The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor
Sparsentan is viewed as a dual antagonist of endothelin type A (ET<sub>A</sub>) receptor and angiotensin II (AngII) receptor and it could be beneficial in patients with focal segmental glomerulosclerosis. Moreover, it could improve glomerular filtration rate and augment protective tissue...
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MDPI AG
2021-12-01
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| Online Access: | https://www.mdpi.com/2227-9059/10/1/86 |
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| author | Tzu-Hsien Chuang Hsin-Yen Cho Sheng-Nan Wu |
| author_facet | Tzu-Hsien Chuang Hsin-Yen Cho Sheng-Nan Wu |
| author_sort | Tzu-Hsien Chuang |
| collection | DOAJ |
| description | Sparsentan is viewed as a dual antagonist of endothelin type A (ET<sub>A</sub>) receptor and angiotensin II (AngII) receptor and it could be beneficial in patients with focal segmental glomerulosclerosis. Moreover, it could improve glomerular filtration rate and augment protective tissue remodeling in mouse models of focal segmental glomerulosclerosis. The ionic mechanisms through which it interacts with the magnitude and/or gating kinetics of ionic currents in excitable cells were not thoroughly investigated. Herein, we aimed to examine the effects of varying sparsentan concentrations on ionic currents residing in pituitary GH<sub>3</sub> somatolactotrophs. From whole-cell current recordings made in GH<sub>3</sub> cells, sparsentan (0.3–100 μM) differentially inhibited the peak and late components of voltage-gated Na<sup>+</sup> current (<i>I</i><sub>Na</sub>). The IC<sub>50</sub> value of sparsentan required to exert a reduction in peak and late <i>I</i><sub>Na</sub> in GH<sub>3</sub> cells was 15.04 and 1.21 μM, respectively; meanwhile, the K<sub>D</sub> value estimated from its shortening in the slow component of <i>I</i><sub>Na</sub> inactivation time constant was 2.09 μM. The sparsentan (10 μM) presence did not change the overall current–voltage relationship of <i>I</i><sub>Na</sub>; however, the steady-state inactivation curve of the current was shifted to more negative potential in its presence (10 μM), with no change in the gating charge of the curve. The window <i>I</i><sub>Na</sub> activated by a brief upsloping ramp was decreased during exposure to sparsentan (10 μM); moreover, recovery of peak <i>I</i><sub>Na</sub> became slowed in its presence. The Tefluthrin (Tef)-stimulated resurgent <i>I</i><sub>Na</sub> activated in response to abrupt depolarization followed by the descending ramp pulse was additionally attenuated by subsequent application of sparsentan. In continued presence of Tef (3 μM) or β-pompilidotoxin (3 μM), further application of sparsentan (3 μM) reversed their stimulation of <i>I</i><sub>Na</sub>. However, sparsentan-induced inhibition of <i>I</i><sub>Na</sub> failed to be overcome by subsequent application of either endothelin 1 (1 μM) or angiotensin II (1 μM); moreover, in continued presence of endothelin (1 μM) or angiotensin II (1 μM), further addition of sparsentan (3 μM) effectively decreased peak <i>I</i><sub>Na</sub>. Additionally, the application of sparsentan (3 μM) inhibited the peak and late components of <i>erg</i>-mediated K<sup>+</sup> current in GH<sub>3</sub> cells, although it mildly decreased the amplitude of delayed-rectifier K<sup>+</sup> current. Altogether, this study provides a distinct yet unidentified finding that sparsentan may perturb the amplitude or gating of varying ionic currents in excitable cells. |
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| spelling | doaj.art-33013b2b1127428faf1c7a36d54539492023-11-23T13:03:34ZengMDPI AGBiomedicines2227-90592021-12-011018610.3390/biomedicines10010086The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a ReceptorTzu-Hsien Chuang0Hsin-Yen Cho1Sheng-Nan Wu2Department of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan 70101, TaiwanDepartment of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan 70101, TaiwanDepartment of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan 70101, TaiwanSparsentan is viewed as a dual antagonist of endothelin type A (ET<sub>A</sub>) receptor and angiotensin II (AngII) receptor and it could be beneficial in patients with focal segmental glomerulosclerosis. Moreover, it could improve glomerular filtration rate and augment protective tissue remodeling in mouse models of focal segmental glomerulosclerosis. The ionic mechanisms through which it interacts with the magnitude and/or gating kinetics of ionic currents in excitable cells were not thoroughly investigated. Herein, we aimed to examine the effects of varying sparsentan concentrations on ionic currents residing in pituitary GH<sub>3</sub> somatolactotrophs. From whole-cell current recordings made in GH<sub>3</sub> cells, sparsentan (0.3–100 μM) differentially inhibited the peak and late components of voltage-gated Na<sup>+</sup> current (<i>I</i><sub>Na</sub>). The IC<sub>50</sub> value of sparsentan required to exert a reduction in peak and late <i>I</i><sub>Na</sub> in GH<sub>3</sub> cells was 15.04 and 1.21 μM, respectively; meanwhile, the K<sub>D</sub> value estimated from its shortening in the slow component of <i>I</i><sub>Na</sub> inactivation time constant was 2.09 μM. The sparsentan (10 μM) presence did not change the overall current–voltage relationship of <i>I</i><sub>Na</sub>; however, the steady-state inactivation curve of the current was shifted to more negative potential in its presence (10 μM), with no change in the gating charge of the curve. The window <i>I</i><sub>Na</sub> activated by a brief upsloping ramp was decreased during exposure to sparsentan (10 μM); moreover, recovery of peak <i>I</i><sub>Na</sub> became slowed in its presence. The Tefluthrin (Tef)-stimulated resurgent <i>I</i><sub>Na</sub> activated in response to abrupt depolarization followed by the descending ramp pulse was additionally attenuated by subsequent application of sparsentan. In continued presence of Tef (3 μM) or β-pompilidotoxin (3 μM), further application of sparsentan (3 μM) reversed their stimulation of <i>I</i><sub>Na</sub>. However, sparsentan-induced inhibition of <i>I</i><sub>Na</sub> failed to be overcome by subsequent application of either endothelin 1 (1 μM) or angiotensin II (1 μM); moreover, in continued presence of endothelin (1 μM) or angiotensin II (1 μM), further addition of sparsentan (3 μM) effectively decreased peak <i>I</i><sub>Na</sub>. Additionally, the application of sparsentan (3 μM) inhibited the peak and late components of <i>erg</i>-mediated K<sup>+</sup> current in GH<sub>3</sub> cells, although it mildly decreased the amplitude of delayed-rectifier K<sup>+</sup> current. Altogether, this study provides a distinct yet unidentified finding that sparsentan may perturb the amplitude or gating of varying ionic currents in excitable cells.https://www.mdpi.com/2227-9059/10/1/86sparsentan (4′-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-<i>N</i>-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)[1,1′-biphenyl]-2-sulfonamide)voltage-gated Na<sup>+</sup> currentwindow Na<sup>+</sup> currentresurgent Na<sup>+</sup> current<i>erg</i>-mediated K<sup>+</sup> currentdelayed-rectifier K<sup>+</sup> current |
| spellingShingle | Tzu-Hsien Chuang Hsin-Yen Cho Sheng-Nan Wu The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor Biomedicines sparsentan (4′-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-<i>N</i>-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)[1,1′-biphenyl]-2-sulfonamide) voltage-gated Na<sup>+</sup> current window Na<sup>+</sup> current resurgent Na<sup>+</sup> current <i>erg</i>-mediated K<sup>+</sup> current delayed-rectifier K<sup>+</sup> current |
| title | The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor |
| title_full | The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor |
| title_fullStr | The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor |
| title_full_unstemmed | The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor |
| title_short | The Evidence for Sparsentan-Mediated Inhibition of <i>I</i><sub>Na</sub> and <i>I</i><sub>K(erg)</sub>: Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor |
| title_sort | evidence for sparsentan mediated inhibition of i i i sub na sub and i i i sub k erg sub possibly unlinked to its antagonism of angiotensin ii or endothelin type a receptor |
| topic | sparsentan (4′-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-<i>N</i>-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)[1,1′-biphenyl]-2-sulfonamide) voltage-gated Na<sup>+</sup> current window Na<sup>+</sup> current resurgent Na<sup>+</sup> current <i>erg</i>-mediated K<sup>+</sup> current delayed-rectifier K<sup>+</sup> current |
| url | https://www.mdpi.com/2227-9059/10/1/86 |
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