ATP-Sensitive K⁺ Channels, Adenosine, and Nitric Oxide–Mediated Mechanisms Account for Coronary Vasodilation During Exercise

From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis.

Correspondence to Robert J. Bache, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail Bache001{at}maroon.tc.umn.edu

Abstract—We previously reported that combined blockade of adenosine receptors and ATP-sensitive K+ channels (K⁺_ATP channels) blunted but did not abolish the response of coronary blood flow to exercise. This study tested the hypothesis that the residual increase in coronary flow in response to exercise after adenosine receptor and K⁺_ATP channel blockade is dependent on endogenous NO. Dogs were studied at rest and during a four-stage treadmill exercise protocol under control conditions, during K⁺_ATP channel blockade with glibenclamide (50 µg · kg^-1 · min^-1 IC) in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT, 5 mg/kg IV), and after the addition of the NO synthase inhibitor N^G-nitro-L-arginine (LNNA, 1.5 mg/kg IC). During control conditions, coronary blood flow was 49±3 mL/min at rest and increased to 92±8 mL/min at peak exercise. LNNA alone or in combination with 8-PT did not alter resting coronary flow and did not impair the normal increase in flow during exercise, indicating that when K⁺_ATP channels are intact, neither NO nor adenosine-dependent mechanisms are obligatory for maintaining coronary blood flow. Combined K⁺_ATP channel and adenosine blockade decreased resting coronary flow to 27±3 mL/min (P<.05), but exercise still increased flow to 45±5 mL/min (P<.05). The subsequent addition of LNNA further decreased resting coronary flow to 20±2 mL/min and markedly blunted exercise-induced coronary vasodilation (coronary vascular conductance, 0.20±0.03 mL · min^-1 · mm Hg^-1 at rest versus 0.24±0.04 mL · min^-1 · mm Hg^-1 during the heaviest level of exercise; P=.22), so that coronary flow both at rest and during exercise was below the control resting level. The findings suggest that K⁺_ATP channels are critical for maintaining coronary vasodilation at rest and during exercise but that when K⁺_ATP channels are blocked, both adenosine and NO act to increase coronary blood flow during exercise. In the presence of combined K⁺_ATP channel blockade and adenosine receptor blockade, NO was able to produce approximately one quarter of the coronary vasodilation that occurred in response to exercise when all vasodilator systems were intact.

Key Words: blood flow • endothelium • K⁺ channel • ischemia • reactive hyperemia

This article has been cited by other articles:

				C. L. Stebbins, J. P. Stice, C. M. Hart, F. N. Mbai, and A. A. Knowlton Effects of Dietary Decosahexaenoic Acid (DHA) on eNOS in Human Coronary Artery Endothelial Cells Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2008; 13(4): 261 - 268. [Abstract] [PDF]

				T. Farzaneh and A. Tinker Differences in the mechanism of metabolic regulation of ATP-sensitive K+ channels containing Kir6.1 and Kir6.2 subunits Cardiovasc Res, September 1, 2008; 79(4): 621 - 631. [Abstract] [Full Text] [PDF]

				D. J. Duncker and R. J. Bache Regulation of Coronary Blood Flow During Exercise Physiol Rev, July 1, 2008; 88(3): 1009 - 1086. [Abstract] [Full Text] [PDF]

				V. J. de Beer, O. Sorop, D. A. Pijnappels, D. H. Dekkers, F. Boomsma, J. M. J. Lamers, D. J. Duncker, and D. Merkus Integrative control of coronary resistance vessel tone by endothelin and angiotensin II is altered in swine with a recent myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2069 - H2077. [Abstract] [Full Text] [PDF]

				G. M. Dick, I. N. Bratz, L. Borbouse, G. A. Payne, U. D. Dincer, J. D. Knudson, P. A. Rogers, and J. D. Tune Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2371 - H2381. [Abstract] [Full Text] [PDF]

				P. P. Dzeja, P. Bast, D. Pucar, B. Wieringa, and A. Terzic Defective Metabolic Signaling in Adenylate Kinase AK1 Gene Knock-out Hearts Compromises Post-ischemic Coronary Reflow J. Biol. Chem., October 26, 2007; 282(43): 31366 - 31372. [Abstract] [Full Text] [PDF]

				T. Yada, H. Shimokawa, O. Hiramatsu, Y. Shinozaki, H. Mori, M. Goto, Y. Ogasawara, and F. Kajiya Important Role of Endogenous Hydrogen Peroxide in Pacing-Induced Metabolic Coronary Vasodilation in Dogs In Vivo J. Am. Coll. Cardiol., September 25, 2007; 50(13): 1272 - 1278. [Abstract] [Full Text] [PDF]

				D. J. Duncker and D. Merkus Exercise hyperaemia in the heart: the search for the dilator mechanism J. Physiol., September 15, 2007; 583(3): 847 - 854. [Abstract] [Full Text] [PDF]

				E. D. van Deel, D. Merkus, R. van Haperen, M. C. de Waard, R. de Crom, and D. J. Duncker Vasomotor control in mice overexpressing human endothelial nitric oxide synthase Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1144 - H1153. [Abstract] [Full Text] [PDF]

				Y. Kokusho, T. Komaru, S. Takeda, K. Takahashi, R. Koshida, K. Shirato, and H. Shimokawa Hydrogen Peroxide Derived From Beating Heart Mediates Coronary Microvascular Dilation During Tachycardia Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1057 - 1063. [Abstract] [Full Text] [PDF]

				D. Merkus, O. Sorop, B. Houweling, B. A. Hoogteijling, and D. J. Duncker KCa+ channels contribute to exercise-induced coronary vasodilation in swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2090 - H2097. [Abstract] [Full Text] [PDF]

				D. Merkus, O. Sorop, B. Houweling, F. Boomsma, A. H. van den Meiracker, and D. J. Duncker NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2075 - H2081. [Abstract] [Full Text] [PDF]

				D. Merkus, D. B. Haitsma, O. Sorop, F. Boomsma, V. J. de Beer, J. M. J. Lamers, P. D. Verdouw, and D. J. Duncker Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2082 - H2089. [Abstract] [Full Text] [PDF]

				N. Westerhof, C. Boer, R. R. Lamberts, and P. Sipkema Cross-talk between cardiac muscle and coronary vasculature. Physiol Rev, October 1, 2006; 86(4): 1263 - 1308. [Abstract] [Full Text] [PDF]

				W. G. Schrage, N. M. Dietz, and M. J. Joyner Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise J Appl Physiol, May 1, 2006; 100(5): 1506 - 1512. [Abstract] [Full Text] [PDF]

				H. Hibino and Y. Kurachi A New Insight Into the Pathogenesis of Coronary Vasospasm Circ. Res., March 17, 2006; 98(5): 579 - 581. [Full Text] [PDF]

				R. Kakkar, B. Ye, D. A. Stoller, M. Smelley, N.-Q. Shi, K. Galles, M. Hadhazy, J. C. Makielski, and E. M. McNally Spontaneous Coronary Vasospasm in KATP Mutant Mice Arises From a Smooth Muscle-Extrinsic Process Circ. Res., March 17, 2006; 98(5): 682 - 689. [Abstract] [Full Text] [PDF]

				P. Zong, J. D. Tune, and H. F. Downey Mechanisms of Oxygen Demand/Supply Balance in the Right Ventricle Experimental Biology and Medicine, September 1, 2005; 230(8): 507 - 519. [Abstract] [Full Text] [PDF]

				R. R. Martinez, S. Setty, P. Zong, J. D. Tune, and H. F. Downey Nitric oxide contributes to right coronary vasodilation during systemic hypoxia Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1139 - H1146. [Abstract] [Full Text] [PDF]

				D. Merkus, B. Houweling, M. van Vliet, and D. J. Duncker Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1306 - H1313. [Abstract] [Full Text] [PDF]

				J. Zhang, G. Gong, Y. Ye, T. Guo, A. Mansoor, Q. Hu, K. Ochiai, J. Liu, X. Wang, Y. Cheng, et al. Nitric oxide regulation of myocardial O2 consumption and HEP metabolism Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H310 - H316. [Abstract] [Full Text] [PDF]

				C. Penna, P. Pagliaro, R. Rastaldo, F. Di Pancrazio, G. Lippe, D. Gattullo, D. Mancardi, M. Samaja, G. Losano, and I. Mavelli F0F1 ATP synthase activity is differently modulated by coronary reactive hyperemia before and after ischemic preconditioning in the goat Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2192 - H2200. [Abstract] [Full Text] [PDF]

				J. D. Tune, M. W. Gorman, and E. O. Feigl Matching coronary blood flow to myocardial oxygen consumption J Appl Physiol, July 1, 2004; 97(1): 404 - 415. [Abstract] [Full Text] [PDF]

				H. M. O. Farouque, S. G. Worthley, and I. T. Meredith Effect of ATP-Sensitive Potassium Channel Inhibition on Coronary Metabolic Vasodilation in Humans Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 905 - 910. [Abstract] [Full Text]

				C. S. Broberg, G. D. Giraud, J. M. Schultz, K. L. Thornburg, A. R. Hohimer, and L. E. Davis Fetal anemia leads to augmented contractile response to hypoxic stress in adulthood Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2003; 285(3): R649 - R655. [Abstract] [Full Text] [PDF]

				D. Merkus, B. Houweling, A. Mirza, F. Boomsma, A. H van den Meiracker, and D. J Duncker Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation Cardiovasc Res, September 1, 2003; 59(3): 745 - 754. [Abstract] [Full Text] [PDF]

				D. Merkus, D. B. Haitsma, T.-Y. Fung, Y. J. Assen, P. D. Verdouw, and D. J. Duncker Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H424 - H433. [Abstract] [Full Text] [PDF]

				H. M. O. Farouque and I. T. Meredith Relative contribution of vasodilator prostanoids, NO, and KATP channels to human forearm metabolic vasodilation Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2405 - H2411. [Abstract] [Full Text] [PDF]

				H. M. O. Farouque and I. T. Meredith Inhibition of vascular ATP-sensitive K+ channels does not affect reactive hyperemia in human forearm Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H711 - H718. [Abstract] [Full Text] [PDF]

				D. Merkus, D. J. Duncker, and W. M. Chilian Metabolic regulation of coronary vascular tone: role of endothelin-1 Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1915 - H1921. [Abstract] [Full Text] [PDF]

				M. B. Gordon, R. Jain, J. A Beckman, and M. A Creager The contribution of nitric oxide to exercise hyperemia in the human forearm Vascular Medicine, August 1, 2002; 7(3): 163 - 168. [Abstract] [PDF]

				B. A. Kingwell, M. Formosa, M. Muhlmann, S. J. Bradley, and G. K. McConell Nitric Oxide Synthase Inhibition Reduces Glucose Uptake During Exercise in Individuals With Type 2 Diabetes More Than in Control Subjects Diabetes, August 1, 2002; 51(8): 2572 - 2580. [Abstract] [Full Text] [PDF]

				Y. Chen, J. H. Traverse, R. Du, M. Hou, and R. J. Bache Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart Circulation, July 9, 2002; 106(2): 273 - 279. [Abstract] [Full Text] [PDF]

				J. P. Walker, J. C. Barbato, and L. G. Koch Cardiac adenosine production in rat genetic models of low and high exercise capacity Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R168 - R173. [Abstract] [Full Text] [PDF]

				J. H. Traverse, Y. Chen, M. Hou, and R. J. Bache Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2278 - H2283. [Abstract] [Full Text] [PDF]

				A. J. M. Cornelissen, J. Dankelman, E. VanBavel, and J. A. E. Spaan Balance between myogenic, flow-dependent, and metabolic flow control in coronary arterial tree: a model study Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2224 - H2237. [Abstract] [Full Text] [PDF]

				J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl Control of Coronary Blood Flow during Exercise Experimental Biology and Medicine, April 1, 2002; 227(4): 238 - 250. [Abstract] [Full Text] [PDF]

				T Reffelmann, H G Klues, P Hanrath, and E R Schwarz Post-stenotic coronary blood flow at rest is not altered by therapeutic doses of the oral antidiabetic drug glibenclamide in patients with coronary artery disease Heart, January 1, 2002; 87(1): 54 - 60. [Abstract] [Full Text] [PDF]

				V. Borutaite, A. Matthias, H. Harris, S. Moncada, and G. C. Brown Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2256 - H2260. [Abstract] [Full Text] [PDF]

				R. Nakamura, K. Egashira, K. Arimura, Y. Machida, T. Ide, H. Tsutsui, H. Shimokawa, and A. Takeshita Increased inactivation of nitric oxide is involved in impaired coronary flow reserve in heart failure Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2619 - H2625. [Abstract] [Full Text] [PDF]

				B. J. Hart, X. Bian, P. A. Gwirtz, S. Setty, and H. F. Downey Right ventricular oxygen supply/demand balance in exercising dogs Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H823 - H830. [Abstract] [Full Text] [PDF]

				J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl KATP+ channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H868 - H875. [Abstract] [Full Text] [PDF]

				N. Paolocci, P. Pagliaro, T. Isoda, F. W. Saavedra, and D. A. Kass Role of Calcium-Sensitive K+ Channels and Nitric Oxide in In Vivo Coronary Vasodilation From Enhanced Perfusion Pulsatility Circulation, January 2, 2001; 103(1): 119 - 124. [Abstract] [Full Text] [PDF]

				Y. Chen, R. Du, J. H. Traverse, and R. J. Bache Effect of sildenafil on coronary active and reactive hyperemia Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2319 - H2325. [Abstract] [Full Text] [PDF]

				B. A. KINGWELL Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease FASEB J, September 1, 2000; 14(12): 1685 - 1696. [Abstract] [Full Text]

				K. N. Richmond, J. D. Tune, M. W. Gorman, and E. O. Feigl Role of KATP+ channels and adenosine in the control of coronary blood flow during exercise J Appl Physiol, August 1, 2000; 89(2): 529 - 536. [Abstract] [Full Text] [PDF]

				J. D. Tune, K. N. Richmond, M. W. Gorman, and E. O. Feigl Role of Nitric Oxide and Adenosine in Control of Coronary Blood Flow in Exercising Dogs Circulation, June 27, 2000; 101(25): 2942 - 2948. [Abstract] [Full Text] [PDF]

				P. Pagliaro, N. Paolocci, T. Isoda, W. F Saavedra, G. Sunagawa, and D. A Kass Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for nitric oxide Cardiovasc Res, March 1, 2000; 45(4): 1001 - 1009. [Abstract] [Full Text] [PDF]

				S. J. Duffy, S. F. Castle, R. W. Harper, and I. T. Meredith Contribution of Vasodilator Prostanoids and Nitric Oxide to Resting Flow, Metabolic Vasodilation, and Flow-Mediated Dilation in Human Coronary Circulation Circulation, November 9, 1999; 100(19): 1951 - 1957. [Abstract] [Full Text] [PDF]

				S. J Duffy, G. New, R. W Harper, and I. T Meredith Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation Cardiovasc Res, August 15, 1999; 43(3): 721 - 730. [Abstract] [Full Text] [PDF]

				D. J. Duncker, J. H. Traverse, Y. Ishibashi, and R. J. Bache Effect of NO on transmural distribution of blood flow in hypertrophied left ventricle during exercise Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1305 - H1312. [Abstract] [Full Text] [PDF]

				M. F Bellamy, J. Goodfellow, A. C Tweddel, F. D.J Dunstan, M. J Lewis, and A. H Henderson Syndrome X and endothelial dysfunction Cardiovasc Res, November 1, 1998; 40(2): 410 - 417. [Abstract] [Full Text] [PDF]

				R. J. Bache Vasodilator Reserve : A Functional Assessment of Coronary Health Circulation, September 29, 1998; 98(13): 1257 - 1260. [Full Text] [PDF]

				S. Setty, J. D. Tune, and H. F. Downey Nitric oxide modulates right ventricular flow and oxygen consumption during norepinephrine infusion Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H696 - H703. [Abstract] [Full Text] [PDF]

				A. J. M. Cornelissen, J. Dankelman, E. VanBavel, and J. A. E. Spaan Balance between myogenic, flow-dependent, and metabolic flow control in coronary arterial tree: a model study Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2224 - H2237. [Abstract] [Full Text] [PDF]