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MethodsPeripheral arterial dye dilution curves (indocyanine green), which had been obtained over a three-year period at the Duke Cardiovascular Laboratory from catheterized patients without shunts, were studied. A total of 114 curves were selected from 70 patients and 2 normal subjects. Of these curves, 109 were from patients with catheterproven valvular heart disease, 3 were from patients proven at catheterization to be hemody-

Many local anesthetics promote reduction in sodium current during repetitive stimulation of excitable membranes. Use-, frequency-, and voltage-dependent responses describe patterns of peak INa when pulse width, pulse frequency, and pulse amplitude are varied. Such responses can be viewed as reflecting voltage-sensitive shifts in equilibrium between conducting, unblocked channels and nonconducting, blocked channels. The modulated-receptor hypothesis postulates shifts in equilibrium as the result of a variable-affinity receptor and modified inactivation gate kinetics in drug-complexed channels. An alternative view considers drug blocking in the absence of these two features. We propose that drug binds to a constant-affinity channel receptor where receptor access is regulated by the channel gates. Specifically, we view channel binding sites as guarded by the channel gate conformation, so that unlike receptors where ligands have continuous access, blocking agent access is variable during the course of an action potential. During the course of an action potential, the m and h gates change conformation in response to transmembrane potential. Conducting channels with both gates open leave the binding site unguarded and thus accessible to drug, whereas nonconducting channels, with gates in the closed conformation, act to restrict drug access to unbound receptors and possibly to trap drug in drug-complexed channels. We develop analytical expressions characterizing guarded receptors as "apparently" variable-affinity binding sites and predicting shifts in "apparent" channel inactivation in the hyperpolarizing direction. These results were confirmed with computer simulations. Furthermore, these results are in quantitative agreement with recent investigations of lidocaine binding in cardiac sodium channels.

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T he increased mortality associated with the use of the class Ic agents encainide and flecainide in the Cardiac Arrhythmia Suppression Trial (CAST)' has led to a critical reexamination of the adequacy of existing therapies for the control of cardiac arrhythmias. Although the reasons for the findings in CAST remain unclear, proarrhythmia due to excessive slowing of conduction has been suggested as a possible contributing cause. prolongation at slow heart rates, which might lead to proarrhythmia. This pattern of activity, that is, reduced efficacy at fast heart rates and increased efficacy at slow heart rates, is opposite to that typically observed with class I agents,9 which tend to exhibit greater pharmacological effects (i.e., more conduction slowing) as heart rate is increased. The decline in class III activity at fast heart rates has been attributed to a phenomenon called "reverse" usedependence,8 by which potassium channel block is relieved by depolarization and enhanced by hyperpolarization, the reverse of what occurs with the sodium channel blockers. This particular paradigm for potassium channel block is based on an analysis of the effects of the class Ia agent quinidine on delayed rectifier potassium currents in guinea pig ventricular myocytes.10In the present article, we review briefly the role of myocardial potassium channels as targets for class I and class III antiarrhythmic drug action, and suggest a model for the drug-channel interaction that is most consistent with the information currently available on potassium channel block in several different cardiac preparations. Our investigations indicate that potassium channel block by both class I and class III antiarrhythmic agents is enhanced by depolarization and removed by hyperpolarization, and is therefore identical to the type of use-dependence described previously for drug block of sodium channels. This model is supported by direct measurements of delayed rectifier currents in cat ventricular myocytes that are consistent with drug block and unblock of open channels. Finally, we demonstrate that agents that prolong refractoriness by delaying the recovery of sodium channels carry some intrinsic potential for arrhythmia aggravation because they can introduce nonuniformities in otherwise homogeneous tissue by prolonging the diastolic "window" over which slow conduction and unidirectional block can occur. This effect is greatest for kinetically slow drugs like the class Ic agents.

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na + channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (∆K1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and ∆K1500 mutant channel. The mutation shifted the potential for half inactivation (V 1/2 h ∞ ) to more negative values and reduced its voltage dependence consistent with a reduction of inactivation valence of 1. The shift in inactivation was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). The potential for half activation (V 1/2 m) was shifted to more positive potentials, and its voltage dependence reduced by 50% in the ∆K1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (∆ charge, -1, -2). For both mutations, V 1/2 h ∞ was shifted back toward control; however, V 1/2 m shifted progressively to more positive potentials. The late component of Na + current was increased in the ∆K1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

Background. The use of flecainide and encainide was terminated in the Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac deaths in the active treatment group. Such events might arise from reentrant rhythms initiated by premature stimulation in the presence of anisotropic sodium channel availability. Drugs that bind to sodium channels increase the functional dispersion of refractoriness by slowing (a result of the drug-unbinding process) the transition from an inexcitable state to an excitable state. It is interesting that encainide and flecainide unbind slowly (15-20 seconds), whereas lidocaine and moricizine unbind rapidly (0.2-1.3 seconds).Methods and Results. With a computer representation of a cable with Beeler-Reuter membrane