 1992, pp. 1393–1426.
 46. Sparks HV, Jr. and Bardenheuer H. Regulation of adenosine formation by the heart. Circ Res 58 (2): 193–201, 1986.
 47. Hanley FL, Grattan MT, Stevens MB and Hoffman JI. Role of adenosine in coronary autoregulation. Am J Physiol 250 (4 Pt 2): H558–H566, 1986.
 48. Kroll K and Feigl EO. Adenosine is unimportant in controlling coronary blood flow in unstressed dog hearts. Am J Physiol 249 (6 Pt 2): H1176–H1187, 1985.
 49. Saito D, Steinhart CR, Nixon DG and Olsson RA. Intracoronary adenosine deaminase reduces canine myocardial reactive hyperemia. Circ Res 49 (6): 1262–1267, 1981.
 50. Giles RW and Wilcken DE. Reactive hyperaemia in the dog heart: inter‐relations between adenosine, ATP, and aminophylline and the effect of indomethacin. Cardiovascul Res 11 (2): 113–121, 1977.
 51. Schutz W, Zimpfer M and Raberger G. Effect of aminophylline on coronary reactive hyperaemia following brief and long occlusion periods. Cardiovascul Res 11 (6): 507–511, 1977.
 52. Martin SE, Tidmore WC and Patterson RE. Adenosine receptor blockade with 8‐p‐sulfophenyltheophylline aggravates coronary constriction. Am J Physiol 260 (6 Pt 2): H1753–H1759, 1991.
 53. Tune JD, Richmond KN, Gorman MW and Feigl EO. Role of nitric oxide and adenosine in control of coronary blood flow in exercising dogs. Circulation 101 (25): 2942–2948, 2000a.
 54. Bache RJ, Dai XZ, Schwartz JS and Homans DC. Role of adenosine in coronary vasodilation during exercise. Circ Res 62 (4): 846–853, 1988.
 55. Bacchus AN, Ely SW, Knabb RM, Rubio R and Berne RM. Adenosine and coronary blood flow in conscious dogs during normal physiological stimuli. Am J Physiol 243 (4): H628–H633, 1982.
 56. Watkinson WP, Foley DH, Rubio R and Berne RM. Myocardial adenosine formation with increased cardiac performance in the dog. Am J Physiol 236 (1): H13–21, 1979.
 57. 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 Physiol 278 (1): H74–h84, 2000b.
 58. 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 Physiol 285 (1): H424–H433, 2003a.
 59. Edlund A, Conradsson T and Sollevi A. A role for adenosine in coronary vasoregulation in man. Effects of theophylline and enprofylline. Clin Physiol 15 (6): 623–636, 1995.
 60. Edlund A and Sollevi A. Theophylline increases coronary vascular tone in humans: evidence for a role of endogenous adenosine in flow regulation. Acta Physiol Scand 155 (3): 303–311, 1995.
 61. Edlund A, Sollevi A and Wennmalm A. The role of adenosine and prostacyclin in coronary flow regulation in healthy man. Acta Physiol Scand 135 (1): 39–46, 1989.
 62. Rubanyi GM and Polokoff MA. Endothelins: molecular biology. biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46 (3): 325–415, 1994.
 63. Frelin C and Guedin D. Why are circulating concentrations of endothelin‐1 so low? Cardiovascul Res 28 (11): 1613–1622, 1994.
 64. Halcox JP, Nour KR, Zalos G and Quyyumi AA. Coronary vasodilation and improvement in endothelial dysfunction with endothelin ET(A) receptor blockade. Circ Res 89 (11): 969–976, 2001.
 65. Merkus D, Houweling B, Mirza A, Boomsma F, van den Meiracker AH and Duncker DJ. Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation. Cardiovascul Res 59 (3): 745–754, 2003b.
 66. Takamura M, Parent R, Cernacek P and Lavallee M. Influence of dual ET(A)/ET(B)‐receptor blockade on coronary responses to treadmill exercise in dogs. J Appl Physiol 89 (5): 2041–2048, 2000.
 67. Haitsma DB, Bac D, Raja N, Boomsma F, Verdouw PD and Duncker DJ. Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations. Cardiovascul Res 52 (3): 417–428, 2001.
 68. Lenz T, Nadansky M, Gossmann J, Oremek G and Geiger H. Exhaustive exercise‐induced tissue hypoxia does not change endothelin and big endothelin plasma levels in normal volunteers. Am J Hypertens 11 (8 Pt 1): 1028–1031, 1998.
 69. Ahlborg G, Weitzberg E and Lundberg J. Metabolic and vascular effects of circulating endothelin‐1 during moderately heavy prolonged exercise. J Appl Physiol 78 (6): 2294–2300, 1995.
 70. Maeda S, Miyauchi T, Goto K and Matsuda M. Alteration of plasma endothelin‐1 by exercise at intensities lower and higher than ventilatory threshold. J Appl Physiol 77 (3): 1399–1402, 1994.
 71. Merkus D, Stepp DW, Jones DW, Nishikawa Y and Chilian WM. Adenosine preconditions against endothelin‐induced constriction of coronary arterioles. Am J Physiol 279 (6): H2593–H2597, 2000.
 72. Gorman MW, Farias M, III, Richmond KN, Tune JD and Feigl EO. Role of endothelin in alpha‐adrenoceptor coronary vasoconstriction. Am J Physiol Heart Circ Physiol 288 (4): H1937–H1942, 2005a.
 73. Merkus D, Duncker DJGM and Chilian WM. Metabolic Regulation of Coronary Vascular Tone‐ Role of Endothelin‐1. Am J Physiol 283 (5): H1915–H1921, 2002b.
 74. Goligorsky MS, Tsukahara H, Magazine H, Andersen TT, Malik AB and Bahou WF. Termination of endothelin signaling: role of nitric oxide. J Cell Physiol 158 (3): 485–494, 1994.
 75. Wiley KE and Davenport AP. Nitric oxide‐mediated modulation of the endothelin‐1 signalling pathway in the human cardiovascular system. Br J Pharmacol 132 (1): 213–220, 2001.
 76. Saitoh S‐I, Zhang C, Tune JD, Potter B, Kiyooka T, Rogers PA, Knudson JD, Dick G, Swafford A and Chilian WM. Hydrogen Peroxide. A Feed‐Forward Dilator That Couples Myocardial Metabolism to Coronary Blood Flow. Arterioscler Thromb Vasc Biol, 26: 2614–2621, 2006.
 77. Zhang C, Brzezinska AK and Chilian WM. Hydrogen Peroxide is a Coronary Vasodilator Linking Myocardial Metabolism to Coronary Blood Flow. Circulation 110 (Suppl): III‐74, 2004.
 78. Yada T, Shimokawa H, Hiramatsu O, Kajita T, Shigeto F, Goto M, Ogasawara Y and Kajiya F. Hydrogen peroxide, an endogenous endothelium‐derived hyperpolarizing factor, plays an important role in coronary autoregulation in vivo. Circulation 107 (7): 1040–1045, 2003.
 79. Hirsch E and Borghard‐Erdle A. The innervation of the human heart. Arch Pathol 71: 384–407, 1961.
 80. Woollard H. The innervation of the heart. J Anat Physiol 60: 345–373, 1926.
 81. Chilian WM. Adrenergic vasomotion in the coronary microcirculation. Basic Res Cardiol 85 (Suppl 1): 111–120, 1990.
 82. Holtz J. Alpha‐adrenoceptor subtypes in the coronary circulation. Basic Res Cardiol 85 (Suppl 1): 81–95, 1990.
 83. Huang AH and Feigl EO. Adrenergic coronary vasoconstriction helps maintain uniform transmural blood flow distribution during exercise. Circ Res 62 (2): 286–298, 1988.
 84. Jackson CV, Pope TK and Lucchesi BR. Coronary artery vasodilation in the canine: physiological and pharmacological roles of beta‐adrenergic receptors. J Cardiovascul Pharmacol 10 (2): 196–204, 1987.
 85. Jones CE and Gwirtz PA. Alpha 1‐adrenergic coronary constriction during exercise and ischemia. Basic Res Cardiol 85 (Suppl 1): 177–192, 1990.
 86. Trivella MG, Broten TP and Feigl EO. Beta‐receptor subtypes in the canine coronary circulation. Am J Physiol 259 (5 Pt 2): H1575–H1585, 1990.
 87. Hein TW, Zhang C, Wang W and Kuo L. Heterogeneous beta2‐adrenoceptor expression and dilation in coronary arterioles across the left ventricular wall. Circulation 110 (17): 2708–2712, 2004a.
 88. Muntz KH, Garcia C and Hagler HK. alpha 1‐Receptor localization in rat heart and kidney using autoradiography. Am J Physiol 249 (3 Pt 2): H512–H519, 1985.
 89. Muntz KH, Meyer L, Gadol S and Calianos TA. Alpha‐2 adrenergic receptor localization in the rat heart and kidney using autoradiography and tritiated rauwolscine. J Pharmacol Exp Ther 236 (2): 542–547, 1986.
 90. Vatner DE, Knight DR, Homcy CJ, Vatner SF and Young MA. Subtypes of beta‐adrenergic receptors in bovine coronary arteries. Circ Res 59 (4): 463–473, 1986.
 91. Mohrman DE and Feigl EO. Competition between sympathetic vasoconstriction and metabolic vasodilation in the canine coronary circulation. Circ Res 42 (1): 79–86, 1978.
 92. Dai XZ, Sublett E, Lindstrom P, Schwartz JS, Homans DC and Bache RJ. Coronary flow during exercise after selective alpha 1‐ and alpha 2‐adrenergic blockade. Am J Physiol 256 (4 Pt 2): H1148–H1155, 1989.
 93. Duncker DJ, Van Zon NS, Crampton M, Herrlinger S, Homans DC and Bache RJ. Coronary pressure‐flow relationship and exercise: contributions of heart rate, contractility, and alpha 1‐adrenergic tone. Am J Physiol 266 (2 Pt 2): H795–810, 1994.
 94. Gwirtz PA, Overn SP, Mass HJ and Jones CE. Alpha 1‐adrenergic constriction limits coronary flow and cardiac function in running dogs. Am J Physiol 250 (6 Pt 2): H1117–H1126, 1986.
 95. Gwirtz PA and Stone HL. Coronary blood flow and myocardial oxygen consumption after alpha adrenergic blockade during submaximal exercise. J Pharmacol Exp Ther 217 (1): 92–98, 1981.
 96. Ishibashi Y, Duncker DJ and Bache RJ. Endogenous nitric oxide masks alpha 2‐adrenergic coronary vasoconstriction during exercise in the ischemic heart. Circ Res 80 (2): 196–207, 1997.
 97. Laxson DD, Dai XZ, Homans DC and Bache RJ. The role of alpha 1‐ and alpha 2‐adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise. Circ Res 65 (6): 1688–1697, 1989.
 98. Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K and Ross J, Jr., Intracoronary alpha 2‐adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res 62 (3): 436–442, 1988.
 99. Bache RJ, Homans DC and Dai XZ. Adrenergic vasoconstriction limits coronary blood flow during exercise in hypertrophied left ventricle. Am J Physiol 260 (5 Pt 2): H1489–H1494, 1991.
 100. Heyndrickx GR, Muylaert P and Pannier JL. alpha‐Adrenergic control of oxygen delivery to myocardium during exercise in conscious dogs. Am J Physiol 242 (5): H805–H809, 1982.
 101. Jones CE, Farrell TA and Ator R. Evidence that a coronary alpha‐adrenergic tone limits myocardial blood flow and oxygenation in acute hemorrhagic hypotension. Circ Shock 11 (4): 329–340, 1983.
 102. Jones CE, Liang IY and Maulsby MR. Cardiac and coronary effects of prazosin and phenoxybenzamine during coronary hypotension. J Pharmacol Exp Ther 236 (1): 204–211, 1986.
 103. Liang IY and Jones CE. Alpha 1‐adrenergic blockade increases coronary blood flow during coronary hypoperfusion. Am J Physiol 249 (6 Pt 2): H1070–H1077, 1985.
 104. Heusch G and Deussen A. The effects of cardiac sympathetic nerve stimulation on perfusion of stenotic coronary arteries in the dog. Circ Res 53 (1): 8–15, 1983.
 105. Saffitz JE. Distribution of alpha I‐adrenergic receptors in myocytic regions and vasculature of feline myocardium. Am J Physiol 257 (1 Pt 2): H162–H169, 1989.
 106. Morita K, Mori H, Tsujioka K, Kimura A, Ogasawara Y, Goto M, Hiramatsu O, Kajiya F and Feigl EO. Alpha‐adrenergic vasoconstriction reduces systolic retrograde coronary blood flow. Am J Physiol 273 (6 Pt 2): H2746–H2755, 1997.
 107. Chilian WM, Layne SM, Eastham CL and Marcus ML. Heterogeneous microvascular coronary alpha‐adrenergic vasoconstriction. Circ Res 64 (2): 376–388, 1989.
 108. Heusch G, Deussen A, Schipke J and Thamer V. Alpha 1‐ and alpha 2‐adrenoceptor‐mediated vasoconstriction of large and small canine coronary arteries in vivo. J Cardiovascul Pharmacol 6 (5): 961–968, 1984.
 109. Chilian WM. Functional distribution of alpha 1‐ and alpha 2‐adrenergic receptors in the coronary microcirculation. Circulation 84 (5): 2108–2122, 1991a.
 110. Nakayama K, Osol G and Halpern W. Reactivity of isolated porcine coronary resistance arteries to cholinergic and adrenergic drugs and transmural pressure changes. Circ Res 62 (4): 741–748, 1988.
 111. Richard V, Tanner FC, Tschudi M and Luscher TF. Different activation of L‐arginine pathway by bradykinin, serotonin, and clonidine in coronary arteries. Am J Physiol 259 (5Pt2): H1433–H1439, 1990.
 112. Tschudi M, Richard V, Buhler FR and Luscher TF. Importance of endothelium‐derived nitric oxide in porcine coronary resistance arteries. Am J Physiol 260 (1 Ft 2): H13–20, 1991a.
 113. Hori M, Kitakaze M, Tamai J, Koretsune Y, Iwai K, Iwakura K, Kagiya T, Kitabatake A, Inoue M and Kamada T. Alpha 2‐adrenoceptor activity exerts dual control of coronary blood flow in canine coronary artery. Am J Physiol 255 (2 Pt 2): H250–H260, 1988.
 114. Hori M, Kitakaze M, Tamai J, Iwakura K, Kitabatake A, Inoue M and Kamada T. Alpha 2‐adrenoceptor stimulation can augment coronary vasodilation maximally induced by adenosine in dogs. Am J Physiol 257 (1 Pt 2): H132–H140, 1989.
 115. Jones CJ, DeFily DV, Patterson JL and Chilian WM. Endothelium‐dependent relaxation competes with alpha 1‐ and alpha 2‐adrenergic constriction in the canine epicardial coronary microcirculation. Circulation 87 (4): 1264–1274, 1993a.
 116. Baumgart D, Haude M, Gorge G, Liu F, Ge J, Grosse‐Eggebrecht C, Erbel R and Heuseh G. Augmented alpha‐adrenergic constriction of atherosclerotic human coronary arteries. Circulation 99 (16): 2090–2097, 1999.
 117. Jones CJ, Kuo L, Davis MJ and Chilian WM. alpha‐adrenergic responses of isolated canine coronary microvessels. Basic Res Cardiol 90 (1): 61–69, 1995a.
 118. DeFily DV, Nishikawa Y and Chilian WM. Endothelin antagonists block alpha 1‐adrenergic constriction of coronary arterioles. Am J Physiol 276 (3 Pt 2): H1028–H1034, 1999.
 119. Tiefenbacher CP, DeFily DV and Chilian WM. Requisite role of cardiac myocytes in coronary alpha 1‐adrenergic constriction. Circulation 98 (1): 9–12, 1998.
 120. Gorman MW, Farias M, 3rd, Richmond KN, Tune JD and Feigl EO. Role of endothelin in alpha‐adrenoceptor coronary vasoconstriction. Am Physiol Heart Circ Physiol 288 (4): H1937–H1942, 2005b.
 121. Murphree SS and Saffitz JE. Delineation of the distribution of beta‐adrenergic receptor subtypes in canine myocardium. Circ Res 63 (1): 117–125, 1988.
 122. Sekiguchi N, Kanatsuka H, Komaru T, Akai K, Sato K, Wang Y, Sugi M, Ashikawa K and Takishima T. Effects of alpha and beta adrenergic blockade on coronary arterial microvessels in the beating canine heart. Cardiovascul Res 26 (4): 415–421, 1992.
 123. Quillen J, Sellke F, Banitt P and Harrison D. The effect of norepinephrine on the coronary microcirculation. J Vasc Res 29 (1): 2–7, 1992.
 124. Sun D, Huang A, Mital S, Kichuk MR, Marboe CC, Addonizio LJ, Michler RE, Koller A, Hintze TH and Kaley G. Norepinephrine elicits beta2‐receptor‐mediated dilation of isolated human coronary arterioles. Circulation 106 (5): 550–555, 2002.
 125. Wang SY, Friedman M, Johnson RG, Weintraub RM and Sellke FW. Adrenergic regulation of coronary microcirculation after extracorporeal circulation and crystalloid cardioplegia. Am J Physiol 267 (6 Pt 2): H2462–H2470, 1994.
 126. DiCarlo SE, Blair RW, Bishop VS and Stone HL. Role of beta 2‐adrenergic receptors on coronary resistance during exercise. J Appl Physiol 64 (6): 2287–2293, 1988.
 127. Duncker DJ, Stubenitsky R and Verdouw PD. Autonomic control of vasomotion in the porcine coronary circulation during treadmill exercise: evidence for feed‐forward beta‐adrenergic control. Circ Res 82 (12): 1312–1322, 1998.
 128. Denn MJ and Stone HL. Automic innervation of dog coronary arteries. J Appl Physiol 41 (1): 30–35, 1976.
 129. Feigl EO. Parasympathetic control of coronary blood flow in dogs. Circ Res 25 (5): 509–519, 1969.
 130. Feigl EO. Coronary Physiology. Physiol Rev 63: 1–205, 1983.
 131. Cox DA, Hintze TH and Vatner SF. Effects of acetylcholine on large and small coronary arteries in conscious dogs. J Pharmacol Exp Ther 225 (3): 764–769, 1983.
 132. Feigl EO, Van Winkle DM and Miyashiro JK. Cholinergic vasodilatation of coronary resistance vessels in dogs, baboons and goats. Blood Vessels 27 (2‐5): 94–105, 1990.
 133. Knight DR, Shen YT, Young MA and Vatner SF. Acetylcholine‐induced coronary vasoconstriction and vasodilation in tranquilized baboons. Circ Res 69 (3): 706–713, 1991.
 134. Van Winkle DM and Feigl EO. Acetylcholine causes coronary vasodilation in dogs and baboons. Circ Res 65 (6): 1580–1593, 1989.
 135. Kalsner S. Cholinergic constriction in the general circulation and its role in coronary artery spasm. Circ Res 65 (2): 237–257, 1989.
 136. Cowan CL and McKenzie JE. Cholinergic regulation of resting coronary blood flow in domestic swine. Am J Physiol 259 (1 Pt 2): H109–H115, 1990.
 137. Young MA, Knight DR and Vatner SF. Autonomic control of large coronary arteries and resistance vessels. Prog Cardiovascul Dis 30 (3): 211–234, 1987.
 138. Young MA, Knight DR and Vatner SF. Parasympathetic coronary vasoconstriction induced by nicotine in conscious calves. Circ Res 62 (5): 891–895, 1988.
 139. Kuo L, Davis MJ and Chilian WM. Myogenic activity in isolated subepicardial and subendocardial coronary arterioles. Am J Physiol 255 (6 Pt 2): H1558–H1562, 1988a.
 140. Myers PR, Banitt PF, Guerra R, Jr. and Harrison DG. Role of the endothelium in modulation of the acetylcholine vasoconstrictor response in porcine coronary microvessels. Cardiovascul Res 25 (2): 129–137, 1991.
 141. Myers PR, Banitt PF, Guerra R, Jr. and Harrison DG. Characteristics of canine coronary resistance arteries: importance of endothelium. Am J Physiol 257 (2 Pt 2): H603–H610, 1989.
 142. Lamping KG, Chilian WM, Eastham CL and Marcus ML. Coronary microvascular response to exogenously administered and endogenously released acetylcholine. Microvasc Res 43 (3): 294–307, 1992.
 143. Komaru T, Lamping KG, Eastham CL, Harrison DG, Marcus ML and Dellsperger KC. Effect of an arginine analogue on acetylcholine‐induced coronary microvascular dilatation in dogs. Am J Physiol 261 (6 Pt 2): H2001–H2007, 1991.
 144. Miller FJ, Jr., Dellsperger KC and Gutterman DD. Pharmacologic activation of the human coronary microcirculation in vitro: endothelium‐dependent dilation and differential responses to acetylcholine. Cardiovascul Res 38 (3): 744–750, 1998.
 145. Kuo L, Chilian WM and Davis MJ. Coronary arteriolar myogenic response is independent of endothelium. Circ Res 66 (3): 860–866, 1990b.
 146. Coupe MO, Mak JC, Yacoub M, Oldershaw PJ and Barnes PJ. Autoradiographic mapping of calcitonin gene‐related peptide receptors in human and guinea pig hearts. Circulation 81 (3): 741–747, 1990.
 147. Gulbenkian S, Edvinsson L, Saetrum Opgaard O, Wharton J, Polak JM and David‐Ferreira JF. Peptide‐containing nerve fibres in guinea‐pig coronary arteries: immunohistochemistry, ultrastructure and vasomotility. J Auton Nerv Syst 31 (2): 153–167, 1990.
 148. Saetrum Opgaard O, Gulbenkian S and Edvinsson L. Innervation and effects of vasoactive substances in the coronary circulation. Eur Heart J 18 (10): 1556–1568, 1997.
 149. Franco‐Cereceda A, Saria A and Lundberg JM. Ischaemia and changes in contractility induce release of calcitonin gene‐related peptide but not neuropeptide Y from the isolated perfused guinea‐pig heart. Acta Physiologica Scandinavica 131 (2): 319–320, 1987b.
 150. Franco‐Cereceda A, Saria A and Lundberg JM. Differential release of calcitonin gene‐related peptide and neuropeptide Y from the isolated heart by capsaicin, ischaemia, nicotine, bradykinin and ouabain. Acta Physiologica Scandinavica 135 (2): 173–187, 1989.
 151. Franco‐Cereceda A, Rudehill A and Lundberg JM. Calcitonin gene‐related peptide but not substance P mimics capsaicin‐induced coronary vasodilation in the pig. Eur J Pharmacol 142 (2): 235–243, 1987a.
 152. Sekiguchi N, Kanatsuka H, Sato K, Wang Y, Akai K, Komaru T and Takishima T. Effect of calcitonin gene‐related peptide on coronary microvessels and its role in acute myocardial ischemia. Circulation 89 (1): 366–374, 1994.
 153. Shen YT, Pittman TJ, Buie PS, Bolduc DL, Kane SA, Koblan KS, Gould RJ and Lynch JJ, Jr., Functional role of alpha‐calcitonin gene‐related peptide in the regulation of the cardiovascular system. J Pharmacol Exp Ther 298 (2): 551–558, 2001.
 154. Kuo L, Davis MJ and Chilian WM. Longitudinal gradients for endothelium‐dependent and ‐independent vascular responses in the coronary microcirculation. Circulation 92 (3): 518–525, 1995a.
 155. Brum JM, Go VL, Sufan Q, Lane G, Reilly W and Bove AA. Substance P distribution and effects in the canine epicardial coronary arteries. Regul Pept 14 (1): 41–55, 1986.
 156. Ezra D, Laurindo FR, Eimerl J, Goldstein RE, Peck CC and Feuerstein G. Tachykinin modulation of coronary blood flow. Eur J Pharmacol 122 (1): 135–138, 1986.
 157. Maxwell GM. Actions of substance P on the general, pulmonary. and coronary haemodynamics and metabolism of intact dogs. Br J Pharmacol 32 (3): 514–522, 1968.
 158. Nakamura Y, Parent R and Lavallee M. Opposite effects of substance P on conductance and resistance coronary vessels in conscious dogs. Am J Physiol 258 (2 Pt 2): H565–H573, 1990.
 159. Hellstrand P and Jarhult J. Effects of nine different gastrointestinal polypeptides on vascular smooth muscle in vitro. Acta Physiologica Scandinavica 110 (1): 89–94, 1980.
 160. Nakamura Y, Parent R and Lavallee M. Disparate effects of substance P on systemic and coronary beds in conscious dogs. Circulation 84 (1): 300–312, 1991.
 161. Maley RH, Vrettos AM, Arden WA, Chein S, Salley RK and Gross DR. Coronary vascular and myocardial effects of substance P in hypercholesterolemic rabbits. Neuropeptides 27 (2): 95–103, 1994.
 162. Cappelli‐Bigazzi M, Nuno DW and Lamping KG. Evidence of a role for compounds derived from arginine in coronary response to serotonin in vivo. Am J Physiol 261 (2 Pt 2): H404–H409, 1991.
 163. Lamping KG, Marcus ML and Dole WP. Removal of the endothelium potentiates canine large coronary artery constrictor responses to 5‐hydroxytryptamine in vivo. Circ Res 57 (1): 46–54, 1985.
 164. Lamping KG, Kanatsuka H, Eastham CL, Chilian WM and Marcus ML. Nonuniform vasomotor responses of the coronary microcirculation to serotonin and vasopressin. Circ Res 65 (2): 343–351, 1989a.
 165. Lamping KG. Response of native and stimulated collateral vessels to serotonin. Am J Physiol 272 (5 Pt 2): H2409–H2415, 1997.
 166. Sellke FW and Quillen JE. Altered effects of vasopressin on the coronary circulation after ischemia. J Thor Cardiovascul Surg 104 (2): 357–363, 1992.
 167. Needleman P, Marshall GR and Sobel BE. Hormone interactions in the isolated rabbit heart. Synthesis and coronary vasomotor effects of prostaglandins, angiotensin, and bradykinin. Circ Res 37 (6): 802–808, 1975.
 168. Heyndrickx GR, Boettcher DH and Vatner SF. Effects of angiotensin, vasopressin, and methoxamine on cardiac function and blood flow distribution in conscious dogs. Am J Physiol 231 (5 Pt. 1): 1579–1587, 1976.
 169. Porsti I, Hecker M, Bassenge E and Busse R. Dual action of angiotensin II on coronary resistance in the isolated perfused rabbit heart. Naunyn‐Schmiedebergs Arch Pharmacol 348 (6): 650–658, 1993.
 170. Zhang C, Hein TW, Wang W and Kuo L. Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. Circ Res 92 (3): 322–329, 2003.
 171. Myers PR, Katwa LC, Tanner M, Morrow C, Guarda E and Parker JL. Effects of angiotensin II on canine and porcine coronary epicardial and resistance arteries. J Vasc Res 31 (6): 338–346, 1994.
 172. Dart AM, Davies HA, Dalai J, Ruttley M and Henderson AH. Angina' and normal coronary arteriograms: a follow‐up study. Eur Heart J 1 (2): 97–100, 1980.
 173. Kemp HG, Jr., Vokonas PS, Cohn PF and Gorlin R. The anginal syndrome associated with normal coronary arteriograms. Report of a six year experience. Am J Med 54 (6): 735–742, 1973.
 174. Kemp HG, Kronmal RA, Vlietstra RE and Frye RL. Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. J Am Coll Cardiol 7 (3): 479–483, 1986.
 175. Likoff W, Segal BL and Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med 276 (19): 1063–1066, 1967.
 176. Marchandise B, Bourassa MG, Chaitman BR and Lesperance J. Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol 41 (2): 216–220, 1978.
 177. Ockene IS, Shay MJ, Alpert JS, Weiner BH and Dalen JE. Unexplained chest pain in patients with normal coronary arteriograms: a follow‐up study of functional status. N Engl J Med 303 (22): 1249–1252, 1980.
 178. Papanicolaou MN, Califf RM, Hlatky MA, McKinnis RA, Harrell FE, Jr., Mark DB, McCants B, Rosati RA, Lee KL and Pryor DB. Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries. Am J Cardiol 58 (13): 1181–1187, 1986.
 179. Pasternak RC, Thibault GE, Savoia M, DeSanctis RW and Hutter AM, Jr., Chest pain with angiographically insignificant coronary arterial obstruction. Clinical presentation and long‐term follow‐up. Am J Med 68 (6): 813–817, 1980.
 180. Proudfit WL, Shirey EK and Sones FM, Jr., Selective cine coronary arteriography. Correlation with clinical findings in 1,000 patients. Circulation 33 (6): 901–910, 1966.
 181. Bass C, Cawley R, Wade C, Ryan KC, Gardner WN, Hutchison DC and Jackson G. Unexplained breathlessness and psychiatric morbidity in patients with normal and abnormal coronary arteries. Lancet 1 (8325): 605–609, 1983a.
 182. Bass C, Wade C, Hand D and Jackson G. Patients with angina with normal and near normal coronary arteries: clinical and psychosocial state 12 months after angiography. Br Med J (Clin Res Ed) 287 (6404): 1505–1508, 1983b.
 183. Davies HA, Jones DB and Rhodes J. Esophageal angina' as the cause of chest pain. Jama 248 (18): 2274–2278, 1982.
 184. Epstein SE, Gerber LH and Borer JS. Chest wall syndrome. A common cause of unexplained cardiac pain. Jama 241 (26): 2793–2797, 1979.
 185. Vantrappen G, Janssens J and Ghillebert G. The irritable oesophagus ‐ a frequent cause of angina‐like pain. Lancet 1 (8544): 1232–1234, 1987.
 186. Wielgosz AT, Fletcher RH, McCants CB, McKinnis RA, Haney TL and Williams RB. Unimproved chest pain in patients with minimal or no coronary disease: a behavioral phenomenon. Am Heart J 108 (1): 67–72, 1984.
 187. Arbogast R and Bourassa MG. Myocardial function during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Comparison with patients having significant coronary artery disease. Am J Cardiol 32 (3): 257–263, 1973.
 188. Kemp HG, Jr., Left ventricular function in patients with the anginal syndrome and normal coronary arteriograms. Am J Cardiol 32 (3): 375–376, 1973.
 189. Cannon RO, III, Leon MB, Watson RM, Rosing DR and Epstein SE. Chest pain and “normal” coronary arteries‐role of small coronary arteries. Am J Cardiol 55 (3): 50B–60B, 1985.
 190. Cannon RO, III, Schenke WH, Leon MB, Rosing DR, Urqhart J and Epstein SE. Limited coronary flow reserve after dipyridamole in patients with ergonovine‐induced coronary vasoconstriction. Circulation 75 (1): 163–174, 1987.
 191. Cannon RO, III, Watson RM, Rosing DR and Epstein SE. Angina caused by reduced vasodilator reserve of the small coronary arteries. J Am Coll Cardiol 1 (6): 1359–1373, 1983.
 192. Buffon A, Rigattieri S, Santini SA, Ramazzotti V, Crea F, Giardina B and Maseri A. Myocardial ischemia‐reperfusion damage after pacing‐induced tachycardia in patients with cardiac syndrome X. Am J Physiol Heart Circ Physiol 279 (6): H2627–2633, 2000.
 193. Quyyumi AA, Cannon RO, Jr., Panza JA, Diodati JG and Epstein SE. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 86 (6): 1864–1871, 1992.
 194. Motz W, Vogt M, Rabenau O, Scheler S, Luckhoff A and Strauer BE. Evidence of endothelial dysfunction in coronary resistance vessels in patients with angina pectoris and normal coronary angiograms. Am J Cardiol 68 (10): 996–1003, 1991.
 195. Cannon RO, III, Cattau EL, Jr., Yakshe PN, Maher K, Schenke WH, Benjamin SB and Epstein SE. Coronary flow reserve, esophageal motility, and chest pain in patients with angiographically normal coronary arteries. Am J Med 88 (3): 217–222, 1990a.
 196. Cannon RO, III, Peden DB, Berkebile C, Schenke WH, Kaliner MA and Epstein SE. Airway hyperresponsiveness in patients with microvascular angina. Evidence for a diffuse disorder of smooth muscle responsiveness. Circulation 82 (6): 2011–2017, 1990b.
 197. Sax FL, Cannon RO, III, Hanson C and Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina. Evidence of a generalized disorder of vascular function? N Engl J Med 317 (22): 1366–1370, 1987.
 198. Chauhan A, Mullins PA, Taylor G, Petch MC and Schofield PM. Both endothelium‐dependent and endothelium‐independent function is impaired in patients with angina pectoris and normal coronary angiograms. Eur Heart J 18 (1): 60–68, 1997.
 199. Epstein SE, Cannon RO, III and Bonow RO. Exercise testing in patients with microvascular angina. Circulation 83 (5 Suppl): III73–III76, 1991.
 200. Bugiardini R, Manfrini O, Pizzi C, Fontana F and Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation 109 (21): 2518–2523, 2004.
 201. Reddy KG, Nair RN, Sheehan HM and Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 23 (4): 833–843, 1994.
 202. Sambuceti G, Parodi O, Giorgetti A, Salvadori P, Marzilli M, Dabizzi P, Marzullo P, Neglia D and L'Abbate A. Microvascular dysfunction in collateral‐dependent myocardium. J Am Coll Cardiol 26 (3): 615–623, 1995.
 203. Tiefenbacher CP, Tillmanns H, Niroomand F, Zimmermann R and Kubler W. Adaptation of myocardial blood flow to increased metabolic demand is not dependent on endothelial vasodilators in the rat heart. Heart 77: 147–153, 1997.
 204. Duncker DJ and Bache RJ. Inhibition of nitric oxide production aggravates myocardial hypoperfusion during exercise int he presence of a coronary artery stenosis. Circ Res 74: 629–640, 1994.
 205. Brandes RP, Schmitz‐Winnenthal FH, Feletou M, Godecke A, Huang PL, Vanhoutte PM, Fleming 1 and Busse R. An endothelium‐derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium‐dependent vasodilator in resistance vessels of wild‐type and endothelial NO synthase knockout mice. Proc Natl Acad Sci USA 97 (17): 9747–9752, 2000.
 206. Ignarro LJ. Endothelium‐derived nitric oxide: actions and properties. FASEB J 3: 31–36, 1989.
 207. Tiefenbacher CP and Kreuzer J. Endothelial dysfunction ‐ is there need to treat? Curr Vasc Pharm 1: 1133–1234, 2003.
 208. Cines DB, Pollak ED, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM and Stern DM. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91: 3527–3561, 1998.
 209. Drexler H, Zeither AM, Meinzer K and Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L‐arginine. Lancet 338: 1546–1550, 1991.
 210. Vasquez Vivar J, Kalyanamaran B, Martasek P, Hogg N, Siler Master BS, Karoui H, Tordos P and Pritchard KAJ. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95: 9220–9225, 1998.
 211. Fukuda Y, Teragawa H, Matsuda K, Yamagata T, Matsuura H and Chayama K. Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia. Heart 87: 264–269, 2001.
 212. Hong HJ, Hsiao G, Cheng TH and Yen MH. Supplemention with tetrahydrobiopterin suppresses the development of hypertension in spontaneously hypertensive rats. Hypertension 38: 1044–1048, 2001.
 213. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T and Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 99 (1): 41–46, 1997.
 214. Tiefenbacher CP, Bleeke T, Vahl C, Amann K, Vogt A and Kubler W. Endothelial dysfunction of coronary resistance arteries in improved by tetrahydrobiopterin in atherosclerosis. Circulation 102: 2172–2179, 2000.
 215. Tiefenbacher CP, Chilian WM, Mitchell M and Defily DV. Restoration of endothelium‐dependent vasodilation after reperfusion injury by tetrahydrobiopterin. Circulation 94: 1423–1429, 1996.
 216. Tiefenbacher CP, Lee C‐H and Dietz V. Reduction of reperfusion injury by sepiapterin reduces myocardial infarct size. Eur Heart J 14 (Suppl): 1076, 2001.
 217. Cai H and Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87 (10): 840–844, 2000.
 218. Schiffrin EL. Vascular endothelin in hypertension. Vascul Pharmacol 43 (1): 19–29, 2005.
 219. Schachinger V, Britten MB and Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long‐term outcome of coronary heart disease. Circulation 101: 95422–95448, 2001.
 220. Boger RH, Bode‐Boger SM, Thiele W, Creutzig A, Alexander K, and Frolich, JC. Restoring vascular nitric oxide formation by L‐arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol. 32 (5): 1336–1344, 1998.
 221. Merkus D, Duncker DJ and Chilian WM. Metabolic regulation of coronary vascular tone: role of endothelin‐1. Am J Physiol Heart Circ Physiol 283 (5): H1915–H1921, 2002a.
 222. Berne RM, Rubio R, Dobson JG, Jr. and Curnish RR. Adenosine and adenine nucleotides as possible mediators of cardiac and skeletal muscle blood flow regulation. Circ Res 28 (Suppl. 1): 115, 1971.
 223. Miller WL, Belardinelli L, Bacchus A, Foley DH, Rubio R and Berne RM. Canine myocardial adenosine and lactate production, oxygen consumption, and coronary blood flow during stellate ganglia stimulation. Circ Res 45 (6): 708–718, 1979.
 224. Rubio R, Wiedmeier VT and Berne RM. Relationship between coronary flow and adenosine production and release. J Mol Cell Cardiol 6 (6): 561–566, 1974.
 225. Gorman MW, Tune JD, Richmond KN and Feigl EO. Feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol 89 (5): 1892–1902, 2000b.
 226. Gorman MW, Tune JD, Richmond KN and Feigl EO. Quantitative analysis of feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol 89 (5): 1903–1911, 2000c.
 227. Miyashiro JK and Feigl EO. Feedforward control of coronary blood flow via coronary beta‐receptor stimulation. Circ Res 73 (2): 252–263, 1993.
 228. 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 (4): H1586–H1590, 2005.
 229. Ishizaka H, Gudi SR, Frangos JA and Kuo L. Coronary arteriolar dilation to acidosis: role of ATP‐sensitive potassium channels and pertussis toxin‐sensitive G proteins. Circulation 99: 558–563, 1999.
 230. Ishizaka H and Kuo L. Acidosis‐induced coronary arteriolar dilation is mediated by ATP‐sensitive potassium channels in vascular smooth muscle. Circ Res 78: 50–57, 1996.
 231. Prasad A, Husain S and Quyyumi AA. Abnormal flow‐mediated epicardial vasomotion in human coronary arteries is improved by angiotensin‐converting enzyme inhibition: a potential role of bradykinin. J Am Coll Cardiol 33 (3): 796–804, 1999.
 232. Ishizaka H and Kuo L. Endothelial ATP‐sensitive potassium channels mediate coronary microvascular dilation to hyperosmolarity. Am J Physiol 273 (1 Pt 2): H104–H112, 1997.
 233. Vlahakes GJ, Giamber SR, Rothaus KO and Powell WJ, Jr., Hyperosmotic mannitol and collateral blood flow to ischemic myocardium. J Surg Res 47 (5): 438–446, 1989.
 234. Sato K, Komaru T, Shioiri H, Takeda S, Takahashi K, Kanatsuka H and Shirato K. Vasodilator signals from the ischemic myocardium are transduced to the coronary vascular wall by pertussis toxin‐sensitive G proteins: a new experimental method for the analysis of the interaction between the myocardium and coronary vessels. J Am Coll Cardiol 39 (11): 1859–1865, 2002.
 235. Tanikawa T, Kanatsuka H, Koshida R, Tanaka M, Sugimura A, Kumagai T, Miura M, Komaru T and Shirato K. Role of pertussis toxin‐sensitive G protein in metabolic vasodilation of coronary microcirculation. Am J Physiol Heart Circ Physiol 279 (4): H1819–H1829, 2000.
 236. Takeda S, Komaru T, Takahashi K, Sato K, Kanatsuka H, Kokusho Y, Shirato K and Shimokawa H. Beating myocardium counteracts myogenic tone of coronary microvessels: involvement of ATP‐sensitive potassium channels. Am J Physiol Heart Circ Physiol, 2006.
 237. Merkus D, Sorop O, Houweling B, Hoogteijling BA and Duncker DJ. K+Ca‐channels contribute to exercise‐induced coronary vasodilation in swine. Am J Physiol Heart Circ Physiol, 2006.
 238. Rogers PA, Dick GM, Knudson JD, Focardi M, Bratz IN, Swafford J, Albert N, Saitoh S, Tune JD and Chilian WM. H202‐induced redox sensitive coronary vasodilation is mediated by 4‐aminopyridine‐sensitive K+ channels. Am J Physiol Heart Circ Physiol, 2006, epub:10.1152/ajpheart.00172.2006.
 239. Duncker DJ, Van Zon NS, Altman JD, Pavek TJ and Bache RJ. Role of K+ATP channels in coronary vasodilation during exercise. Circulation 88 (3): 1245–1253, 1993.
 240. Richmond KN, Tune JD, Gorman MW and Feigl EO. Role of K + ATP channels in local metabolic coronary vasodilation. Am J Physiol 277 (6 Pt 2): H2115–H2123, 1999.
 241. Tune JD, Richmond KN, Gorman MW and Feigl EO. K(ATP)(+) channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation. Am J Physiol Heart Circ Physiol 280 (2): H868–H875, 2001.
 242. Murray PA, Belloni F, and Sparks HV. The role of potassium in the metabolic control of coronary vascular resistance of the dog. Circ Res 44: 77–780, 1979.
 243. Rivers RJ, Hein TW, Zhang C, and Kuo L. Activation of barium‐sensitive inward rectifier potassium channels mediates remote dilation of coronary arterioles. Circulation 104: 1749–1753, 2001.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Regulation of Coronary Microvascular Resistance in Health and Disease
 

How to Cite

Cuihua Zhang, Paul A Rogers, Daphne Merkus, Judy M Muller‐Delp, Christiane P Tiefenbacher, Barry Potter, Jarrod D Knudson, Petra Rocic, William M Chilian. Regulation of Coronary Microvascular Resistance in Health and Disease. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 521-549. First published in print 2008. doi: 10.1002/cphy.cp020412