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Cardiovascular Physiology Concepts

Richard E. Klabunde, PhD

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Click here for information on Cardiovascular Physiology Concepts, 2nd edition, a textbook published by Lippincott Williams & Wilkins (2011)


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Click here for information on Normal and Abnormal Blood Pressure, a textbook published by Richard E. Klabunde (2013)



Regulation of Pacemaker Activity

autonomic control of heart rate
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 transmission at the SA node by antagonizing the muscarinic receptors that bind to acetylcholine, which is the neurotransmitter released by the vagus nerve.

sympathetic and vagal effects on sinoatrial nodal action potentials
Parasympathetic (vagal) activation, which releases acetylcholine (ACh) onto the SA node, decreases pacemaker rate by increasing gK+ and decreasing slow inward gCa++ and gNa+; the pacemaker current (If) is suppressed.  These ionic conductance changes 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 results in a longer time to reach threshold voltage.

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.  Sympathetic activation, which releases norepinephrine (NE),  increases pacemaker rate by decreasing gK+ and increasing slow inward gCa++ and gNa+; the pacemaker current (If) is enhanced.  These changes increase the slope of phase 4 so that the pacemaker potential more rapidly reaches the threshold for action potential generation.
  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.  Hypokalemia increases the rate of phase 4 depolarization and causes tachycardia.  It apparently does this by decreasing gK during phase 4.
  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 a loss of normal ion gradients across the membrane that are required to produce a negative membrane potential. Because a hyperpolarized state at the end of phase 3 is necessary for pacemaker channels to become activated, 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.

Pacemaker activity is influenced dramatically by age. The maximal heart rate that can be achieved in an individual is estimated by

Maximal Heart Rate = 220 beats/min − age in years

Therefore a 20-year-old person will have a maximal heart rate of about 200 beats/min, and this will decrease to about 170 beats/min when the person is 50 years of age. This maximal heart rate is genetically determined and cannot be modified by exercise training or by external factors.

Revised 5/10/13



DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.