Nisoldipine exhibits very high affinity binding to smooth and cardiac muscle membranes. Calcium channels in isolated membranes probably exist in the inactivated state, and electrophysiological studies by Kass et al.  have shown that this state of the channel has the highest affinity for nisoldipine. Therefore, it is likely that binding studies allow us to examine the high affinity association of drug with inactivated calcium channels.
[3H] (±) nisoldipine exhibits one of the highest affinities of the Ca2+ antagonists that we have studied, and its rate of dissociation from cardiac membranes is extremely slow . The binding of the racemic mixture of [3H]nisoldipine to cardiac membranes exhibits complex on and off rates . These results are probably due to the presence of two radiolabelled isomers and also to the presence of high- and low- affinity binding sites.
We have now studied the binding of the enantiomer [3H](+)nisoldipine to rat and rabbit ventricular microsomes and to bovine aortic sarcolemma. This ligand exhibits the expected high affinity binding to cardiac and smooth muscle membranes (Kd = 0.04 nM at 25°C). Adler et al.  found a similar affinity using purified cardiac sarcolemma membranes from dog ventricle. The dissociation rate of [3H](+)nisoldipine did not exhibit two phases. At 25°C, the t1/2 for the dissociation of [3H](+)nisoldipine was 10 times that for [3H]nifedipine, in general agreement with the results obtained using the racemic mixture. The partitioning of nisoldipine into biological membranes is also much greater than that of nifedipine (Herbette, L. personal communication), and this should also contribute to its greater apparent affinity of binding. These factors are likely to contribute to the long duration of action of nisoldipine.
KeywordsCalcium Channel Antagonist High Affinity Binding Site Cardiac Membrane Ligand Binding Study Smooth Muscle Membrane
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