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 dihydropyridine (DHP) L-type Ca 2+ 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 determine 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 concentration-effect relation observed in vivo.