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Regulation of Cardiac Contraction

Page history last edited by PBworks 16 years, 11 months ago

Regulation of Cardiac Contraction


Cardiac output = Heart rate x Stroke volume


In order to understand the control of cardiac output it is imperative to recognize the major factors that determine heart rate and stroke volume. Two unique characteristics of cardiac muscle are worthy of note. First, because of the pacemaker property of the heart, the heart initiates its own contraction. The heart rate may be influenced by outside forces, but the initiating stimulus is normally the pacemaker. Secondly, cardiac muscle acts as a syncitial unit; when one cell contracts, they all contract in turn. Thus the force of contraction of the heart is not affected by recruitment of motor units, temporal or spatial summation, or tetany as is seen in skeletal muscle. Yet force of contraction of the heart can be varied to meet demand in various ways.


I. Control of Heart Rate (Chronotropic Effects)


A. Sympathetic Nervous System Innervation of the Heart:


The sympathetic nervous system innervates all segments of the heart, pacemaker, conduction, and contractile cells. The effect of sympathetic stimulation on the heart is to increase the frequency of contraction, increase the velocity of spread of depolarization through the heart, and increase the contractility of the heart. On a cellular level, sympathetic stimulation increases the rate of rise of phase zero, shortens phase two and increases the rate of repolarization of phase three of the pacemaker action potential. Thus the duration of systole is shortened. More significant is the extent of shortening of phase four, dramatically shortening the duration of diastole.


  • 1. Anatomy of sympathetic innervation of the heart


From cell bodies in the intermediolateral columns of the spinal cord, axons of preganglionic sympathetic neurons exit the spinal cord at the lower two cervical and the upper six thoracic segments of the spinal cord and synapse in the bilateral stellate ganglia (combination of superior and middle cervical ganglia) or inferior cervical ganglia.


The postganglionic sympathetic fibers exit the ganglia and follow along the outer surface of the great blood vessels. Upon reaching the base of the heart, these fibers are distributed over the heart through an extensive epicardial plexus. Often these fibers penetrate the heart with the coronary vessels.


  • 2. Mechanism of sympathetic action


Action potentials in the sympathetic fibers cause release of norepinephrine that activates β-adrenergic receptors located at the pacemaker tissue or in the myocardium. Cardiac β receptors (Beta-one receptors) are stimulated by the pharmacological agonist isoproterenol and are blocked by the antagonist propranolol.


Activation of β1 adrenergic receptors of pacemaker tissue increases the inward transmembrane Na+ current (if) and the Ca2+ current of pacemaker cells, increasing the rate of phase 4 depolarization of the pacemaker potential and enhancing automaticity.

Activation of β1 receptors on myocardial fibers increases Ca2+ uptake, sarcoplasmic release of Ca2+, and the turnover rate of actin-myosin cross bridges. These actions of β1 receptor stimulation serve to increase cardiac contractility. Some β1 adrenergic receptors are coupled to Ca2+ channels through G proteins, and others are coupled through an adenylyl cyclase second messenger.



B. Parasympathetic Nervous System Innervation of the Heart


Parasympathetic fibers effectively innervate only the SA node, the AV node and the atrial conduction pathways. There is no effective parasympathetic innervation of the contractile fibers of the ventricles. Strong parasympathetic stimulation of the heart will produce slowing of the heart rate to the point that the heart may stop. It also produces slowing of conduction through the heart, especially in the AV node.


  • 1. Anatomy of parasympathetic innervation of the heart


The cell bodies of the preganglionic neurons are located in vagal nuclei (dorsal motor n. of the vagus and nucleus ambiguus) of the medulla. Axons from these neurons form part of the bilateral Vagus nerves which pass caudally alongside the common carotid arteries and synapse on postganglionic neurons located on the surface of the heart, very close to the SA and AV nodes.


Although considerable overlap occurs, the right vagus has greater innervation and impact on the SA node while the left vagus has greater effect on the AV node. Thus electrical stimulation of the right vagus decreases the automaticity of the SA node (and thus may slow or even stop the heart) while stimulation of the left vagus is more likely to produce various degrees of AV conduction block by slowing conduction through that tissue.


  • 2. Mechanism of parasympathetic action


Action potentials in the postganglionic parasympathetic neurons cause release of the neurotransmitter, Acetylcholine. Acetylcholine (ACh) binds to muscarinic cholinergic receptors and directly (and rapidly) opens ligand-gated ion channels, causing K+ conductance to increase in the pacemaker cells. The resulting outward current hyperpolarizes the membrane potential and decreases the rate of phase 4 depolarization and pacemaker automaticity. Slowing of heart rate results. Parasympathetic stimulation of the heart does not have a significant effect on ventricular contractility. Muscarinic receptors are stimulated by the parasympathetic agonist, muscarine and are blocked by the muscarinic antagonist, atropine.


Parasympathetic action on the cardiac muscle is rapidly terminated by the enzymatic degradation of acetylcholine by acetylcholinesterase. The high concentrations of cholinesterase present in the SA and AV nodes cause vagal inhibition of heart rate to be very brief (50 - 100 msec.). Because parasympathetic actions occur rapidly and dissipate just as rapidly, parasympathetic action is able to influence heart rate on a beat by beat basis. By contrast, the effects of β1 adrenergic receptor stimulation dissipate much more slowly.


  • 3. Interaction of Sympathetic and Parasympathetic Influences on the Heart


As shown in the diagram below, simultaneous blockade of both parasympathetic and sympathetic input to the heart results in a rapid heart rate (100/min.). Atropine (a muscarinic cholinergic antagonist) causes the heart rate to increase considerably, whereas administration of propranolol (a beta-one adrenergic antagonist) decreases heart rate only slightly. These observations indicate that in normal humans the intrinsic resting heart rate (100/min.) is normally being restrained by parasympathetic (vagal) suppression.



  • 4. Control of Autonomic Influence on the Heart.


The level of activity in sympathetic and parasympathetics neurons controlling the heart is clearly important to control of the heart. These influences include the influence of higher centers of the brain stem, hypothalamus, and frontal cortex (emotion, fear) and various cardiovascular reflexes (baroreceptor and others).


C. Respiratory (sinus) arrhythmia

In healthy individuals (especially in young people) heart rate is faster during inspiration than during expiration. In fact, if the R to R interval of the EKG is measured during expiration and during inspiration, the ratio (R-Rexp)/(R-Rinsp) will be 1.1 or higher. This normal fluctuation of the heart rate with the respiratory cycle is called "sinus arrhythmia" (see figure below).


During inspiration, the decreased intrathoracic pressure increases return of blood to the right atrium. This, through the Bainbridge reflex, increases heart rate. Simultaneously, return of blood to the left heart decreases; as a result stroke volume and arterial blood pressure decrease. The decreased pressure in the carotid sinus triggers an increased heart rate via the baroreceptor reflex. During expiration, increased intrathoracic pressure increases return of blood to the left heart; as a result, stroke volume and arterial pressure increase. The increased pressure in the carotid sinus triggers a decrease in heart rate. The efferent limb of the baroreceptor reflex is mediated by a decrease in vagal tone to the SA node during inspiration and an increase during expiration.


The absence of sinus arrhythmia is a clinical sign of deterioration of the autonomic nervous system. For example, the sinus arrhythmia disappears in the neuropathy that develops in some long-term diabetics.


D. Effect of extracellular K+ concentration on cardiac excitability and the EKG.


Because K conductance is so large relative to other ions, changes in extracellular K concentration [K]o produce marked changes in resting transmembrane potential, conduction velocity, pacemaker activity, and cardiac excitability. Not surprisingly then, either increases or decreases in [K]o can produce changes in cardiac function that ultimately lead to arrhythmia or even to ventricular fibrillation. The hallmarks of hyperkalemia [high K]o on the EKG record are a prolonged PR interval and a prolonged QRS interval (evidence of slow impulse-conduction), and tall tent-shaped T waves (evidence of rapid, synchronized ventricular repolarization). The hallmarks of hypokalemia [low K]o on the EKG record are low amplitude T waves and the development of U waves (evidence of slow ventricular repolarization).


The effects of changing extracellular [K] on various cardiac functions are difficult to explain simply on the basis of changes in electrochemical gradient for K ion. This is because K ion itself acts on K channel protein to modulate its gating. For example, a rise in [K]o reduces the electrochemical gradient across the membrane for K, and one would expect the K efflux to be also reduced. However, this is not the case, because [K]o acts on the channel to increase its open probability (more active) for certain types of K channels. There are some things that you can figure out based on changes in electrochemical gradient but others that you cannot. Therefore, it is best for now to simply memorize what hyper- and hypokalemia do to cardiac function.


E. Temperature Effects


All chemical reactions are sensitive to temperature. With increased body temperature, heart rate increases.



II. Control of Force of Cardiac Contraction


The factors that affect the force of cardiac contraction can be grouped into three categories of mechanisms; Preload effects, Afterload effects, and Contractility (or Inotropic) effects.


A. Effect of Cardiac Filling: Preload Effect


As with skeletal muscle, the force (tension) developed by contracting cardiac muscle is proportional to the length of the muscle (preload) at the moment contraction is initiated. For cardiac muscle, the ventricular end-diastolic volume reflects the resting length (preload), and the pressure developed in the ventricle is a measure of force. With greater end-diastolic volume producing stronger contraction, stroke volume and ejection fraction should also increase. This phenomenon was described separately by persons named Frank and Starling. It is commonly known as the Starling Effect or the Frank-Starling Effect.


With an increase in cardiac filling, ventricular volume increases and stretches the ventricular wall. Lengthening the resting muscle fibers increases the probability of actin-myosin cross bridge formation. Since force generated is proportional to the number of cross bridges forming per unit time per cross section of muscle, greater force develops in the pre-stretched muscle. As with skeletal muscle, stretch beyond an optimum length, decreases the active tension (pressure) the muscle develops.


Within limits, this mechanism assures that the stroke volume of each ventricle is adjusted to match the venous return and ventricular filling of that ventricle. This allows the heart to respond appropriately to changes in venous return caused by changes in posture, exercise, and other causes. It also allows the heart to adapt to short term changes in venous return and to differences in venous return between the two sides of the heart. Even in a denervated heart, e.g. post-transplant, the stroke volume and cardiac output of each side of the heart will adapt to the venous return (end diastolic volume) of that ventricle.


B. Effect of Aortic (Pulmonary Artery) Pressure: Afterload Effect


In order for blood to flow from left ventricle into the aorta, intraventricular pressure must be raised by contraction of the ventricle until it exceeds aortic pressure. Part of the contractile ability of the ventricular muscle must be employed to raise intraventricular pressure to this level. With a low aortic pressure, intraventricular pressure easily exceeds aortic pressure and continued contraction of the ventricle ejects a large proportion of the blood. In the face of elevated arterial pressure, a greater proportion of the contractile effort of the ventricular muscle is employed to raise pressure to exceed the higher aortic pressure and less contractile ability remains to eject blood. Therefore, just as in any isotonic contraction, the greater the afterload, the smaller will be the resulting contraction in terms of extent and velocity of shortening of the ventricular muscle.


Elevated arterial pressure reduces ejection fraction, stroke volume, and cardiac output. Lower arterial pressure results in lower afterload on the ventricle. This effect is seen on both ventricles. While aortic pressure typically fluctuates between 120 and 80 mmHg, pulmonary artery pressure varies from 25 to 10 mmHg during each cardiac cycle. Therefore, the afterload on the left ventricle is much greater than on the right. This is directly related to the greater thickness of the left ventricle muscle as compared to the right. However, in the face of pulmonary artery hypertension, serious afterload effects can reduce cardiac output in the right heart as well.


Incidentally, stenosis of the aortic or pulmonic valves can also cause a drastic increase in afterload, not because the arterial pressure is elevated, but because the resistance to blood flow out of the ventricle is elevated.


C. Effect of Changes in Cardiac Muscle Function: Contractility or Inotropy


As described above, the sympathetic nervous system stimulation of the cardiac muscle ensures that the subsequent contractions of the cardiac muscle generate greater force, even in the absence of any change in preload or afterload, because of the changes in calcium handling of the cardiac muscle. Therefore, sympathetic stimulation provokes a change in force of contraction that is not related to any change in preload (end diastolic volume) or afterload (arterial pressure). Such a change in force of contraction, in the absence of changes in preload or afterload, is known as a change in "Contractility" of the muscle. Under these conditions, an increase in contractility is also known as a 'positive inotropic' effect.


A variety of agents can cause an increase in contractility. Among those agents having a positive inotropic effect are the following:

  • 1. Sympathetic nerve stimulation - as described above.
  • 2. Humor agents with beta-one adrenergic activity, including norepinephrine and epinephrine released from the adrenal medulla
  • 3. Pharmacological agonists with β1 adrenergic activity, including isoproterenol
  • 4. Cardiac glycosides increase cardiac contractility via a non-adrenergic mechanism.


Digitalis partially inhibits the Na+/K+ ATPase pump in the sarcolemma. As a result, intracellular Na+ concentration rises. The increased [Na+]i decreases the effectiveness of an exchanger that normally moves Ca2+ out of the cell and extracellular Na+ in to the cell. The net effect, then, of the glycoside is to increase the intracellular Ca2+ concentration, thus enhancing the contractile mechanism.


One commonly used measure of contractility is the maximum change in pressure/change in time (dP/dt) generated by the left or right ventricle during the isovolumic contraction phase of the cardiac cycle. Intraventricular pressure is measured continuously by cardiac catheterization.

Reprinted from Circulatory Physiology-the essentials 2nd ed., (1984) by J.J.Smith & J.P. Kampine, Figure 5.9, page 85, Lippincott, Williams & Wilkins.


D. Rate induced-increase in the force of contraction


There is a small group of interesting phenomena that demonstrate changes in force of contraction produced by changes in heart rate. In each case the underlying mechanism appears to involve changes in intracellular free Ca2+ concentrations.

(Reprinted from Principles of Physiology 3rd ed., (2000) by R.M.Berne & M.N.Levy, page 221 with permission from Elsevier.)

Staircase or Treppe phenomenon: In many circumstances (e.g. exercise) heart rate and contractility increase together. It is important to note, however, that increasing the heart rate increases the force of contraction independently of any simultaneous beta adrenergic-induced increase in contractility. Increasing the heart rate increases the force of contraction by two mechanisms: First, a more rapid heart rate means more plateaus (phase 2 of the cardiac action potential) per unit time, and it is during the plateaus than Ca2+ enters. Secondly, if the heart rate is suddenly increased, the magnitude and duration of the inward Ca2+ current increases with each action potential until a new steady state is achieved.

(Reprinted from Principles of Physiology 3rd ed., (1993) by R.M.Berne & M.N. Levy, page 430, Fig25-23, with permission from Elsevier.)

Post-extrasystolic potentiation: When a premature extra-sytole occurs, the force developed by the ventricle is smaller than normal and force developed during the subsequent contraction is greater than normal (post-extra-systolic potentiation). One of the reasons for the diminished force of the premature contraction, and the augmented contraction of the post-extra-sytolic contraction involves the Frank-Starling mechanism. Specifically, the premature contraction occurs when the resting fiber length was small (incomplete filling had occurred) and the post-extra-systolic contraction occurs when the resting fiber length was especially long (extra filling had occurred during the compensatory pause). Surprisingly, a weak premature contraction and an augmented post-extra-systolic contraction can be demonstrated in isovolumic preparations. A reasonable explanation is that when the premature contraction occurred, a smaller than normal amount of Ca2+ was released from the sarcoplasmic reticulum since it takes about 500 msec for all of the Ca2+ released during, and taken up after, the previous contraction to again become available for release. During the postextrasytolic contraction, the pool of releasable Ca2+ is greater than normal, because the Ca2+ in the sarcoplasmic reticulum had accumulated during the last two heartbeats.

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