SIO 63/BME 511 1 Dr. Janis Burt February 19, 27 MRB 422; 626-6833 MUSCLE EXCITABILITY - Ventricle READING: Boron & Boulpaep pages: 483-57 OBJECTIVES: 1. Draw a picture of the heart in vertical (frontal plane) section. Include the elements of the conduction system in your drawing. 2. Describe the sequence of activation of the heart. List the three benefits of the sequence in optimizing cardiac function. 3. Draw an action potential characteristic of ventricular cells, label its phases, describe the membrane's relative ion permeabilities for each phase, and compare these relative permeabilities to those of skeletal muscle and nerve. 4. Discuss the significance for cardiac function of the high resting potassium permeability. 5. Relative to an action potential, illustrate the timing of the three refractory periods observed in a cardiac myocyte. rovide a definition for each refractory period. State which channel s activation/inactivation characteristics determine the refractory state of the heart. Graph the relationship between that channel s availability and membrane potential. State the significance of refractory periods to normal pulsatile function of the heart. LECTURE OUTLINE I. Sequence of Activation Overview (Objectives 1, 2) A. Normal Sequence of Activation: Sinoatrial node right atrium, interatrial tracts, and internodal tracts atrioventricular node and left atria atrioventricular node Bundle of HIS bundle branches urkinje fibers ventricle (apex to base, endocardial surface to epicardial surface) B. Benefits of normal activation sequence 1. Maximizes ventricular filling 2. Optimizes ventricular contraction by stabilizing valve leaflets and septum early in contraction 3. Maximizes ejection by synchronizing contractile activation in the ventricular wall II. Excitability of Ventricular Cells: A. The Action potential - Figure 1&2 (Objectives 3 & 4) 1. Action potential duration is 1x longer than in SKM or nerve with 4 distinct phases. 2. During hase 4 the membrane potential is dominated by K (I K1 channels), which are ~1x more numerous than in SKM or nerve. a) High resting K : stabilizes the resting membrane potential; minimizes arrhythmias by necessitating a large stimulus (depolarization of neighboring cells) to result in successful activation (ventricles are slaves to the pacemaker cells). b) The resting permeabilities for K : Na : Cl are: 1 :.5 :.1 (note: Na is 1-5x higher than in nerve or SKM; Cl is comparable to nerve, 1x less than SKM. c) The density of Na,K-ATase enzymes in heart membrane is greater than SKM or nerve. 3. During phase, the action potential upstroke, Na increases resulting in an influx of Na + (Na-channel comparable to nerve and SKM but with slower kinetics). 4. hase 1, the early repolarization phase, involves a transient increase in K (resulting in efflux of K + ) and Na-channel inactivation.
SIO 63/BME 511 2 Dr. Janis Burt February 19, 27 MRB 422; 626-6833 5. hase 2, the plateau phase, requires an increase in Ca and a decrease in K (decrease in I K1 activity). a) The calcium channel is voltage activated, dihydropyridine sensitive, and regulated by cam-dependent protein kinase. b) K decreases as Mg 2+ blocks the I K1 channels. 6. hase 3, repolarization, voltage activated K channels open (I K - delayed rectifiers) and Ca channels close. As the membrane repolarizes Mg 2+ block of I K1 channels is relieved and resting membrane permeabilities are restored. 7. As heart rate increases action potential duration decreases; however time between action potentials shortens to a greater extent than the action potential. B. Refractory periods Figures 1,3,4 (Objective 5) 1. absolute refractory period - the period of time during which no action potential can be initiated, regardless of stimulus strength (AR in Figure 1) and is considerably longer in duration than observed in skeletal muscle. 2. effective refractory period, the period of time during which no propagated action potentials can be elicited regardless of stimulus strength. 3. relative refractory period (RR) the period of time in which a response can be elicited but the stimulus required is larger than normal and the amplitude of the action potential is abnormally small. 4. supranormal period (SN) the period during which a slightly smaller than normal stimulus elicits a propagated response, although the amplitude of the action potential is reduced compared to normal. 5. Full recovery time (FRT) represents the time before a normal action potential can be elicited with a normal stimulus. 6. Refractory properties reflect the recovery of Na-channels to a state from which they can be activated. 7. The long duration of the action potential and the refractory characteristics of the cell insure that cardiac cells are nearly completely relaxed by the time they are repolarized. Cardiac muscle cannot be tetanized because of these membrane properties. LECTURE NOTES I. Sequence of Activation (Objectives 1 & 2) The normally functioning heart follows a specific pattern of activation every time it contracts. This pattern optimizes function by maximizing ventricular filling, contraction and ejection. The activation sequence begins with an action potential at the sinoatrial node, the pacemaker of the heart. The electrical event spreads via gap junctions to the surrounding atria and along specialized interatrial and internodal conduction pathways to the left atrium and atrioventricular node (AV node), respectively. The AV node represents the only point of electrical continuity between the atrium and ventricle. When the excitatory event leaves the AV node, it passes rapidly along the Bundle of HIS, the bundle branches and the purkinje network to the ventricles. Activation of the ventricles occurs initially at the septum and apex of the heart and progresses towards the base of the heart, and from the endocardial surfaces towards the epicardial surfaces. Activation of the ventricles begins ~.15 sec after the atria. This delay between atrial and ventricular activation assures maximal ventricular filling. The sequence of activation within the ventricle insures efficient contraction and ejection by: i) stabilizing the septum and valve leaflets early in the contraction, and ii) activating from apex-to-base and endocardium-to-epicardium. The latter results in pushing the blood towards the aortic valve and
SIO 63/BME 511 3 Dr. Janis Burt February 19, 27 MRB 422; 626-6833 prevents cells located at the epicardial surface from having to contract against "flacid" cells near the endocardial surface. How do the electrical properties of the cells of the heart insure that this sequence occurs beat after beat? When this pathway of normal activation fails, what properties insure a back-up strategy for activation of the heart? What circumstances predispose the heart to arrhythmias? These are the questions we will address over the next week or two. II. Excitability in Ventricular, Atrial and Non-nodal Conducting Cells (Objectives 3 & 4) A. The Action potential: The action potentials of ventricular and non-nodal conduction system cells last for ~25-3 msec; atrial cell action potentials last ~15 msec. These long duration potentials are characterized by several phases (-4) as shown in Figure 1. hase 4 -- diastole or rest. The resting permeability of the ventricular cell membrane is dominated by potassium. Ventricular cells have an approximate ten fold higher resting permeability to potassium than do skeletal muscle or nerve cells. This high resting potassium permeability (like the high chloride permeability in skeletal muscle) stabilizes the resting membrane potential reducing the risk of arrhythmias by necessitating a large stimulus to excite the cells. The ventricles are thereby rendered slaves to the pacemaker cells of the heart. The permeabilities of Na and Cl (relative to potassium) are ( K : Cl : Na ) 1 :.1 :.5. Note that the ventricular cell is more permeable to Na + at rest than other excitable cells. As a consequence of the high Na + permeability, the density of Na,K-ATase enzymes in the membrane is high. Since this pump is electrogenic, its activity contributes several millivolts to the resting membrane potential. hase -- action potential upstroke. As in skeletal muscle and nerve the upstroke results from an increase in Na. The voltage gated Na channel expressed in the heart is a different gene product than that expressed by skeletal muscle or neural tissues. hase 1 -- early repolarization. The ionic basis of this phase is a transient increase in potassium permeability (I K-to ) and Na-channel inactivation. hase 2 -- plateau. This is the most distinctive feature of the cardiac action potential. The plateau requires two changes in membrane permeability: 1) an increase in calcium permeability through voltage-activated, L-type Ca channels that are dihydrophyridine sensitive; and 2) a decrease in potassium permeability. During the plateau phase potassium permeability is ~ 1/1 the resting potassium permeability. This decrease in K is indirectly voltage dependent at depolarized potentials Mg 2+ enters and blocks the I K1 channels. hase 3 -- repolarization. Repolarization occurs as Ca 2+ channels inactivate and voltage activated K channels open (delayed rectifiers - I K ). As repolarization proceeds the I K channels deactivate and the Mg 2+ block of the I K1 channels is relieved, which restores the resting permeabilities of the membrane. Figure 1 Action potential and underlying permeability changes for ventricular and purkinje cells. (modified from reference 2) 1 1 * 2 3 4
SIO 63/BME 511 4 Dr. Janis Burt February 19, 27 MRB 422; 626-6833 It is interesting to note that the permeability of most excitable cells is lowest when the membrane potential is at the resting level. This conserves energy by reducing the number of Na + and K + ions that need to be pumped. Cardiac tissue is the exception to the rule. The cardiac cell s overall membrane permeability is actually less during the active phase (dominated by the plateau) than during the rest phase. In large part, this difference reflects high resting permeability to K + and the block of the underlying potassium channels (I K1 ) that occurs with depolarization. Lower permeability during activation is advantageous to the heart during high heart rates because K + efflux is spared and the energy required to restore that K + to the intracellular space (via the Na,K-ATase) conserved for contraction. Figure 2 - Epinephrine (black vs. grey curves) shortens the ventricular action potential by enhancing I Ca-L and I K. (modified from reference 2) Sympathetic and arasympathetic Control The ventricles are well innervated by sympathetic fibers that release norepinephrine. This transmitter binds to β-adrenergic receptors, which transduce the activation of protein kinase A. This kinase enhances the activity of I Ca-L and I K channels (see figure 2). In addition to delivering more calcium to the contractile apparatus (stronger contractions), these changes in channel activity cause a shortening of the action potential s duration. B. Refractory eriods (Objective 5) Due to the activation/inactivation characteristics of the voltage-gated Na + channel underlying phase, cardiac muscle is refractory to stimulation until it is repolarized. At the cellular level, the period of time during which no action potential can be initiated, regardless of stimulus strength, is called the absolute refractory period (AR - Figure 1). At the tissue level, the absolute refractory period translates into the effective refractory period, which is defined as the period of time during which no propagated action potentials can be elicited. The AR lasts until the membrane potential repolarizes to levels more negative than -65 mv. The AR is followed by a period in which an action potential can be elicited but the stimulus required is larger than normal and the amplitude of the elicited action potential is abnormally small. This period is the relative refractory period (RR). As the membrane potential repolarizes an increasing fraction of the total Na + channels becomes available for activation (Figure 3). Thus, a stimulus delivered at the beginning of the RR will elicit an action potential of small amplitude, and one delivered towards the end of the RR will elicit an action potential of larger amplitude. The RR is followed by the supranormal period (SN) during which a slightly smaller than normal stimulus elicits a normal propagated response. Full recovery time (FRT) represents the time after which a normal action potential can be elicited with a normal stimulus. 1 Figure 3 - Na-channel availability determines the refractory properties of the heart. (modified from reference 2) Repolarize % Na Channels Available FRT SN RR AR otential (mv)
SIO 63/BME 511 5 Dr. Janis Burt February 19, 27 MRB 422; 626-6833 The refractory properties of the cardiac cell are suited to the function of the organ. The timing of the electrical and contractile events is such that the heart relaxes before it can contract again (Figure 4). At a heart rate of 72 beats/min (bpm) and action potential duration of ~3 msec, the time between beats (referred to as electrical diastole) is around 53 msec. At a heart rate of 2 bpm and an action potential duration of 3 msec the interval between beats would be msec. Since it is during diastole that the heart has time to fill with blood, it is clear that in order to be an effective pump at fast heart rates the duration of the action potential must decrease. In general, the duration of the action potential varies inversely with the frequency. Shortening of the action potential reflects the effects of sympathetic drive on Ca and K channel function. C. Action otential Duration Action potential duration, even within the ventricle, varies. The purkinje fibers have the longest duration (~3 or longer msec at resting heart rates), atrial cells the shortest (15-2msec at resting heart rates); within the ventricle cells closest to the chamber have longer duration action potentials than the those at the epicardial surface. Figure 4 - Cardiac contraction is nearly complete with the onset of phase 4 (top panel). Consequently, tetanus is not possible in this muscle type. In skeletal muscle, repolarization occurs early in contraction, making summation and tetanus possible. otential (mv) otential This latter comparison is worth remembering the ramifications of this are that despite depolarizing after ventricular cells near the endocardium, the epicardial cells repolarize first. How can so many different durations result from the same types of channels? Although all these cells have the same array of channel types, their relative numbers differ considerably. You might expect that delayed rectifiers would be more numerous in cells with shorter duration action potentials, if so, you would be correct. You might also expect that Ca-channel density is lower in regions with short action potentials, this too is true. +5 1-85 3 msec References Cited in Figures: 1. hysiology by L.S. Costanzo. W.B. Saunders Co., hiladelphia, 1998. 2. hysiology of the Heart (2nd ed.) by A.M. Katz, Raven ress, N.Y. 1992. 3. Ionic Channels of Excitable s by Bertil Hille. (mv) 2 Tension 3 4 Tension