Figure 192

The principal receptors or drug binding sites at the calcium channel. These sites are linked to the opening and closing of the channel and to each other by activating (+) or inhibiting (—) allosteric mechanisms. The 1,4-DHP site is a receptor site for a number of 1,4-dihydropyridine compounds; D600 is the designation for a close chemical relative of verapamil.

Site III

The actions of these drugs must be viewed from the perspective of cellular Ca++ regulation (Fig. 19.1). Ca++ is fundamentally important as a messenger, linking cellular excitation and cellular response. This role is made possible by the high inwardly directed Ca++ concentration and electrochemical gradients, by the existence of specific high-affinity Ca++ binding proteins (e.g., calmodulin) that serve as intracellular Ca++ receptors, and by the existence of Ca++-specific influx, efflux, and sequestration processes. Calcium, in excess, serves as a mediator of cell destruction and death during myo-cardial and neuronal ischemia, neuronal degeneration, and cellular toxicity. The control of excess Ca++ mobilization is thus an important contributor to cell and tissue protection.

The available Ca++ channel blockers exert their effects primarily at voltage-gated Ca++ channels of the plasma membrane. There are at least several types of channels—L, T, N, P/Q and R—distinguished by their electrophysiological and pharmacological characteristics. The blockers act at the L-type channel at three distinct receptor sites (Fig. 19.2). These different receptor interactions underlie, in part, the qualitative and quantitative differences exhibited by the three principal classes of channel blockers.

Cellular stimuli that involve Ca++ mobilization by processes other than that at the L-type voltage-gated channels will be either completely or relatively insensitive to the channel blockers. This differential sensitivity contributes to the variable sensitivity of vascular and

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