Clevidipine blockade of L-type Ca2+ currents: Steady-state and kinetic electrophysiological studies in guinea pig ventricular myocytes

Xiaobin Yi, Benoît Vivien, Carl Lynch

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8 Scopus citations

Abstract

Steady-state and transient effects of clevidipine, a rapidly degraded dihydropyridine (DHP) L-type Ca2+ channel antagonist, were examined on I(Ca) in guinea pig ventricular myocytes. When myocytes were voltage-clamped with holding potential (V(H)) at -80 mV, 10 nM clevidipine decreased I(Ca) at 0 mV by ~30%, but >50% when V(H) was -40 mV. Rapid (<50 ms) perfusion switching and repeated depolarizations delivered at 0.5-2 Hz were used to det00000000ermine the time constants of onset (τ(on)) and recovery from (τ(off)) clevidipine inhibition of I(Ca). The τ(on) and τ(off) were monoexponential functions of time. The τ(on) of I(Ca) inhibition decreased from 21.5 ± 1.2 to 9.9 ± 0.9 s when the rapidly applied [clevidipine] was increased from 10 to 100 nM at V(H) = -80 mV; τ(off) was independent of the applied [clevidipine] and was 23.9 ± 1.1 s. The dissociation constant (K(D)) calculated for clevidipine at V(H) = -80 mV was 65 ± 3 nM, similar to the IC(50) of 78 nM determined in steady-state measurements. Decreasing V(H) to -40 mV increased τ(off) more than threefold to 81 ± 6 s, and K(D) was markedly decreased to 9.0 ± 0.8 nM (IC(50), 7.1 nM at V(H) = -40 mV). The increased affinity at depolarized V(H) may contribute to the varying concentrationeffect relation observed in vivo.

Original languageEnglish
Pages (from-to)592-600
Number of pages9
JournalJournal of cardiovascular pharmacology
Volume36
Issue number5
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

Keywords

  • Calcium channels
  • Dihydropyridine
  • Dissociation constant
  • Guinea pig heart
  • Pharmacodynamics

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