Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation Research. 2006;98:579-581
doi: 10.1161/01.RES.0000215571.12500.ab
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hibino, H.
Right arrow Articles by Kurachi, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hibino, H.
Right arrow Articles by Kurachi, Y.
Related Collections
Right arrowRelated Article
(Circulation Research. 2006;98:579.)
© 2006 American Heart Association, Inc.

Editorials

A New Insight Into the Pathogenesis of Coronary Vasospasm

Hiroshi Hibino, Yoshihisa Kurachi

From the Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan.

Correspondence to Dr Yoshihisa Kurachi, Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail ykurachi{at}pharma2.med.osaka-u.ac.jp



See related article, pages 682–689


Key Words: ATP-sensitive K+ (KATP) channels • coronary spasm • vascular constriction • K+ channel opening drugs (KCO)

To elucidate the control mechanisms of coronary vascular tone is one of the central interests in cardiac pathophysiology, because ischemic heart disease is one of the major causes of death in many countries. Although the coronary vascular tone is finally determined by the contractile state of smooth muscle, exo-smooth muscle mechanisms including autonomic nerves, endothelial cells, and blood cells have been shown indispensable for the control. Particular types of receptors, ion channels, and intracellular signal-cascades exist in coronary smooth muscle cells and mediate the controls by exo-smooth muscle elements (Figure). For example, stimulation of {alpha}1-adrenergic receptor, which is physiologically achieved by noradrenaline (NA) released from sympathetic presynapses, increases the intracellular Ca2+ (Ca2+i) via phosphatidylinositol (PI)-turnover and also probably via opening of receptor-activated Ca2+-permeable TRP channel. Membrane depolarization does so via opening voltage-dependent Ca2+ channels. The augmentation of Ca2+i results in contraction of the smooth muscle cells and thus constriction of the coronary artery.1 Activation of ß2-adrenergic receptor, in turn, inhibits the coronary smooth muscle contraction through protein-kinase A pathway.2 The contraction is also suppressed by protein-kinase G activated by a dilating factor, nitric oxide (NO), which is produced in the endothelial cells.


Figure 1
View larger version (29K):
[in this window]
[in a new window]
  		The mechanism for control of vascular tone. Activation of voltage-gated Ca2+ channel at the presynapse of sympathetic nerve increases intracellular Ca2+, which triggers a release of norepinephrine (NE). NE stimulates adrenergic {alpha}1 receptor ({alpha}1R) in the smooth muscle cells and drives PI-turnover as described in this scheme. The intracellular Ca2+, which flows into the cells via smooth-muscle’s Ca2+ channel or moves from endoplasmic reticulum (ER), contracts the cells. The constriction of smooth muscle cells is prevented by activation of adrenergic ß2 receptor (ß2R), or by a vasodilator NO that is produced by stimulation of receptors such as acetylcholine M3 receptor (M3R), adenosine type 2 receptor (A2R), and adrenergic {alpha}2 receptor ({alpha}2R). Functional KATP channels are expressed in the presynapse, the smooth muscle cells, and endothelial cells. These KATP channels are considered to be involved in vasodilatation process. Opening of presynaptic KATP channel may hyperpolarize the membrane potential, which would close the Ca2+ channel and attenuate NA release. Endothelial KATP channel enhances A2R- and {alpha}2R-induced dilatation by increasing NO-production. Activation of the KATP channel in smooth muscle cells, which is also called KNDP channel, has been believed to contribute to an inhibition of the constriction. However, the present study in this issue questions this hypothesis.

In addition to these elements, it has been recently revealed that various types of ATP-sensitive K+ (KATP) channels distribute not only in smooth muscle cells but also in nerve termini and endothelial cells of the coronary artery3–10 (Figure). At present, it has not been fully elucidated how these KATP channels play respective roles in the control of coronary artery tone. Yet without direct evidence, it has been widely considered that KATP channel in coronary smooth muscle cells is the key player. Two lines of experiments using gene-targeting mice for either Kir6.1 or SUR2 have been thought to provide the somehow final evidence for this notion.11,12 In this issue of Circulation Research, Kakkar et al has reported the observations to question the current consensus.13

The KATP channels distribute in a variety of cells and associate with diverse cellular functions such as insulin secretion from pancreatic ß-cells, shortening of cardiac action potential and cellular loss of K+ during metabolic inhibition in the heart, regulation of skeletal muscle excitability, control of vasculature tone, and neuronal function.14–16 KATP channels are hetero-octamers comprising a pore-forming inwardly rectifying K+ (Kir) channel subunit, Kir6.x, and a regulatory subunit, sulfonylurea receptor (SURx).17–22 Whereas SURs contribute to the regulation of KATP channels by various pharmacological agents and intracellular nucleotides, Kir6.xs determine the single-channel properties and the sensitivity to intracellular ATP (ATP)i. Kir6.2/SUR1 and Kir6.2/SUR2A represent the pancreatic ß-cell and cardiac and skeletal-myocyte KATP channels, respectively.17,19 These channels are inhibited by ATPi in micromolar range and shows a single-channel conductance of &80 pS with 150 mmol/L extracellular K+ ([K+]o).17,19 On the other hand, the channel comprising Kir6.1 and SUR2B, an alternatively spliced form of SUR2A, reconstituted the vascular KATP channel (or alternatively called KNDP channel),20,21 which does not open spontaneously in the absence of ATPi and requires intracellular nucleoside diphosphates, such as ADP, GDP, and UDP, for activation.23,24 The single-channel conductance of the KNDP channel is &40 pS with 150 mmol/L [K+]o. Physiologically, this KNDP channel appears to be involved in regulation of resting coronary tone, coronary vasodilatory response to exercise and hypoxia, and endotoxic vasodilatation.25–27

The mutant mice lacking either Kir6.1- or SUR2-gene lost the KNDP-conductance from their coronary smooth muscle cells, ensuring that the vascular KATP channel (ie, KNDP channel) is of an assembly of Kir6.1 and SUR2B.11,12 Both Kir6.1- and SUR2-null mice showed an identical phenotype of spontaneous coronary artery spasm and resultant sudden death, resembling Prinzmetal (or variant) angina in humans.11,12 Because of abundant expression of Kir6.1- and SUR2B-proteins in the vascular smooth muscle cells,3 dysfunction of the smooth muscle induced by loss of the KNDP channel was thought to be the main cause of the phenotypes in the mice.

In this issue of Circulation Research, Kakkar et al attempted to test this hypothesis by generating and analyzing the transgenic mice that harbored the KNDP channel only in vascular smooth muscle cells but not in any other cells.13 The authors engineered the SUR2-null mice to express SUR2B-protein specifically in vascular smooth muscle by using its specific promoter, SM22{alpha}. Kakkar et al observed not only protein expression but also restoration of the functional KNDP channel in the smooth muscle cells. Unexpectedly, this selective expression of the KNDP channel could not rescue the phenotypes of SUR2-null mice. The transgene-restored SUR2-null mice still exhibited vasospasm, abnormality in ECG, high coronary perfusion pressure, and sudden death. These results now clearly indicate the need of reevaluation of the current consensus regarding the role of KNDP channels in the control of coronary artery tone.

For example, application of the drugs that open KATP channels (K+ channel opening drugs [KCOs]) such as cromakalim and nicorandil dilates coronary artery.16,28,29 It has been believed that the action of KCOs on coronary artery can be attributed mainly to direct effect of these agents on vascular smooth muscle KNDP channel containing SUR2B and Kir6.1. Based on this concept, a number of KCOs have been developed in the last several decades targeting ischemic heart diseases as well as hypertension.15 Among them only nicorandil is clinically proven to be effective in anti-anginal therapy, and many others cannot be adopted for clinical usage because of their significant side effects including lower-extremity edema.30 The study of Kakkar et al indicates the possibility that exo-smooth muscle mechanism might be involved in the action of some KCOs, which might result in clinically different effectiveness.13

The possible exo-smooth muscle mechanisms associated with KATP channels in the coronary artery are: In the endothelial cells the KATP channels are activated by adenosine and {alpha}2-AR stimulation and contribute to generation of NO,31,32 in the sympathetic neurons opening of presynaptic KATP channels attenuates NA-release9 (Figure). KCOs would enhance these exo-smooth muscle actions of the KATP channels and dilate the coronary artery. Thus, in Kir6.1- or SUR2-null mice, loss of the endothelial KATP channels may attenuate NO production and provide vascular hypercontractility, resulting in coronary vasospasm. And lack of the KATP channels in sympathetic neurons would decrease the threshold for NA release, which could associate with vasospasm. Indeed, the hyperactivity of sympathetic nerve is reported to cause coronary spasm in animals.33 To identify the mechanisms of the coronary vasospasm and sudden death in the SUR2- or Kir6.1-null mice, it is necessary to conduct further extensive studies, such as generation and analyses of transgenic mice that restore the KATP channels in other specific regions. It should be also kept in mind that the mechanisms for the coronary vasospasm in humans and those in null-mice might not be the same. Nevertheless, it is certain that the present work by Kakkar et al has pointed out an important possibility that exo-smooth muscle KATP channels may play critical roles in the pathogenesis of the coronary vasospasm and thus should be considered for development of new therapies.


*    Acknowledgments
 
Dr Kurachi’s laboratory is supported by following research grants and funds: Leading Project for Biosimulation "Development of models for disease and drug action" (to Y.K.), Grant in Aid for Scientific Research on Priority Areas 17079005 (to Y.K.), Grant in Aid for Scientific Research on Priority Areas 17081012 (to H.H.), Grant in Aid for Scientific Research A 15209008 (to Y.K.), Grant in Aid for Young Scientists (A) 17689012 (to H.H.), and Japan France Integrated Action Program (SAKURA) (to Y.K.), from the Ministry of Education, Science, Sports and Culture of Japan; and Uehara Memorial Foundation (to Y.K.).


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 *References
 

  1. Feigl EO. Coronary physiology. Physiol Rev. 1983; 63: 1–205.[Abstract/Free Full Text]
  2. Sun D, Huang A, Mital S, Kichuk MR, Marboe CC, Addonizio LJ, Michler RE, Koller A, Hintze TH, Kaley G. Norepinephrine elicits beta2-receptor-mediated dilation of isolated human coronary arterioles. Circulation. 2002; 106: 550–555.[Abstract/Free Full Text]
  3. Morrissey A, Rosner E, Lanning J, Parachuru L, Dhar Chowdhury P, Han S, Lopez G, Tong X, Yoshida H, Nakamura TY, Artman M, Giblin JP, Tinker A, Coetzee WA. Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature. BMC Physiol. 2005; 5: 1.[CrossRef][Medline] [Order article via Infotrieve]
  4. Yoshida H, Feig JE, Morrissey A, Ghiu IA, Artman M, Coetzee WA. K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits. J Mol Cell Cardiol. 2004; 37: 857–869.[CrossRef][Medline] [Order article via Infotrieve]
  5. Schnitzler MM, Derst C, Daut J, Preisig-Muller R. ATP-sensitive potassium channels in capillaries isolated from guinea-pig heart. J Physiol. 2000; 525: 307–317.[Abstract/Free Full Text]
  6. Zhou M, Tanaka O, Sekiguchi M, Sakabe K, Anzai M, Izumida I, Inoue T, Kawahara K, Abe H. Localization of the ATP-sensitive potassium channel subunit (Kir6. 1/uK(ATP)-1) in rat brain. Brain Res Mol Brain Res. 1999; 74: 15–25.[Medline] [Order article via Infotrieve]
  7. Thomzig A, Pruss H, Veh RW. The Kir6.1-protein, a pore-forming subunit of ATP-sensitive potassium channels, is prominently expressed by giant cholinergic interneurons in the striatum of the rat brain. Brain Res. 2003; 986: 132–138.[CrossRef][Medline] [Order article via Infotrieve]
  8. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L. Hypothalamic K(ATP) channels control hepatic glucose production. Nature. 2005; 434: 1026–1031.[CrossRef][Medline] [Order article via Infotrieve]
  9. Burgdorf C, Dendorfer A, Kurz T, Schomig E, Stolting I, Schutte F, Richardt G. Role of neuronal KATP channels and extraneuronal monoamine transporter on norepinephrine overflow in a model of myocardial low flow ischemia. J Pharmacol Exp Ther. 2004; 309: 42–48.[Abstract/Free Full Text]
  10. Thomas GD, Hansen J, Victor RG. ATP-sensitive potassium channels mediate contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle. J Clin Invest. 1997; 99: 2602–2609.[Medline] [Order article via Infotrieve]
  11. Miki T, Suzuki M, Shibasaki T, Uemura H, Sato T, Yamaguchi K, Koseki H, Iwanaga T, Nakaya H, Seino S. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med. 2002; 8: 466–472.[CrossRef][Medline] [Order article via Infotrieve]
  12. Chutkow WA, Pu J, Wheeler MT, Wada T, Makielski JC, Burant CF, McNally EM. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. J Clin Invest. 2002; 110: 203–208.[CrossRef][Medline] [Order article via Infotrieve]
  13. Kakkar R, Ye B, Stoller DA, Smelley M, Shi N-Q, Galles K, Hadhazy M, Makielski JC, McNally EM. Spontaneous coronary vasospasm in KATP mutant mice arises from a smooth muscle extrinsic process. Circ Res. 2006; 98: 682–689.[Abstract/Free Full Text]
  14. Ashcroft FM. Adenosine 5'-triphosphate-sensitive potassium channels. Annu Rev Neurosci. 1988; 11: 97–118.[CrossRef][Medline] [Order article via Infotrieve]
  15. Edwards G, Weston AH. The pharmacology of ATP-sensitive potassium channels. Annu Rev Pharmacol Toxicol. 1993; 33: 597–637.[CrossRef][Medline] [Order article via Infotrieve]
  16. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol Apr. 1995; 268: C799–C822.
  17. Inagaki N, Gonoi T, Clement JP 4th, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995; 270: 1166–1170.[Abstract/Free Full Text]
  18. Sakura H, Ammala C, Smith PA, Gribble FM, Ashcroft FM. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett. 1995; 377: 338–344.[CrossRef][Medline] [Order article via Infotrieve]
  19. Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, Seino S. A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron. 1996; 16: 1011–1017.[CrossRef][Medline] [Order article via Infotrieve]
  20. Isomoto S, Kondo C, Yamada M, Matsumoto S, Higashiguchi O, Horio Y, Matsuzawa Y, Kurachi Y. A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. J Biol Chem. 1996; 271: 24321–24324.[Abstract/Free Full Text]
  21. Yamada M, Isomoto S, Matsumoto S, Kondo C, Shindo T, Horio Y, Kurachi Y. Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. J Physiol. 1997; 499: 715–720.[Medline] [Order article via Infotrieve]
  22. Isomoto S, Kurachi Y. Function, regulation, pharmacology, and molecular structure of ATP-sensitive K+ channels in the cardiovascular system. J Cardiovasc Electrophysiol. 1997; 8: 1431–1446.[Medline] [Order article via Infotrieve]
  23. Kajioka S, Kitamura K, Kuriyama H. Guanosine diphosphate activates an adenosine 5'-triphosphate-sensitive K+ channel in the rabbit portal vein. J Physiol. 1991; 444: 397–418.[Abstract/Free Full Text]
  24. Beech DJ, Zhang H, Nakao K, Bolton TB. K channel activation by nucleotide diphosphates and its inhibition by glibenclamide in vascular smooth muscle cells. Br J Pharmacol. 1993; 110: 573–582.[Medline] [Order article via Infotrieve]
  25. Ishibashi Y, Duncker DJ, Zhang J, Bache RJ. ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise. Circ Res. 1998; 82: 346–359.[Abstract/Free Full Text]
  26. Kingsbury MP, Robinson H, Flores NA, Sheridan DJ. Investigation of mechanisms that mediate reactive hyperaemia in guinea-pig hearts: role of K(ATP) channels, adenosine, nitric oxide and prostaglandins. Br J Pharmacol Mar. 2001; 132: 1209–1216.[CrossRef][Medline] [Order article via Infotrieve]
  27. Landry DW, Oliver JA. The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest. 1992; 89: 2071–2074.[Medline] [Order article via Infotrieve]
  28. Goldschmidt M, Landzberg BR, Frishman WH. Nicorandil: a potassium channel opening drug for treatment of ischemic heart disease. J Clin Pharmacol. 1996; 36: 559–572.[Abstract]
  29. Escande D, Thuringer D, Leguern S, Cavero I. The potassium channel opener cromakalim (BRL 34915) activates ATP-dependent K+ channels in isolated cardiac myocytes. Biochem Biophys Res Commun. 1988; 154: 620–625.[CrossRef][Medline] [Order article via Infotrieve]
  30. IONA-Study-Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002; 359: 1269–1275.[CrossRef][Medline] [Order article via Infotrieve]
  31. Gendron ME, Thorin E, Perrault LP. Loss of endothelial KATP channel-dependent, NO-mediated dilation of endocardial resistance coronary arteries in pigs with left ventricular hypertrophy. Br J Pharmacol. 2004; 143: 285–291.[CrossRef][Medline] [Order article via Infotrieve]
  32. Kuo L, Chancellor JD. Adenosine potentiates flow-induced dilation of coronary arterioles by activating KATP channels in endothelium. Am J Physiol. 1995; 269: H541–H549.[Medline] [Order article via Infotrieve]
  33. Cohen RA. Role of autonomic nerves and endothelium in coronary vasospasm. Prog Clin Biol Res. 1986; 219: 353–362.[Medline] [Order article via Infotrieve]

Related Article:

Spontaneous Coronary Vasospasm in KATP Mutant Mice Arises From a Smooth Muscle–Extrinsic Process
Rahul Kakkar, Bin Ye, Douglas A. Stoller, Matthew Smelley, Nian-Qing Shi, Kevin Galles, Michele Hadhazy, Jonathan C. Makielski, and Elizabeth M. McNally
Circ. Res. 2006 98: 682-689. [Abstract] [Full Text] [PDF]



This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
C. J. Pepine
Provoked Coronary Spasm and Acute Coronary Syndromes
J. Am. Coll. Cardiol., August 12, 2008; 52(7): 528 - 530.
[Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hibino, H.
Right arrow Articles by Kurachi, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hibino, H.
Right arrow Articles by Kurachi, Y.
Related Collections
Right arrowRelated Article

Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2006 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.