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Review
. 2000 Jul;84(1):14-24.
doi: 10.1136/heart.84.1.14.

Antiarrhythmics--from cell to clinic: past, present, and future

J C Hancox  1 , K C Patel, J V Jones
Affiliations
Review

Antiarrhythmics--from cell to clinic: past, present, and future

J C Hancox et al. Heart. 2000 Jul.
No abstract available

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Figures

Figure 1
Figure 1
Schematic illustration of representative action potentials from (A) cardiac pacemaker cell, (B) ventricular cell, and (C) atrial cell.
Figure 2
Figure 2
Ionic and membrane potential gradients determine the direction of ion flow across the cell membrane. (A) Direction of sodium movement (shown by arrow) with normal transmembrane Na gradient. Reversal/equilibrium potential (ENa) is calculated using the Nernst equation (left panel inset shows this for Na at physiological temperature). When transmembrane potential (VM) is less positive than ENa the electrochemical gradient favours Na entry (left panel). Right panel: If VM exceeds ENa (for example, by depolarising the cell beyond ENa—illustrated by +++), the electrochemical gradient favours sodium exit. (B) Direction of potassium movement (shown by arrow) with normal transmembrane K gradient when VM is more positive than EK (left panel) and more negative than EK (right panel; - - - represents applied hyperpolarisation).
Figure 3
Figure 3
(A) Ion channels undergo changes in protein conformation that determine whether ionic current flows or not. At rest channels are closed (C), but when an appropriate stimulus is applied (a change in membrane potential for voltage operated channels, an appropriate ligand, for example, acetylcholine, for ligand operated channels), the channel conformation changes (during a process called "activation"; C→O) to allow the relevant ion to pass through the channel pore, here shown for ions passing from inside to outside of the cell. Many voltage operated channels undergo a second transition; in the presence of a sustained depolarising stimulus, the channel conformation undergoes a further change to prevent current flow—this process is called inactivation (O→I). Inactivation can occur in two ways; either a blocking particle moves to occlude the internal face of the channel pore (N type inactivation), or a change to the outer portion of the channel pore prevents ion flow (C type inactivation). The net result is that ions can no longer pass through the channel pore. (B) Measurements of ionic current from heart cells are made using voltage or patch clamp methods. These techniques allow detailed study of drug-channel interactions. To introduce ionic current records to the reader unfamiliar with this technique, we present example currents, recorded from an individual ventricular myocyte using whole cell patch clamp. The membrane potential is controlled by the experimenter, allowing measurements of whole cell membrane current to be made in response to applied voltage commands. In this example, the cell membrane potential is held at -80 mV and a double step pulse applied. The first step to −40 mV elicits a large and brief downward current deflection. This represents a large, rapidly activating and inactivating current through Na channels. The second step to +10 mV elicits a second downward deflection (of smaller amplitude than INa), which then gradually returns to baseline during the command step. This represents current flow through L type Ca channels and shows that ICa,L activates quickly, and then subsequently inactivates (at a slower rate than inactivation of INa). Both ICa,L and INa are inward or depolarising currents. A current deflection in the opposite direction (with an amplitude positive to 0 on the current axis) would represent an outward, or repolarising current.
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References

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