TY - JOUR
T1 - Clevidipine blockade of L-type Ca2+ currents
T2 - Steady-state and kinetic electrophysiological studies in guinea pig ventricular myocytes
AU - Yi, Xiaobin
AU - Vivien, Benoît
AU - Lynch, Carl
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
KW - Calcium channels
KW - Dihydropyridine
KW - Dissociation constant
KW - Guinea pig heart
KW - Pharmacodynamics
UR - http://www.scopus.com/inward/record.url?scp=0033753786&partnerID=8YFLogxK
U2 - 10.1097/00005344-200011000-00008
DO - 10.1097/00005344-200011000-00008
M3 - Article
C2 - 11065219
AN - SCOPUS:0033753786
SN - 0160-2446
VL - 36
SP - 592
EP - 600
JO - Journal of cardiovascular pharmacology
JF - Journal of cardiovascular pharmacology
IS - 5
ER -