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.
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 degrees 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.
Park
Chan Guk
CG
Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, South Korea.
Kim
Young Dae
YD
Kim
Man Yoo
MY
Kim
Jun Soo
JS
Choi
Seok
S
Yeum
Cheol Ho
CH
Parajuli
Shankar Prasad
SP
Park
Jong Seong
JS
Jeong
Han Seong
HS
So
Insuk
I
Kim
Ki Whan
KW
Jun
Jae Yeoul
JY
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007421:Intestine, Small / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; C073601:KT 5823; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D005905:Glyburide; D002118:Calcium