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 identify the functional types of membrane receptors and ion channels. Molecular genetic studies identify the gene coding for the key cardiac ion channels and elucidate 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 4 functional domains (D I to D IV). Each of these domains has the 6 membrane-spanning regions characteristic of the voltage-gated potassium channel and is structurally similar to the α subunit of the potassium channel. The single, large α subunit of the sodium channel assembles with regulatory β subunits to form the functional unit of the sodium channel (Fig. 15–1A). 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.29 Seven specific receptor sites are currently identified on the α subunit, with different xenobiotics binding at the specific sites: tetrodotoxin, saxitoxin, μ-conotoxin (site 1); aconitine, batrachotoxin, grayanotoxin, veratridine (site 2); α scorpion toxins, sea anemone toxins (site 3); β scorpion toxins, Chinese bird spider toxin (site 4); brevetoxins, ciguatoxins (site 5); δ-conotoxins (site 6); pyrethroids (site 7), and local anesthetics and related antidysrhythmics and antiepileptics binding at overlapping receptor sites.14,57,61,71
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 analogous to one of the potassium channel α subunits. One of these molecules assembles with β subunits to form the membrane sodium channel. Sites 1–7 are shown with individual toxins known to bind at these sites. (B) The structure of the α-subunit of the voltage-gated potassium channel. The protein molecule has 6 membrane-spanning regions (1–6); the voltage-sensitive region is at 4 and the actual ion channel is ...