BAY 41-2272, a potent activator of soluble guanylyl cyclase, stimulates calcium elevation and calcium-activated potassium current in pituitary GH 3 cells

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Abstract

1. The effects of BAY 41-2272, a nitric oxide-independent activator of soluble guanylyl cyclase, on Ca2+ signalling and ion currents were investigated in pituitary GH3 cells. 2. Intracellular Ca2+ concentrations ([Ca2+]i) in these cells were increased by BAY 41-2272. Removing extracellular Ca2+ abolished the BAY 41-2272-induced increase in [Ca2+]i. After [Ca 2+]i was elevated by BAY 41-2272 (300 nmol/L), subsequent application of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl) indazole (YC-1; 1 μmol/L) did not increase [Ca2+]i further. 3. In whole-cell recordings, BAY 41-2272 reversibly stimulated Ca 2+-activated K+ current (IK(Ca)) with an EC50 of 225 ± 8 nmol/L. At 3 μmol/L, BAY 41-2272 slightly and significantly decreased L-type Ca2+ current. 4. In the cell-attached configuration, BAY 41-2272 (300 nmol/L) enhanced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. After BKCa channel activity was stimulated by spermine NONOate (30 μmol/L) or YC-1 (10 μmol/L) in cell-attached patches, subsequent application of BAY 41-2272 (300 nmol/L) further increased the channel open probability. 5. In the inside-out configuration, BAY 41-2272 applied to the intracellular surface of excised patches enhanced BKCa channel activity. Unlike 1 μmol/L paxilline, 1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one (ODQ; 10 μmol/L) or heme (10 μmol/L) had no effect on BAY 41-2272-stimulated channel activity. BAY 41-2272 caused no shift in the activation curve of BKCa channels; however, it did increase the Ca2+ sensitivity of these channels. 6. At 300 nmol/L, BAY 41-2272 reduced the firing rate of spontaneous action potentials stimulated by thyrotropin-releasing hormone (10 μmol/L). The BKCa channel activity was also enhanced by 300 nmol/L BAY 41-2272 in neuroblastoma IMR-32 cells. 7. Therefore, the BAY 41-2272-induced increase in [Ca2+] i is primarily explained by an increase in Ca2+ influx. The BAY 41-2272-mediated simulation of IK(Ca) may result from direct activation of BKCa channels and indirectly as a result of elevated [Ca2+]i.

Original languageEnglish
Pages (from-to)1078-1087
Number of pages10
JournalClinical and Experimental Pharmacology and Physiology
Volume32
Issue number12
DOIs
Publication statusPublished - 2005 Dec 1

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Somatotrophs
Potassium
Calcium
Soluble Guanylyl Cyclase
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
Indazoles
Calcium-Activated Potassium Channels
Quinoxalines
Thyrotropin-Releasing Hormone
Patch-Clamp Techniques

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

@article{3f0e5b7576b54ae49030384428025c6c,
title = "BAY 41-2272, a potent activator of soluble guanylyl cyclase, stimulates calcium elevation and calcium-activated potassium current in pituitary GH 3 cells",
abstract = "1. The effects of BAY 41-2272, a nitric oxide-independent activator of soluble guanylyl cyclase, on Ca2+ signalling and ion currents were investigated in pituitary GH3 cells. 2. Intracellular Ca2+ concentrations ([Ca2+]i) in these cells were increased by BAY 41-2272. Removing extracellular Ca2+ abolished the BAY 41-2272-induced increase in [Ca2+]i. After [Ca 2+]i was elevated by BAY 41-2272 (300 nmol/L), subsequent application of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl) indazole (YC-1; 1 μmol/L) did not increase [Ca2+]i further. 3. In whole-cell recordings, BAY 41-2272 reversibly stimulated Ca 2+-activated K+ current (IK(Ca)) with an EC50 of 225 ± 8 nmol/L. At 3 μmol/L, BAY 41-2272 slightly and significantly decreased L-type Ca2+ current. 4. In the cell-attached configuration, BAY 41-2272 (300 nmol/L) enhanced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. After BKCa channel activity was stimulated by spermine NONOate (30 μmol/L) or YC-1 (10 μmol/L) in cell-attached patches, subsequent application of BAY 41-2272 (300 nmol/L) further increased the channel open probability. 5. In the inside-out configuration, BAY 41-2272 applied to the intracellular surface of excised patches enhanced BKCa channel activity. Unlike 1 μmol/L paxilline, 1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one (ODQ; 10 μmol/L) or heme (10 μmol/L) had no effect on BAY 41-2272-stimulated channel activity. BAY 41-2272 caused no shift in the activation curve of BKCa channels; however, it did increase the Ca2+ sensitivity of these channels. 6. At 300 nmol/L, BAY 41-2272 reduced the firing rate of spontaneous action potentials stimulated by thyrotropin-releasing hormone (10 μmol/L). The BKCa channel activity was also enhanced by 300 nmol/L BAY 41-2272 in neuroblastoma IMR-32 cells. 7. Therefore, the BAY 41-2272-induced increase in [Ca2+] i is primarily explained by an increase in Ca2+ influx. The BAY 41-2272-mediated simulation of IK(Ca) may result from direct activation of BKCa channels and indirectly as a result of elevated [Ca2+]i.",
author = "Yen-Chin Liu and Sheng-Nan Wu",
year = "2005",
month = "12",
day = "1",
doi = "10.1111/j.1440-1681.2005.04315.x",
language = "English",
volume = "32",
pages = "1078--1087",
journal = "Clinical and Experimental Pharmacology and Physiology",
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T1 - BAY 41-2272, a potent activator of soluble guanylyl cyclase, stimulates calcium elevation and calcium-activated potassium current in pituitary GH 3 cells

AU - Liu, Yen-Chin

AU - Wu, Sheng-Nan

PY - 2005/12/1

Y1 - 2005/12/1

N2 - 1. The effects of BAY 41-2272, a nitric oxide-independent activator of soluble guanylyl cyclase, on Ca2+ signalling and ion currents were investigated in pituitary GH3 cells. 2. Intracellular Ca2+ concentrations ([Ca2+]i) in these cells were increased by BAY 41-2272. Removing extracellular Ca2+ abolished the BAY 41-2272-induced increase in [Ca2+]i. After [Ca 2+]i was elevated by BAY 41-2272 (300 nmol/L), subsequent application of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl) indazole (YC-1; 1 μmol/L) did not increase [Ca2+]i further. 3. In whole-cell recordings, BAY 41-2272 reversibly stimulated Ca 2+-activated K+ current (IK(Ca)) with an EC50 of 225 ± 8 nmol/L. At 3 μmol/L, BAY 41-2272 slightly and significantly decreased L-type Ca2+ current. 4. In the cell-attached configuration, BAY 41-2272 (300 nmol/L) enhanced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. After BKCa channel activity was stimulated by spermine NONOate (30 μmol/L) or YC-1 (10 μmol/L) in cell-attached patches, subsequent application of BAY 41-2272 (300 nmol/L) further increased the channel open probability. 5. In the inside-out configuration, BAY 41-2272 applied to the intracellular surface of excised patches enhanced BKCa channel activity. Unlike 1 μmol/L paxilline, 1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one (ODQ; 10 μmol/L) or heme (10 μmol/L) had no effect on BAY 41-2272-stimulated channel activity. BAY 41-2272 caused no shift in the activation curve of BKCa channels; however, it did increase the Ca2+ sensitivity of these channels. 6. At 300 nmol/L, BAY 41-2272 reduced the firing rate of spontaneous action potentials stimulated by thyrotropin-releasing hormone (10 μmol/L). The BKCa channel activity was also enhanced by 300 nmol/L BAY 41-2272 in neuroblastoma IMR-32 cells. 7. Therefore, the BAY 41-2272-induced increase in [Ca2+] i is primarily explained by an increase in Ca2+ influx. The BAY 41-2272-mediated simulation of IK(Ca) may result from direct activation of BKCa channels and indirectly as a result of elevated [Ca2+]i.

AB - 1. The effects of BAY 41-2272, a nitric oxide-independent activator of soluble guanylyl cyclase, on Ca2+ signalling and ion currents were investigated in pituitary GH3 cells. 2. Intracellular Ca2+ concentrations ([Ca2+]i) in these cells were increased by BAY 41-2272. Removing extracellular Ca2+ abolished the BAY 41-2272-induced increase in [Ca2+]i. After [Ca 2+]i was elevated by BAY 41-2272 (300 nmol/L), subsequent application of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl) indazole (YC-1; 1 μmol/L) did not increase [Ca2+]i further. 3. In whole-cell recordings, BAY 41-2272 reversibly stimulated Ca 2+-activated K+ current (IK(Ca)) with an EC50 of 225 ± 8 nmol/L. At 3 μmol/L, BAY 41-2272 slightly and significantly decreased L-type Ca2+ current. 4. In the cell-attached configuration, BAY 41-2272 (300 nmol/L) enhanced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. After BKCa channel activity was stimulated by spermine NONOate (30 μmol/L) or YC-1 (10 μmol/L) in cell-attached patches, subsequent application of BAY 41-2272 (300 nmol/L) further increased the channel open probability. 5. In the inside-out configuration, BAY 41-2272 applied to the intracellular surface of excised patches enhanced BKCa channel activity. Unlike 1 μmol/L paxilline, 1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one (ODQ; 10 μmol/L) or heme (10 μmol/L) had no effect on BAY 41-2272-stimulated channel activity. BAY 41-2272 caused no shift in the activation curve of BKCa channels; however, it did increase the Ca2+ sensitivity of these channels. 6. At 300 nmol/L, BAY 41-2272 reduced the firing rate of spontaneous action potentials stimulated by thyrotropin-releasing hormone (10 μmol/L). The BKCa channel activity was also enhanced by 300 nmol/L BAY 41-2272 in neuroblastoma IMR-32 cells. 7. Therefore, the BAY 41-2272-induced increase in [Ca2+] i is primarily explained by an increase in Ca2+ influx. The BAY 41-2272-mediated simulation of IK(Ca) may result from direct activation of BKCa channels and indirectly as a result of elevated [Ca2+]i.

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U2 - 10.1111/j.1440-1681.2005.04315.x

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JO - Clinical and Experimental Pharmacology and Physiology

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