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

Steady-state and transient effects of clevidipine, a rapidly degraded dihyd ropyridine (DHP) L-type Ca2+ channel antagonist, were examined on I-Ca in g uinea pig ventricular myocytes. When myocytes were voltage-clamped with hol ding potential (V-H) at -80 mV, 10 nM clevidipine decreased I-Ca at 0 mV by similar to 30%. but >50% when V-H was -40 mV. Rapid (<50 ms) perfusion swi tching and repeated depolarizations delivered at 0.5-2 Hz were used to dete rmine the time constants of onset (<tau>(on)) and recovery from (tau (off)) clevidipine inhibition of I-Ca. The tau (on) and tau (off) were monoexpone ntial functions of time. The tau (on) of I-Ca inhibition decreased from 21. 5 +/- 1.2 to 9.9 +/- 0.9 s when the rapidly applied [clevidipine] was incre ased from 10 to 100 nM at V-H = -80 mV; tau (off) was independent of the ap plied [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 IC50 of 78 nM determined in steady-state measurements. Decreasing V-H to - 40 mV increased tau (off) mon than threefold to 81 +/- 6 s, and K-D was mar kedly decreased to 9.0 +/- 0.8 nM (IC50, 7.1 nM at V-H = -40 mV). The incre ased affinity at depolarized V-H may contribute to the varying concentratio n-effect relation observed in vivo.