Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1

Nature Medicine volume 8, pages 466–472 (2002)Cite this article

Abstract

The inwardly rectifying K+ channel Kir6.1 forms K+ channels by coupling with a sulfonylurea receptor in reconstituted systems, but the physiological roles of Kir6.1-containing K+ channels have not been determined. We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block as seen on an electrocardiogram. The K+ channel opener pinacidil did not induce K+ currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil. The administration of methylergometrine, a vasoconstrictive agent, elicited ST elevation followed by cardiac death in Kir6.1-null mice but not in wild-type mice, indicating a phenotype characterized by hypercontractility of coronary arteries and resembling Prinzmetal (or variant) angina in humans. The Kir6.1-containing K+ channel is critical in the regulation of vascular tonus, especially in the coronary arteries, and its disruption may cause Prinzmetal angina.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted disruption of the gene encoding Kir6.1 and survival analysis of Kir6.1-null mice.
Figure 2: Representative ECGs from wild-type and Kir6.1-null mice using radio telemetry.
Figure 3: In situ hybridization of Kir6.1 in heart.
Figure 4: Electrophysiological analyses and flavoprotein oxidation in cardiomyocytes.
Figure 5: Functional analysis of vascular smooth muscle.
Figure 6: Methylergometrine-induced changes in ECG and CPP.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Jan, L.Y. & Jan, Y.N. Voltage-gated and inwardly rectifying potassium channels. J. Physiol. 505, 267–282 (1997).

    Article  CAS  Google Scholar 

  2. Nichols, C.G. & Lopatin, A.N. Inward rectifier potassium channels. Annu. Rev. Physiol. 59, 171–191 (1997).

    Article  CAS  Google Scholar 

  3. Abraham, M.R., Jahangir, A., Alekseev, A.E. & Terzic, A. Channelopathies of inwardly rectifying potassium channels. FASEB J. 13, 1901–1910 (1999).

    Article  CAS  Google Scholar 

  4. Inagaki, N. et al. Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J. Biol. Chem. 270, 5691–5694 (1995).

    Article  CAS  Google Scholar 

  5. Inagaki, N. et al. Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor. Science 270, 1166–1170 (1995).

    Article  CAS  Google Scholar 

  6. Ashcroft, F.M. & Gribble, F.M. Correlating structure and function in ATP-sensitive K+ channels. Trends. Neurosci. 21, 288–294 (1998).

    Article  CAS  Google Scholar 

  7. Aguilar-Bryan, L. & Bryan, J. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr. Rev. 20, 101–135 (1999).

    CAS  Google Scholar 

  8. Seino, S. ATP-sensitive potassium channels: A model of heteromultimeric potassium channel/receptor assemblies. Annu. Rev. Physiol. 61, 337–362 (1999).

    Article  CAS  Google Scholar 

  9. Inagaki, N. et al. A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron 16, 1011–1017 (1996).

    Article  CAS  Google Scholar 

  10. Isomoto, S. et al. A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. J. Biol. Chem. 271, 24321–24324 (1996).

    Article  CAS  Google Scholar 

  11. Miki, T. et al. Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc. Natl. Acad. Sci. USA. 95, 10402–10406 (1998).

    Article  CAS  Google Scholar 

  12. Li, R.A., Leppo, M., Miki, T., Seino, S. & Marban, E. Molecular basis of electrocardiographic ST-segment elevation. Circ. Res. 87, 837–839 (2000).

    Article  CAS  Google Scholar 

  13. Suzuki, M. et al. Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ. Res. 88, 570–577 (2001).

    Article  CAS  Google Scholar 

  14. Miki, T. et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nature Neurosci. 4, 507–512 (2001).

    Article  CAS  Google Scholar 

  15. Suzuki, M. et al. Role of sarcolemmal KATP channels in cardioprotection against ischemia/reperfusion injury in mice. J. Clin. Invest. 109, 509–516 (2002).

    Article  CAS  Google Scholar 

  16. Ämmälä, C., Moorhouse, A. & Ashcroft, F.M. The sulphonylurea receptor confers diazoxide sensitivity on the inwardly rectifying K+ channel Kir6.1 expressed in human embryonic kidney cells. J. Physiol. 494, 709–714 (1996).

    Article  Google Scholar 

  17. Kono, Y. et al. The properties of the Kir6.1-6.2 tandem channel co-expressed with SUR2A. Pflugers. Arch. 440, 692–698 (2000).

    Article  CAS  Google Scholar 

  18. Yamada, M. et al. Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. J. Physiol. 499, 715–720 (1997).

    Article  CAS  Google Scholar 

  19. Standen, N.B. et al. Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 245, 177–180 (1989).

    Article  CAS  Google Scholar 

  20. Kajioka, S., Kitamura, K. & Kuriyama, H. Guanosine diphosphate activates an adenosine 5′-triphosphate-sensitive K+ channel in the rabbit portal vein. J. Physiol. 444, 397–418 (1991).

    Article  CAS  Google Scholar 

  21. Beech, D.J., Zhang, H., Nakao, K. & Bolton, T.B. K channel activation by nucleotide diphosphates and its inhibition by glibenclamide in vascular smooth-muscle cells. Br. J. Pharmacol. 110, 573–582 (1993).

    Article  CAS  Google Scholar 

  22. Prinzmetal, M. et al. Angina pectoris. 1. A variant form of angina pectoris: Preliminary report. Am. J. Med. 27, 375–378 (1959).

    Article  CAS  Google Scholar 

  23. Maseri, A. Role of coronary artery spasm in symptomatic and silent myocardial ischemia. J. Am. Coll. Cardiol. 9, 249–262 (1987).

    Article  CAS  Google Scholar 

  24. Liu, Y., Sato, T., O'Rourke, B. and Marban, E. Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection? Circulation 97, 2463–2469 (1998).

    Article  CAS  Google Scholar 

  25. Egashira, K. et al. Mechanism of ergonovine-induced hyperconstriction of the large epicardial coronary artery in conscious dogs a month after arterial injury. Circ. Res. 71, 435–442 (1992).

    Article  CAS  Google Scholar 

  26. Myerburg, R.J., Interian, A., Jr Mitrani, R.M., Kessler, K.M. & Castellanos, A. Frequency of sudden cardiac death and profiles of risk. Am. J. Cardiol. 80, 10F–19F (1997).

    Article  CAS  Google Scholar 

  27. Keating, M.T. & Sanguinetti, M.C. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104, 569–580 (2001).

    Article  CAS  Google Scholar 

  28. Gutstein, D.E. et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ. Res. 88, 333–339 (2001).

    Article  CAS  Google Scholar 

  29. Robbins, J. & Dorn, G.W. 2nd. Listening for hoof beats in heart beats. Nature Med. 6, 968–970 (2000).

    Article  CAS  Google Scholar 

  30. Kupershmidt, S. et al. Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. Circ. Res. 84, 146–152 (1999).

    Article  CAS  Google Scholar 

  31. Drici, M.D. et al. Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome. Circ. Res. 83, 95–102 (1998).

    Article  CAS  Google Scholar 

  32. Barry, D.M., Xu, H., Schuessler, R.B. & Nerbonne, J.M. Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 α subunit. Circ. Res. 83, 560–567 (1998).

    Article  CAS  Google Scholar 

  33. Seharaseyon, J., et al. Evidence against functional heteromultimerization of the KATP channel subunits Kir6.1 and Kir6.2. J. Biol. Chem. 275, 17561–17565 (2000).

    Article  CAS  Google Scholar 

  34. Suzuki, M. et al. Kir6.1: A possible subunit of ATP-sensitive K+ channels in mitochondria. Biochem. Biophys. Res. Commun. 241, 693–697 (1997).

    Article  CAS  Google Scholar 

  35. Thomzig, A. et al. Kir6.1 is the principal pore-forming subunit of astrocyte but not neuronal plasma membrane K-ATP channels. Mol. Cell. Neurosci. 18, 671–690 (2001).

    Article  CAS  Google Scholar 

  36. Okumura, K. et al. Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. Hyperreactivity to the constrictor effects of acetylcholine and the dilator effects of nitroglycerin. J. Am. Coll. Cardiol. 27, 45–52 (1996).

    Article  CAS  Google Scholar 

  37. MacAlpin, R.N. Cardiac arrest and sudden unexpected death in variant angina: Complications of coronary spasm that can occur in the absence of severe organic coronary stenosis. Am. Heart J. 125, 1011–1017 (1993).

    Article  CAS  Google Scholar 

  38. Beltrame, J.F., Sasayama, S. & Maseri, A. Racial heterogeneity in coronary artery vasomotor reactivity: Differences between Japanese and Caucasian patients. J. Am. Coll. Cardiol. 33, 1442–1452 (1999).

    Article  CAS  Google Scholar 

  39. Pristipino, C. et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation 101, 1102–1108 (2000).

    Article  CAS  Google Scholar 

  40. Tanaka, J. et al. Cellular distribution of the P2X4 ATP receptor mRNA in the brain and non-neuronal organs of rats. Arch. Histol. Cytol. 59, 485–490 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Tamagawa and Y. Reien for technical assistance. This work was supported by Grants-in-Aid for Creative Scientific Research (10NP0201) and for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology; by a Scientific Research Grant from the Ministry of Health, Labour and Welfare, Japan; and by grants from the Uehara Memorial Foundation, from the Kanae Foundation, from Mitsui Life Insurance Research Foundation, from K. Watanabe Research Fund, and from the Yamanouchi Foundation for Research on Metabolic Disorders.

Author information

Authors and Affiliations

  1. Departments of Cellular and Molecular Medicine, Chiba, Japan

    Takashi Miki, Tadao Shibasaki, Kaori Yamaguchi & Susumu Seino

  2. Departments of Pharmacology, Chiba, Japan

    Masashi Suzuki, Hiroko Uemura, Toshiaki Sato & Haruaki Nakaya

  3. Departments of Molecular Embryology, Graduate School of Medicine, Chiba, Japan

    Haruhiko Koseki

  4. Laboratory of Anatomy, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan

    Toshihiko Iwanaga

  5. Departments of Gene Research Center, Chiba University, Chiba, Japan

    Takashi Miki

Authors
  1. Takashi Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masashi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tadao Shibasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroko Uemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshiaki Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kaori Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haruhiko Koseki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshihiko Iwanaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Haruaki Nakaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Susumu Seino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susumu Seino.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miki, T., Suzuki, M., Shibasaki, T. et al. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med 8, 466–472 (2002). https://doi.org/10.1038/nm0502-466

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0502-466

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing