Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state.
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 [3H]nitrendipine 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 [3H]nitrendipine binding to membranes. These results make it seem very likely that the high-affinity [3H]nitrendipine binding site is an inactivated state of the Ca2+ channel.
D000818:Animals; D002118:Calcium; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009568:Nitrendipine
D002121:Calcium Channel Blockers; D007473:Ion Channels; D009568:Nitrendipine; D009543:Nifedipine; D002118:Calcium