Nitrendipine blocked calcium currents very potently at depolarized membrane potentials (Kd 0.36 nM) compared to hyperpolarized potentials (Kd ~700 nM), indicating high-affinity binding to the inactivated state.
Nitrendipine binds with high affinity to the inactivated state of cardiac calcium channels, explaining its potent block of Ca2+ currents at depolarized membrane potentials.
Effect estimate: Kd 0.36 nM at depolarized potentials vs ~700 nM at hyperpolarized potentials
Block of Ca2+ currents by the dihydropyridine drug nitrendipine was studied in single canine ventricular cells by using the whole-cell variant of the patch clamp technique. When cells were held at depolarized membrane potentials at which Ca2+ currents were approximately equal to 70% inactivated, nitrendipine blocked Ca2+ currents very potently, with half-block by subnanomolar concentrations. The concentration dependence of block had the form expected for 1:1 binding, with an apparent dissociation constant (Kd) of 0.36 nM. In contrast, when cells were held at hyperpolarized potentials, nitrendipine blocked Ca2+ currents much less potently (Kd approximately equal to 700 nM). The results can be explained if nitrendipine binds very tightly to the inactivated state of the Ca2+ channel and only weakly to the normal resting state. The Kd estimated for binding to the inactivated state is very similar to the dissociation constants previously found for high-affinity 3Hnitrendipine binding to membrane fragments from heart, smooth muscle, brain, and other tissues; moreover, the concentration-dependent kinetics of binding to the inactivated state are similar to those reported for 3Hnitrendipine binding to membranes. These results make it seem very likely that the high-affinity 3Hnitrendipine binding site is an inactivated state of the Ca2+ channel.
Bruce P. Bean (Mon,) reported a other. Nitrendipine was evaluated on Block of Ca2+ currents (dissociation constant, Kd) (Kd 0.36 nM at depolarized potentials vs ~700 nM at hyperpolarized potentials). Nitrendipine blocked calcium currents very potently at depolarized membrane potentials (Kd 0.36 nM) compared to hyperpolarized potentials (Kd ~700 nM), indicating high-affinity binding to the inactivated state.