The Selectivity of Action of Calcium Channel Blockers

Although the available Ca++ channel blockers exert their effects through an interaction at one type of channel, they do so at different sites. Figure 19.2 shows that the channel blockers act at three discrete receptor sites to mediate channel blockade indirectly rather than by a direct or physical channel block. The existence of the different receptor sites is one basis for the different pharmacological profiles exhibited by these agents.

The activity of the Ca++ channel blockers increases with increasing frequency of stimulation or intensity and duration of membrane depolarization. This use-dependent activity is consistent with a preferred interaction of the antagonists with the open or inactivated states of the Ca++ channel rather than with the resting state. This activity is not shared equally by all Ca++ blockers and so may provide a further basis for the therapeutic differences between them. For example, verapamil and diltiazem are approximately equipotent in cardiac and vascular smooth muscle, whereas nifedipine and all other agents of the 1,4-dihydropyridine class are significantly more active in vascular smooth muscle. Furthermore, different members of the 1,4-dihydropyri-dine class have different degrees of vascular selectivity. These differences are broadly consistent with the observation that verapamil and diltiazem act preferentially through the open channel state, and nifedipine and its analogues act through the inactivated state.

The clinically available calcium channel antagonists have also proved to be invaluable as molecular probes with which to identify, isolate, and characterize calcium channels of the voltage-gated family. In particular, the 1,4-dihydropyridines with their high affinity, agonist-antagonist properties, and selectivity have become defined as molecular markers for the L-type channel.

Synthetic drugs of comparable selectivity and affinity to the 1,4-dihydropyridines do not yet exist for the other channel types,T, N, P/Q, and R; these remain characterized by complex polypeptide toxins of the aga- and conotoxin classes. Neuronal pharmacology, including that of the central nervous system (CNS), is dominated by the N, P/Q, and R channels. This underscores the normally weak effect of L-channel antagonists on CNS function. Drugs that act at the N, P, and R channels with comparable selectivity and affinity to the 1,4-dihydropyridines may be expected to offer major potential for a variety of CNS disorders, including neuronal damage and death from ischemic insults.

The Ca++channel blockers also differ in the extent of their additional pharmacological properties. Verapamil and to a lesser extent diltiazem possess a number of receptor-blocking properties, together with Na+ and K+ channel-blocking activities, that may contribute to their pharmacological profile. Nifedipine and other 1,4-dihy-dropyridines are more selective for the voltage-gated Ca++ channel, but they may also affect other pharmacological properties because their nonpolar properties may lead to cellular accumulation. Together with their channel-blocking properties, these properties may con tribute to the recently described antiatherogenic actions seen in experimental and clinical states.

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