The clinical tool most commonly used to assess cardiac function is the surface electrocardiogram (ECG). The ECG records the sum of the electrical changes occurring within the myocardium. The electrophysiologic basis of cardiac function and the ECG are complex and are subject to alteration by numerous xenobiotics. Ion currents flowing through various ion channels are responsible for cardiac function. Electrophysiologic studies have identified the functional types of membrane receptors and ion channels. Molecular genetic studies have identified the gene coding for the key cardiac ion channels and have elucidated the structural and physiologic relationships that lead to the toxic effects of many xenobiotics. These channels are critical for maintenance of the intracellular ion concentrations necessary for action potential development, impulse conduction throughout the heart, and myocyte contraction. This chapter will first review the individual ion channels and their currents, and then summarize their contribution and effects on the ECG.
ION CHANNELS OF THE MYOCARDIAL CELL MEMBRANE
The voltage-sensitive sodium channels are responsible for the initiation of depolarization of the myocardial membrane. All currently identified voltage-sensitive channels, including the sodium and calcium channels, have structures similar to the potassium channel assembly. The sodium channel gene encodes a single protein that contains four functional domains (D I to D IV). Each of these domains has the six membrane-spanning regions characteristic of the voltage-gated potassium channel and is structurally similar to an α subunit of the potassium channel (Fig. 16–1A). The single, large α subunit of the sodium channel assembles with regulatory β subunits to form the functional unit of the sodium channel. The best characterized of the sodium channels, the SCN5A gene-encoded α channel, is inactivated by xenobiotic interactions between the D III and the D IV domains to physically block the inner mouth of the sodium channel pore.32 Six specific receptor sites are identified on the α subunit with different xenobiotics binding at specific sites: tetrodotoxin, saxitoxin, conotoxin (site 1); veratridine, batrachotoxin, grayanotoxin (site 2); α scorpion toxins, sea anemone toxins (site 3); β-scorpion toxins (site 4); brevetoxins, ciguatoxins (site 5); delta conotoxins (site 6); and local anesthetic and related antidysrhythmic and antiepileptic binding at another receptor site.15
Structure of the sodium and potassium channels. (A) The structure of the α subunit of the sodium channel. The protein molecule has 4 functional domains (D I–D IV) each analagous to one of the potassium channel α subunits. One of these molecules assembles with β subunits to form the membrane sodium channel. (B) The structure of the α subunit of the voltage gated potassium channel. The protein molecule has six membrane spanning regions (S1–S6); the voltage sensitive region is S4 and the actual ion channel is located between S5 and S6. Four of these α subunits assemble with four β subunits to form the potassium channel complex.