Clevidipine : a state-of-the-art antihypertensive drug under the scope.
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 approximately 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 (tau(on)) and recovery from (tau(off)) clevidipine inhibition of I(Ca). The tau(on) and tau(off) were monoexponential 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 increased from 10 to 100 nM at V(H) = -80 mV; tau(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 IC50 of 78 nM determined in steady-state measurements. Decreasing V(H) to -40 mV increased tau(off) more than threefold to 81 +/- 6 s, and K(D) was markedly decreased to 9.0 +/- 0.8 nM (IC50, 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.