Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

13 Scopus Citations
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Author(s)

  • Matthias Löhn
  • Ulf Muzzulini
  • Kirill Essin
  • Suk-Ying Tsang
  • Torsten Kirsch
  • Jennifer Litteral
  • Patricia Waldron
  • Heinke Conrad
  • Norbert Klugbauer
  • Franz Hofmann
  • Hermann Haller
  • Friedrich C. Luft
  • Maik Gollasch

Detail(s)

Original languageEnglish
Pages (from-to)885-893
Journal / PublicationJournal of Hypertension
Volume20
Issue number5
Publication statusPublished - May 2002
Externally publishedYes

Abstract

Cilnidipine is a novel dihydropyridine (DHP) antagonist. However, its pharmacological effects on vascular DHP-sensitive L-type channels and protein kinase C (PKC)-mediated arterial contraction is incompletely understood. To address this issue, we studied the effects of cilnidipine on multi-subunit, C-class L-type Ca<sup>2+</sup> channels in rat aortic A7r5 cells, as well as on Ca<sup>2+</sup> channel (L-type) α<sub>1C-b</sub> and (T-type) α<sub>1G</sub> subunits in the Xenopus oocyte expression system. Cilnidipine dose- and time-dependently inhibited Ba<sup>2+</sup> currents in A7r5 cells, with half-maximal inhibitions (IC<sub>50</sub>) at 10 nmol/l after 10 min. Unlike classical pharmacological Ca<sup>2+</sup> channel blockers, cilnidipine's block of Ca<sup>2+</sup> currents did not reach steady-state levels within 10 min, indicating steady-state half-maximal inhibition of native, multi-subunit L-type channels at &lt;10 nmol/l. In contrast, smooth muscle α<sub>1Cb</sub> currents were blocked by cilnidipine at much higher doses (steady-state IC<sub>50</sub>, 20 μmol/l) whereas α<sub>1G</sub> currents were not inhibited by cilnidipine (30 μmol/l). Cilnidipine dose-dependently inhibited depolarization- and Ca<sup>2+</sup>-induced contractions of rat aortic rings, with an IC<sub>50</sub> of 10 nmol/l at 10 min. However, the onset of the effects was very slow, with approximately 71% inhibition by 3 nmol/l cilnidipine after 90 min exposure to cilnidipine. In contrast, cilnidipine did not inhibit phorbol 12-myristate-13-acetate (100 nmol/l)-mediated contractions. We conclude that cilnidipine represents an extremely slow-acting DHP that targets multi-subunit L-type channels, but not PKC in arterial smooth muscle. Because cilnidipine is less potent in cells expressing the pore-forming α<sub>1C-b</sub> subunit, the data further suggest that this unique slow-acting mechanism of cilnidipine is mediated by a complex interaction of cilnidipine with α<sub>1C-b</sub> and accessory channel subunits. © 2002 Lippincott Williams & Wilkins.

Research Area(s)

  • C class channels, Calcium channel blockers, Patch clamp, Smooth muscle cells, α1C subunit

Bibliographic Note

Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to lbscholars@cityu.edu.hk.

Citation Format(s)

Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C. / Löhn, Matthias; Muzzulini, Ulf; Essin, Kirill; Tsang, Suk-Ying; Kirsch, Torsten; Litteral, Jennifer; Waldron, Patricia; Conrad, Heinke; Klugbauer, Norbert; Hofmann, Franz; Haller, Hermann; Luft, Friedrich C.; Huang, Yu; Gollasch, Maik.

In: Journal of Hypertension, Vol. 20, No. 5, 05.2002, p. 885-893.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review