Modeling ion channel blockade at guarded binding sites: application to tertiary drugs.

Excitable membranes exposed to sodium channel blocking agents (D; local anesthetics and antiarrhythmic drugs) show a progressive reduction of peak sodium current when repetitively depolarized (use dependence). Thus, with repetitive excitation, use dependence reflects a net rightward shift in the balance between unblocked channels (U) and blocked channels (B): U + D in equilibrium with B. The modulated receptor hypothesis (a 7-parameter model) has been proposed to account for this shift and is based on a channel lumen binding site whose affinity varies with channel state and where drug-complexed channels exhibit modified inactivation gate kinetics. Alternatively, we consider use-dependent binding as the result of transient access to a constant-affinity binding site. In this setting, the channel gate conformation is viewed as controlling the flux of drug as it diffuses between drug pools and the binding site. Apparent variation in binding rates is therefore considered the result of variations in the fraction of accessible sites. This guarded receptor hypothesis, with three fewer parameters, is able to predict apparent changes in channel binding and apparent shifts in channel inactivation without incorporating modified gating parameters in drug-complexed channels. Furthermore, with this model one is able to characterize both relaxation kinetics and channel blockade associated with tertiary amines as well as hydrophobic and hydrophilic agents. The pH dependence of repriming rates is utilized to estimate several of the important parameters associated with this simplified hypothesis.