Basic Research in Cardiology

, Volume 102, Issue 1, pp 73–79 | Cite as

Nicorandil opens mitochondrial KATP channels not only directly but also through a NO-PKG-dependent pathway

  • A. Kuno
  • S. D. Critz
  • M. V. Cohen
  • J. M. Downey
ORIGINAL CONTRIBUTION
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Abstract

Nicorandil, a hybrid of nitrate generator and potassium channel opener, protects ischemic myocardium by opening mitochondrial ATP sensitive potassium (mitoKATP) channels. We recently found that nitric oxide (NO) opened KATP channels in rabbit hearts by a protein kinase G (PKG) mechanism. This study examined whether the NO-donor property of nicorandil also contributes to opening of mitoKATP channels through PKG. MitoKATP channel opening was monitored in adult rabbit cardiomyocytes by measuring reactive oxygen species (ROS) production, an established marker of channel opening. Nicorandil increased ROS production in a dose-dependent manner. The selective mitoKATP channel inhibitor 5-hydroxydecanoate (200 μM) completely blocked ROS production by nicorandil at all doses. The PKG inhibitor 8-bromoguanosine-3’,5’-cyclic monophosphorothioate, Rpisomer (Rp-8-Br-cGMPs, 50 μM) shifted the dose-ROS production curve to the right with an increase of the EC50 from 2.4 x 10–5 M to 6.9 x 10–5 M. Rp- 8-Br-cGMPs did not affect the increase in ROS production by the selective mitoKATP channel opener diazoxide while it completely blocked increased ROS production from the NO donor S-nitroso-N-acetylpenicillamine (1 μM). Furthermore ODQ, an antagonist of soluble guanylyl cyclase, blocked nicorandil’s ability to increase ROS generation. These results indicate that nicorandil, in addition to its direct effect on the channels, opens mitoKATP channels indirectly via a NO-PKG signaling pathway.

Key words

mitoKATP channels nicorandil nitric oxide protein kinase G reactive oxygen species 
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Copyright information

© Steinkopff-Verlag 2006

Authors and Affiliations

  • A. Kuno
    • 1
  • S. D. Critz
    • 2
  • M. V. Cohen
    • 1
    • 3
  • J. M. Downey
    • 1
  1. 1.Dept. of Physiology, MSB 3070College of Medicine University of South AlabamaMobileUSA
  2. 2.Dept. of Cell Biology and NeuroscienceCollege of Medicine University of South AlabamaMobileUSA
  3. 3.Dept. of MedicineCollege of Medicine University of South AlabamaMobileUSA

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