Cardiovascular Drugs and Therapy

, Volume 26, Issue 3, pp 217–226 | Cite as

H2 Mediates Cardioprotection Via Involvements of KATP Channels and Permeability Transition Pores of Mitochondria in Dogs

  • Akemi Yoshida
  • Hiroshi Asanuma
  • Hideyuki Sasaki
  • Shoji Sanada
  • Satoru Yamazaki
  • Yoshihiro Asano
  • Yoshiro Shinozaki
  • Hidezo Mori
  • Akito Shimouchi
  • Motoaki Sano
  • Masanori Asakura
  • Tetsuo Minamino
  • Seiji Takashima
  • Masaru Sugimachi
  • Naoki Mochizuki
  • Masafumi Kitakaze



Inhalation of hydrogen (H2) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H2 gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mKATP) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H2 gas in canine hearts.


The left anterior descending coronary artery of beagle dogs was occluded for 90 min followed by reperfusion for 6 h. Either 1.3% H2 or control gas was inhaled from 10 min prior to start of reperfusion until 1 h of reperfusion, in the presence or absence of either 5-hydroxydecanoate (5-HD; a selective mKATP blocker), or atractyloside (Atr; a mPTP opener).


Systemic hemodynamic parameters did not differ among the groups. Nevertheless, H2 gas inhalation reduced infarct size normalized by risk area (20.6 ± 2.8% vs. control gas 44.0 ± 2.0%; p < 0.001), and administration of either 5-HD or Atr abolished the infarct size-limiting effect of H2 gas (42.0 ± 2.2% with 5-HD and 45.1 ± 2.7% with Atr; both p < 0.001 vs. H2 group). Neither Atr nor 5-HD affected infarct size per se. Among all groups, NAD content and the number of apoptotic and 8-OHdG positive cells was not significantly different, indicating that the cardioprotection afforded by H2 was not due to anti-oxidative actions or effects on the NADH dehydrogenase pathway.


Inhalation of H2 gas reduces infarct size in canine hearts via opening of mitochondrial KATP channels followed by inhibition of mPTP. H2 gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy.

Key words

Hydrogen gas Reperfusion injury Myocardial infarction Mitochondrial KATP channel Mitochondrial permeability transition pore 



This work was supported by the Grants-in-aid from the Ministry of Health, Labor, and Welfare-Japan (H23-Nanchi-Ippan-22 to M.K.) and Grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology-Japan (21390251 to M.K.) and Grants from the Japan Heart Foundation and Grants from the Japan Cardiovascular Research Foundation. The authors thank Akiko Ogai for her technical assistance; Hatsue Ishibashi-Ueda for advice about TUNEL staining and Imai Nobuyoshi for his technical assistance with TUNEL staining; Kyoko Shioya for her assistance with animal care; Toshiyasu Asahara and Masaharu Onogi (TAIYO NIPPON SANSO Co.) for providing information about hydrogen.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Akemi Yoshida
    • 1
    • 3
  • Hiroshi Asanuma
    • 2
  • Hideyuki Sasaki
    • 1
  • Shoji Sanada
    • 4
  • Satoru Yamazaki
    • 1
  • Yoshihiro Asano
    • 4
  • Yoshiro Shinozaki
    • 5
  • Hidezo Mori
    • 5
  • Akito Shimouchi
    • 6
  • Motoaki Sano
    • 7
  • Masanori Asakura
    • 1
  • Tetsuo Minamino
    • 4
  • Seiji Takashima
    • 4
  • Masaru Sugimachi
    • 8
  • Naoki Mochizuki
    • 3
  • Masafumi Kitakaze
    • 1
  1. 1.Department of Cardiovascular Medicine, National Cerebral and Cardiovascular CenterOsakaJapan
  2. 2.Department of Cardiovascular Science and Technology, Kyoto Prefectural University of MedicineOsakaJapan
  3. 3.Department of Structural AnalysisNational Cerebral and Cardiovascular Research CenterSuitaJapan
  4. 4.Department of Cardiovascular MedicineOsaka University Graduate School of MedicineSuitaJapan
  5. 5.Department of Physiological ScienceTokai University Graduate School of MedicineIseharaJapan
  6. 6.Department of Cardiac PhysiologyNational Cerebral and Cardiovascular Research CenterSuitaJapan
  7. 7.Department of CardiologyKeio University School of MedicineTokyoJapan
  8. 8.Department of Cardiovascular Dynamics, Research InstituteNational Cerebral and Cardiovascular CenterSuitaJapan

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