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Inhibition of pacemaker currents by nitric oxide via activation of ATP-sensitive K+ channels in cultured interstitial cells of Cajal from the mouse small intestine

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Abstract

We investigated the role of nitric oxide (NO) in pacemaker activity and signal mechanisms in cultured interstitial cells of Cajal (ICC) of the mouse small intestine using whole cell patch-clamp techniques at 30°C. ICC generated pacemaker potential in the current clamp mode and pacemaker currents at a holding potential of –70 mV. (±)-S-nitroso-N-acetylpenicillamine (SNAP; a NO donor) produced membrane hyperpolarization and inhibited the amplitude and frequency of the pacemaker currents, and increased resting currents in the outward direction. These effects were blocked by the use of glibenclamide (an ATP-sensitive K+ channel blocker), but not by the use of 5-hydroxydecanoic acid (a mitochondrial ATP-sensitive K+ channel blocker). Pretreatment with ODQ (a guanylate cyclase inhibitor) almost blocked the NO-induced effects. The use of cell-permeable 8-bromo-cyclic GMP also mimicked the action of SNAP. However, the use of KT-5823 (a protein kinase G inhibitor) did not block the NO-induced effects. Spontaneous [Ca2+]i oscillations in ICC were inhibited by the treatment of SNAP, as seen in recordings of intracellular Ca2+ ([Ca2+]i). These results suggest that NO inhibits pacemaker activity by the activation of ATP-sensitive K+ channels via a cyclic GMP dependent mechanism in ICC, and the activation of ATP-sensitive K+ channels mediates the inhibition of spontaneous [Ca2+]i oscillations.

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Acknowledgements

This work was supported by a grant from the Clinical Research Center of the Chosun University Hospital (2006) and by the Korea Science and Engineering Foundation (KOSEF) funded by the Korea Government (MOST) [M10639010001].

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Authors and Affiliations

  1. Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, South Korea

    Chan Guk Park, Young Dae Kim & Man Yoo Kim

  2. Department of Physiology, College of Medicine, Chosun University, 375 Seosuk-Dong, Dong-ku, Gwangju, 501-759, South Korea

    Jun Soo Kim, Seok Choi, Cheol Ho Yeum, Shankar Prasad Parajuli & Jae Yeoul Jun

  3. Department of Physiology, College of Medicine, Chonnam National University, Gwangju, South Korea

    Jong Seong Park & Han Seong Jeong

  4. Department of Physiology and Biophysics, College of Medicine, Seoul National University, Seoul, South Korea

    Insuk So & Ki Whan Kim

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  1. Chan Guk Park
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Park, C.G., Kim, Y.D., Kim, M.Y. et al. Inhibition of pacemaker currents by nitric oxide via activation of ATP-sensitive K+ channels in cultured interstitial cells of Cajal from the mouse small intestine. Naunyn-Schmied Arch Pharmacol 376, 175–184 (2007). https://doi.org/10.1007/s00210-007-0187-1

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