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.
|Number of pages||10|
|Journal||Clinical and Experimental Pharmacology and Physiology|
|Publication status||Published - 2005 Dec 1|
All Science Journal Classification (ASJC) codes
- Pharmacology (medical)
- Pharmacology, Toxicology and Pharmaceutics(all)