Cardiac Action Potentials

Overview

The heart is composed nearly entirely of muscle, but each of the four chambers contracts in a timed fashion so that blood flows from the atria to the ventricles and then out of the heart. The stimulus to contract arises from a pacemaker (see below) within the heart itself, not from nervous inputs as in skeletal muscle. Action potentials from this pacemaker in the right atrium are carried by modified muscle cells which act as cables, carrying the action potentials into the ventricles, which subsequently contract. Anything that goes wrong with the pacemaker or the conduction system will affect how the heart beats, possibly impairing filling and emptying of the chambers.

Electrical wiring of the heart

In the normal heart, pacemaker cells in the sinoatrial node (SA node) control the rate of contractions of the heart. Action potentials generated cyclically by the SA node spread around the right atrium and left atrium, causing them to contract, forcing their contents into the ventricles. This wave of depolarisation then reaches the atrioventricular node (AV node) which is the entry point for action potentials to the ventricles. The atria and ventricles are electrically isolated from one another by the so-called cardiac skeleton. This consists of a framework of connective tissue (not bone as the name might suggest) which isolates the atria and ventricles and provides a framework for supporting the heart valves. The AV node connects to the bundle of His, which is effectively a cable to conduct action potentials and spread them into the ventricles. Crucially, conduction through the AV node itself is a bit sluggish (about 100 ms), preventing the ventriclular excitation from occurring before the atria have finished contracting.

Figure 1: Initiation and conduction of depolarisation in the heart. Pacemaker action potentials originate in the SA node and spread around the atria causing contraction. When this wave of depolarisation reaches the AV node it is conducted into the ventricles by the bundle of His, which branches into left and right bundles supplying each side of the heart.

The bundle of His is made up of Purkinje fibres, which are modified muscle cells and conduct depolarisation more rapidly than muscle cells. In this way, the action potential is spread around all the musculature of the ventricles more or less simultaneously, rather than spreading slowly as a wave. This produces an efficient, rapid contraction of the ventricles. If anything goes wrong with the conduction system, heart block occurs. The effects of this on the performance of the heart depend on the site and nature of the block in the system.

Cardiac pacemakers

The SA node isn’t the only region of the heart capable of cyclically generating action potentials, it is merely the dominant one that overrides the others. The AV node can also generate action potentials, but it fires at only 40-60 action potentials per minute compared to the faster SA node rate of 70-100. So, an action potential from the SA node will depolarise the AV node before it has had a chance to generate an action potential; it is “driven” by the SA node. The bundle of His is also capable of automaticity when it is not driven by the SA node. So, when something goes wrong with conduction to the ventricles they may still contract, but spontaneously and out of sync with the atria. These are known as ectopic beats.

SA node action potentials

The electrophysiological basis of the SA node pacemaker potential is a fascinating bit of biology. You really could take someone’s heart out of their body and it would still be beating because the SA node doesn’t require any neural input generate action potentials. A small collection of ion channels opening and closing according to simple rules is all that is required to produce automaticity. Here’s the simple version of how it works (see Figure 2, left hand side):

• The membrane is leaky to K+ most of the time, but is much leakier when voltage dependent potassium channels open in response to depolarisation. So, the membrane potential is determined mainly by K+, and if depolarisation occurs then the increased K+ current that follows in response will drive membrane potential back down again.
  
• Na⁺ also leaks into SA nodal cells and this current was termed for many years as the funny current, or I_f. It’s an odd (funny) channel because it is voltage-dependent but opens during membrane hyperpolarisation rather than depolarisation. This slow, depolarising baseline drift is the key to automaticity. SA nodal cells constantly depolarise slowly, except during hyperpolarisation – such as when K+ leaves the cell abruptly (see above).
  
• There are two sets of voltage-gated Ca²⁺ channels that contribute to the upstroke of the action potential. The first channel to come into play is the T-type Ca²⁺ channel, which opens at a specific level of membrane depolarisation. These open transiently (thus T-type), providing the initial depolarising kick to fire the action potential proper, which is mediated by the opening of L-type (L for long-lasting) Ca²⁺ channels. In non-pacemaker atrial myocytes this entry of Ca²⁺ causes contraction.
  
• After a brief delay the L-type calcium channels close and the voltage gated K⁺ channels open, resetting the membrane potential. This hyperpolarisation opens the Na⁺ leak channels, starting the process again. Without this creeping depolarisation, the membrane potential would sit at the same level and the pacemaker would cease.
  
  

Figure 2: Comparison of the ionic currents underlying SA node and ventricular myocyte action potentials. The constant leak of Na⁺ from SA node pacemaker cells leads to a continuously depolarising baseline. This ultimately opens voltage gated ion channels leading to an action potential. In ventricular myocytes, the membrane potential is stable until the depolarising stimulus arrives, again causing voltage gated ion channels to open. Note that the ionic currents underlying the action potential in each case are different: Ca²⁺ for SA node cells and Na⁺ for ventricular cells. (Redrawn from Vander’s physiology: The mechanisms of body function, 2008.)

In years past, this simple description of the SA node action potential sufficed, but we know a lot more now. By combining molecular biological and electrophysiological techniques we have identified each individual protein involved and the genes that encode them. In this way we have come to understand, for example, that what we used to think of as simply a potassium current is really a collection of potassium channels acting in concert. The current conducting the funny current now has a name - HCN4 - which lacks charm entirely. Decide for yourself how much extra detail you need to add to the simple model above. Much more detailed versions are abound, but might be beyond your needs!

Ventricular action potentials

• Fast Na⁺ channels open, rapidly depolarising the cell.
• This opens L-type Ca^2+> channels, as in SA node cells. This Ca²⁺ entry initiates contraction.
• Voltage-gated K⁺ channels open as the Na⁺ and Ca²⁺ begin to close, causing hyperpolarisation and bringing the membrane potential back to its resting level.
  

As in skeletal muscle, there is a refractory period during which ventricular myocytes cannot sustain an action potential due to the inactivation of Na⁺ channels. Unlike skeletal muscle, this period is quite long in ventricular myocytes, so that tetanic contraction is impossible. This ensures that after contraction relaxation occurs, allowing the filling of the ventricles.

Autonomic control of the SA node

The rate of production of action potentials by the SA node is limited by how fast Na⁺ leaks in through HCN channels – the funny current. If more HCN channels are open, Na⁺ leaks in faster, reaching the threshold for activating voltage-dependent Ca²⁺ channels more quickly and shortening the distance between action potentials (Figure 3).

Figure 3: Regulation of SA-node action potential generation, and hence heart rate. The funny current (dashed line, consisting of Na⁺ leaking through HCN channels) limits the time between action potentials by setting the time to reach the activation threshold (dotted line). If the leak current is larger, this point is reached more quickly and heart rate increases.

The sympathetic and parasympathetic branches of the autonomic nervous system have opposite effects on heart rate by opening and closing HCN channels (Figure 4). Noradrenaline released by sympathetic nerves binds to β₁ adrenoceptors which couple via the G-protein Gs (s for stimulate) which stimulates the enzyme adenylate cyclase to increase production of the second mediator cyclic AMP (cAMP). Adrenaline circulating in the blood also binds β₁ adrenoceptors. HCN channels are sensitive to cAMP and open when levels rise. Thus, the funny current is increased and the time between SA node action potentials decreases. Acetylcholine released by parasympathetic nerves has the opposite effect since it binds to M2 muscarinic receptors which are linked to Gi, inhibiting adenylate cyclase and hence closing HCN channels.

Figure 4: Opening and closing of HCN channels is regulated by the intracellular second messenger cAMP. Increased cAMP occurs when noradrenaline or adrenaline bind to Gs-coupled β₁ receptors, whereas acetylcholine has the opposite effect when bound to Gi-coupled M2 receptors.