Regulation of Pacemaker Activity

The SA node displays intrinsic automaticity (spontaneous pacemaker activity) at a rate of 100-110 action potentials ("beats") per minute. This intrinsic rhythm is primarily influenced by autonomic nerves, with vagal influences being dominant over sympathetic influences at rest. This "vagal tone" reduces the resting heart rate down to 60-80 beats/min. The SA node is predominantly innervated by efferent branches of the right vagus nerves, although some innervation from the left vagus is often observed. Experimental denervation of the right vagus to the heart leads to an abrupt increase in SA nodal firing rate if the resting heart rate is below 100 beats/min. A similar response is noted when a drug such as atropine is administered. This drug blocks vagal influences at the SA node by antagonizing the muscarinic receptors that bind to acetylcholine, which is the neurotransmitter released by the vagus nerve. For heart rate to increase during physical activity, the medullary centers controlling autonomic function reduce vagal efferent activity and increase sympathetic efferent activity to the SA node. High heart rates cannot be achieved in the absence of vagal inhibition.

The rate of SA nodal firing can be altered by:

1. Changes in autonomic nerve activity (sympathetic and vagal)

To increase heart rate, the autonomic nervous system increases sympathetic outflow to the SA node, with concurrent inhibition of vagal tone. Inhibition of vagal tone is necessary for the sympathetic nerves to increase heart rate because vagal influences inhibit the action of sympathetic nerve activity at the SA node.

Norepinephrine released by sympathetic activation of the SA node binds to beta-adrenoceptors. This increases the rate of pacemaker firing primarily by increasing the slope of phase 4, which decreases the time to reach threshold. This occurs by increasing I f ("funny" pacemaker currents) and increasing slow inward Ca++ currents. Sympathetic activation also lowers the threshold for initiating phase 0 of the action potential. Parasympathetic (vagal) activation, which releases acetylcholine onto the SA node that binds to muscarinic receptors, decreases pacemaker rate (phase 4 slope) by increasing gK+ and decreasing the pacemaker currents (I f ) and slow inward Ca++ currents. These changes in ion currents decrease the slope of phase 4 of the action potential, thereby increasing the time required to reach threshold. Vagal activity also hyperpolarizes the pacemaker cell during Phase 4, which contributes to the longer time to reach threshold voltage.

2. Circulating hormones

Pacemaker activity is also altered by hormones. For example, hyperthyroidism induces tachycardia and hypothyroidism induces bradycardia. Circulating epinephrine causes tachycardia by a mechanism similar to norepinephrine released by sympathetic nerves.

3. Serum ion concentrations

Changes in the serum concentration of ions, particularly potassium, can cause changes in SA nodal firing rate. Hyperkalemia induces bradycardia or can even stop SA nodal firing. Hyperkalemia causes membrane depolarization, which diminishes the degree of hyperpolarization that occurs at the end of phase 3. This, in turn, prevents full reactivation of pacemaker channels for Na+ and Ca++ so that the slope of phase 4 is decreased. Hypokalemia increases the rate of phase 4 depolarization and causes tachycardia by enhancing phase 3 repolarization, which causes greater activation of channels responsible for the inward pacemaker currents. Note, however, that the effects of changes in serum potassium are complex with multiple channels and ion pumps being affected by potassium concentration.

4. Cellular hypoxia

Cellular hypoxia (usually due to ischemia) depolarizes the membrane potential causing bradycardia. Without adequate oxygen, ATP dependent ion pumps in the cell membrane cannot operate. This leads to cellular depolarization because of a loss of normal ion gradients (particularly K+) across the membrane. Because a hyperpolarized state at the end of phase 3 is necessary for pacemaker channels to become reactivated, pacemaker channels remain inactivated in depolarized cells. This suppresses pacemaker currents and decreases the slope of phase 4. This is one reason why cellular hypoxia, which depolarizes the cell and alters phase 3 hyperpolarization, leads to a reduction in pacemaker rate (i.e., produces bradycardia). Severe hypoxia completely stops pacemaker activity.

5. Drugs

Various drugs used as antiarrhythmics also affect SA nodal rhythm. Calcium-channel blockers, for example, cause bradycardia by inhibiting the slow inward Ca++ currents during phase 4 and phase 0. Drugs affecting autonomic control or autonomic receptors (e.g., beta-blockers, muscarinic antagonists) directly or indirectly alter pacemaker activity. Digitalis causes bradycardia by increasing parasympathetic (vagal) activity on the SA node; however, at toxic concentrations, digitalis increases automaticity and therefore can cause tachyarrhythmias. This toxic effect is related to the inhibitory effects of digitalis on the membrane Na+/K+-ATPase, which leads to cellular depolarization, increased intracellular calcium, and changes in ion conductances.

6. Age

Pacemaker activity is influenced dramatically by age. Many different formulas have been developed to estimate the effects of age on maximal HR (HR max ); however, the following simple formula is commonly used and serves to illustrate how age generally affects HR max :

HR max = 220 — age in years

Using this formula, a 20-year-old person will have a HR max of about 200 beats/min, and this will decrease to about 170 beats/min when the person is 50 years of age. HR max cannot be modified appreciably by exercise training; therefore, even highly conditioned older athletes will have a reduced HR max . Please note that for any given individual, their HR max will be strongly influenced by genetic factors as well as by other factors previously mentioned.

Revised 10/15/19