Appraisal
and reappraisal
Edited
C. DeGraff
bv Arthur
and Julian
of cardiac therapy
Frieden
Electrophysiology and pharmacology of cardiac arrhythmias IX. Cardiac electrophysiologic effects of beta adrenergic receptor stimulation and blockade. Part A Andrew L. Wit, Ph.D.” Brian F. Hoffman, M.D. Michael R. Rosen, M.D.* Neu
York.
N. I’.
The effects of the sympathetic nervous system on the heart are partly or wholly responsible for many cardiac arrhythmias and pharmacological agents which interfere with these actions may therefore be antiarrhythmic. Of all the drugs which can prevent or counteract sympathetic effects on the heart, the beta receptor blocking drugs have achieved the greatest usefulness as antiarrhythmic agents. In order to comprehend how these drugs exert a cardiac antiarrhythmic effect, an understanding of the electrophysiological effects of sympathetic activation and catecholamines is required. We first will consider these effects and then discuss the antiarrhythmic properties of beta receptor blocking drugs. In addition, beta receptor blocking drugs affect cardiac electrophysiology by means other than sympathetic inhibition and the importance of these actions also will be considered. I. The
sympathetic
innervation
of the
heart
The human heart is richly innervated by the sympathetic nervous system. The cardiac branches of the sympathetic trunk arise in the cervical and thoracic regions and contribute to and form the cardiac plexi which lie on the anterior and posterior walls of the pulmonary From the Department of Pharmacoiogy, of Physicians and Surgeons, New York, Certain United 08508.
Columbia N. Y.
University
of the studies reported in this review were supported States Public Health Service Grants HL-12738
Received
for publication
June
*Drs. Wit and Rosen are Senior Association
October,
College in part by and HL-
23, 1975. Investigators
of the New
1975, Vol. 90, No. 4, pp. 521-533
York
Heart
truncus.’ Extensions of these pulmonary plexi form additional nerve networks over the atria and ventricles. The postganglionic sympathetic fibers from these nerve networks innervate all types of cardiac fibers although they are most dense in the sinus and atrioventricular (AV) nodes.“’ Adrenergic nerve fiber density also is high throughout the atria although not to the extent seen in the nodes. Ventricular muscle fibers receive ext,ensive sympathetic innervation but the density of nerve endings varies markedly in different regions.,’ Compared to other regions of the heart, the Purkinje system appears to have only limited adrenergic innervation.” !I. The
beta
adrenergic
receptors
The catecholamine, norepinephrine, is released from post ganglionic sympathetic nerve terminals on activation of these nerves. In 1906 Sir Henry Dale postulated that catecholamines interact with receptors on the effector organ to cause their physiological effect.’ Subsequent studies by AhlquistG demonstrated that functionally there appears to be two types of catecholamine receptors on effector organs: (1) an adrenergic receptor which, when activated, usually gives rise to an excitatory response such as the hypertensive response to norepinephrine resulting from arteriolar constriction, and (2) an adrenergic receptor which in most tissues is responsible for an inhibitory response such as the hypotensive response to epinephrine due to arteriolar dilatation. The excitatory receptor was termed the alpha receptor, and the inhibitory receptor, the beta receptor. Some tissues have variable numbers of both
American
Heart
CJournaI
521
Wit,
HoEman,
HO-
and
Roeen
0 /\
-
CH I OH
CH,-
NH,
HO/
CATEC
HOL
RING
FTHANOLAMfNE SfDE
\
\
CHAIN I
\
I \
I
CELL MEMBRAN ATP+CYCLlC
AMP
PHYsloLoGlC RESPONSE Fig. 1. Schematic representation of the mechanism of catecholamine action. The structure of the catecholamine norepinephrine is shown above. Binding of the catechol at the ring hydroxyls to the beta receptor on the cell membrane is probably an important factor in “activating” the receptor. The ethanolamine side chain of the catecholamine molecule may be an additional binding site. Binding of the catecholamine molecule to the beta receptor activates adenyl cyclase located in the membrane which converts ATP to cyclic AMP. This results in the physiologic response. (Adapted from Lefkowitz, R. J.: Isolated hormone receptors; physiologic and clinical implications, N. Engl. J. Med. 288: 1061, 1973.)
receptors; others have only one receptor type. Although the heart contains mostly beta receptors, in this organ beta receptor stimulation results in an excitatory (e.g., increased contractility, rate, etc.) rather than an inhibitory response. These responses are blocked by beta receptor blocking drugs. The identity of the catecholamine beta receptor and how it functions to cause a physiological response when it interacts with catecholamines have been the subject of intense investigation for many years.’ These investigations have suggested that the beta receptor is probably composed of protein binding sites with crucially located sulfhydryl groups, located on the outer surface of the
522
cell membrane. Once norepinephrine is releasec from the nerve terminal, it may bind to the oute; surface of the cell membrane at these binding sites? (Fig. 1). Binding of the neurotransmittel may occur at several distinct points of contact One likely point of attachment is at the catecho ring which might be bound through the two ring hydroxyls.7 Experimental evidence suggests an additional binding site which is specific for and attaches to the ethanolamine side chain of the catecholamine molecule (Fig. 1). No structural alterations of the catecholamine molecule occur consequent to its binding to the cell membrane and it is not consumed by virtue of its reaction with the receptor.’ Beta adrenergic receptors in different tissues may have different properties. The beta receptors in the heart have been designated as beta,, those in other tissues as beta, based in part upon their different susceptibility to blockade by certain beta blocking drugs (see below).” Although this concept is still in the investigative stage, a difference between properties of beta receptors in the heart and beta receptors in other tissues has important clinical implications since it should permit the development of pharmacological agents to specifically stimulate or block the cardiac beta receptor without affecting other tissues. At present there are several agents which show a relatively greater specificity for interacting with beta, receptors than with beta, receptors.!’ Binding of catecholamines to the beta receptor triggers a series of reactions which eventually lead to the physiological response. The exact nature of these reactions is uncertain but it has been suggested that the formation of cyclic adenosine monophosphate (CAMP) may be the link between beta receptor stimulation and the response of the target organ. Studies of a variety of tissues have shown that beta receptor stimulation increases the activity of the membrane bound enzyme, adenylate cyclase. Adenylate cyclase then catalyzes the formation of CAMP from ATP.‘” The sequence of events can be prevented by beta receptor blockade. The exact manner by which the formation of CAMP causes the subsequent physiological reaction is uncertain but some possibilities are discussed in a later section. Caution must still be applied in interpreting the experimental evidence, however, as the increase in cyclic AMP levels which results from beta re-
October,
1975, Vol. 90, No. 4
Electrophysiology and pharmacology of cardiac arrhythmias
Fig. 2. Catecholamine induced spontaneous activity in a canine Purkinje fiber (I-‘anel A) and in a human specialized atria1 fiber (Panel B). Norepinephrine caused the appearance of spontaneous diastolic depolarization in R. J.: Isolated hormone receptors; physiologic and ciinical both fiber types. (Adapted from Lefkowitz, implications, N. Engl. J. Med. 288: 1061, 1973. Reproduced by permission.)
ceptor activation the physiological III. The effects normal cardiac
may not be causally response.
related
of beta-adrenergic stimulation cellular electrophysiology
to on
Cardiac beta adrenergic receptor stimulation either by norepinephrine released from intrinsic cardiac sympathetic nerves, or by exogenously administered catecholamines, elicits a wide variety of electrophysiological responses in different fibers. Such stimulation also results in positive inotropy. Recent studies have also indicated that some electrophysiological responses to catecholamines are mediated by alpha receptor stimulation. However, unless we specifically indicate that a response is due to alpha receptor stimulation, it can be assumed that it results from activation of beta receptors. Sinus node. The action potentials of pacemaker cells within the sinus node show marked spontaneous diastolic (phase 4) depolarization, which proceeds to threshold potential, initiating the regenerative depolarization phase of the action potential. Sympathetic stimulation or catecholamines predominantly increase the slope of phase 4 depolarization (accelerate the decline in membrane potential from maximum diastolic to threshold potential) and thereby shorten the cycle length between spontaneous action potentials. There is little consistent effect on maximum diastolic potential, although it may be increased slightly.“-’ i If this does occur, it probably is not sufficient to affect spontaneous firing rate. The effect of catecholamines on threshold potential of sinus node fibers is also uncertain and does not explain the acceleratory effects of catecholamines on impulse initiation. An increase in rate of rise of phase 0 depolarization and overshoot of the sinus node action potential also occur as a consequence of catecholamine action. It is
American Heart Journal
uncertain whether this represents a direct effect on the magnitude of inward current during the action potential or is secondary to the enhanced phase 4 depolarization; in sinus node fibers, unlike Purkinje fibers, enhancing phase 4 depolarization may increase q,,,,, and amplitude of the action potential upstroke.” An additional effect of symphathetic nerve stimulation is to shift the pacemaker site within the sinus node.‘: This may be a consequence of the uneven distribution of nerve fibers within the node. Sympathetic activation may result in greater increase in local concentration of norepinephrine in some regions of the node more than in others, enhancing phase 4 depolarization more in some nodal fibers than in others, and causing a shift in the pacemaker site to the nodal fibers which have the great,est response. A second possible mechanism for the pacemaker shift is that some sinus node fibers may be more sensitive to t,he actions of catecholamine than others, although this has not been proved. Atrium. Beta adrenergic receptor stimulation has little effect on the action potential of working atria1 myocardium. Catecholamines may accelerate slightly the time course of repolarization in some species (dog, cat), and prolong it in others (rabbit, guinea pig, rat).‘& Part of t,his effect may be due to stimulation of alpha adrenergic receptors. ’ ., Catecholamines in high concentrations accelerate repolarization of normal human working atria1 myocardial cells. When rest,ing membrane potential and Qnlal of phase 0 are within the normal range, catecholamines do not affect these electrophysiological parameters. Catecholamines, and presumably sympathetic stimulation, do have significant effects on “specialized” atria1 fibers located in the crista terminalis. Such fibers have “Purkinje-like” action potentials; there is a significant plateau phase
523
Wit, Hoffman,
and Rosen
CL= l750mmr~c
-1 MOomsk
Fig. 3. Effects of catecholamines on action potentials of cardiac fibers in the mitral valve leaflet of the monkey. The top panel shows control recordings. Only the bottom part of the action potential is displayed. Note that the fiber repolarizes to a membrane potential which is more negative than the membrane potential at which the upstroke is initiated, and then membrane potential gradually declines. The middle panel shows the effects of 1 ag/ml., epinephrine. The catecholamine has elicited a delayed after-depolarization (arrow) which does not result in a regenerative action potential. The bottom panel demonstrates the effects of decreasing stimulus cycle length on the amplitude of the catecholamine induced after depolarization. The stimulus cycle length was abruptly decreased from 2500 msec. (not shown) to 1750 msec. At this stimulus cycle length the amplitude of the after depolarization gradually increased yirst 4 action potentials.) After the fifth stimulated action potential (arrow) the after depolarization reached threshold and continuous spontaneous activity occurred.
during repolarization and these cells may develop spontaneous diastolic depolarization.‘” Betaadrenergic stimulation results in the appearance of spontaneous diastolic depolarization in fibers which do not demonstrate this phenomenon prior to stimulation, or enhances the slope of phase 4 depolarization in fibers in which it is present prior to catecholamine administration (Fig. 2). As a result, these atria1 fibers may spontaneously initiate action potentials and function as pacemaker cells.“’ Catecholamines also enhance pacemaker activity in atria1 fibers in the mitral valve leaflet.” This effect is exerted by a mechanism differing from that which occurs in the atrium or sinus node. Catecholamines initiate a delayed afterdepolarization in mitral valve fibers, the amplitude of which is rate sensitive (Fig. 3). In the presence of catecholamines an increase in the rate at which mitral valve fibers are stimulated results in an increase in the amplitude of the catecholamine 524
induced delayed afterdepolarization until it reaches threshold, at which time spontaneous action potentials occur.‘x The mitral valve leaflets are richly innervated with adrenergic fibers indicating that these effects may occur in situ as well as in vitro.” Atrioventricular (AV) node. Beta adrenergic receptor stimulation improves or speeds impulse conduction through the AV node. The exact cellular effects of catecholamines which cause this response have not been studied in detail due to the technical difficulties of maintaining action potential recordings from single nodal fibers during exposure to catecholamines. Nevertheless, some data are available. Electrophysiologically, the AV node is composed of several different regions, each of which has its characteristic action potentials. Fibers in the upper (AN) region have low maximum diastolic potentials, and action potentials with a slow upstroke which may have several notches, and a low amplitude. Much of October,
1975, Vol. 90, No. 4
Electrophysiology
AC-CC
ZOOO-+G
titCL630--1~
and pharmacology
of cardiac
arrhythmias
tllS%C
4. Catecholamine induced hyperpolarization of a canine Purkinje tiher. Panel A shows the transmembrane action potential recorded from an electrically stimulated Purkinje fiber with a low resting potential tapproximately -6.5 mV.). At this membrane potential the Na carrier system is mostly inactivated and therefore upstroke velocity is low and the cell does not depolarize to positive potentials (top trace = 0 potential). Epinephrine was added to the perfusion fluid between panels A and B at the arrow. In panels B through G resting membrane potential, velocity and amplitude of depolarization all increase as a result of the epinephrine effect. The increase in upstroke velocity is indicated on the bottom trace of panels D to (; hy the height of the differentiated signal of the upstroke velocity. In panel H the rate of electrical stimulation is itrc,reased and in pane/ I t.he Purkinje fiber action potential and the differentiated signal of the upstroke velocity are displayed at a more rapid sweep speed. Epinephrine has restored a normal looking action potential t C’ompcrre panels A and I) From Singer, I). H., Lazzara, R., and Hoffman, B. F.: Interrelationships between automaticity and conduction in Purkinje fiber
and reappraisal
Edited
C. DeGraff
bv Arthur
and Julian
of cardiac therapy
Frieden
Electrophysiology and pharmacology of cardiac arrhythmias IX. Cardiac electrophysiologic effects of beta adrenergic receptor stimulation and blockade. Part A Andrew L. Wit, Ph.D.” Brian F. Hoffman, M.D. Michael R. Rosen, M.D.* Neu
York.
N. I’.
The effects of the sympathetic nervous system on the heart are partly or wholly responsible for many cardiac arrhythmias and pharmacological agents which interfere with these actions may therefore be antiarrhythmic. Of all the drugs which can prevent or counteract sympathetic effects on the heart, the beta receptor blocking drugs have achieved the greatest usefulness as antiarrhythmic agents. In order to comprehend how these drugs exert a cardiac antiarrhythmic effect, an understanding of the electrophysiological effects of sympathetic activation and catecholamines is required. We first will consider these effects and then discuss the antiarrhythmic properties of beta receptor blocking drugs. In addition, beta receptor blocking drugs affect cardiac electrophysiology by means other than sympathetic inhibition and the importance of these actions also will be considered. I. The
sympathetic
innervation
of the
heart
The human heart is richly innervated by the sympathetic nervous system. The cardiac branches of the sympathetic trunk arise in the cervical and thoracic regions and contribute to and form the cardiac plexi which lie on the anterior and posterior walls of the pulmonary From the Department of Pharmacoiogy, of Physicians and Surgeons, New York, Certain United 08508.
Columbia N. Y.
University
of the studies reported in this review were supported States Public Health Service Grants HL-12738
Received
for publication
June
*Drs. Wit and Rosen are Senior Association
October,
College in part by and HL-
23, 1975. Investigators
of the New
1975, Vol. 90, No. 4, pp. 521-533
York
Heart
truncus.’ Extensions of these pulmonary plexi form additional nerve networks over the atria and ventricles. The postganglionic sympathetic fibers from these nerve networks innervate all types of cardiac fibers although they are most dense in the sinus and atrioventricular (AV) nodes.“’ Adrenergic nerve fiber density also is high throughout the atria although not to the extent seen in the nodes. Ventricular muscle fibers receive ext,ensive sympathetic innervation but the density of nerve endings varies markedly in different regions.,’ Compared to other regions of the heart, the Purkinje system appears to have only limited adrenergic innervation.” !I. The
beta
adrenergic
receptors
The catecholamine, norepinephrine, is released from post ganglionic sympathetic nerve terminals on activation of these nerves. In 1906 Sir Henry Dale postulated that catecholamines interact with receptors on the effector organ to cause their physiological effect.’ Subsequent studies by AhlquistG demonstrated that functionally there appears to be two types of catecholamine receptors on effector organs: (1) an adrenergic receptor which, when activated, usually gives rise to an excitatory response such as the hypertensive response to norepinephrine resulting from arteriolar constriction, and (2) an adrenergic receptor which in most tissues is responsible for an inhibitory response such as the hypotensive response to epinephrine due to arteriolar dilatation. The excitatory receptor was termed the alpha receptor, and the inhibitory receptor, the beta receptor. Some tissues have variable numbers of both
American
Heart
CJournaI
521
Wit,
HoEman,
HO-
and
Roeen
0 /\
-
CH I OH
CH,-
NH,
HO/
CATEC
HOL
RING
FTHANOLAMfNE SfDE
\
\
CHAIN I
\
I \
I
CELL MEMBRAN ATP+CYCLlC
AMP
PHYsloLoGlC RESPONSE Fig. 1. Schematic representation of the mechanism of catecholamine action. The structure of the catecholamine norepinephrine is shown above. Binding of the catechol at the ring hydroxyls to the beta receptor on the cell membrane is probably an important factor in “activating” the receptor. The ethanolamine side chain of the catecholamine molecule may be an additional binding site. Binding of the catecholamine molecule to the beta receptor activates adenyl cyclase located in the membrane which converts ATP to cyclic AMP. This results in the physiologic response. (Adapted from Lefkowitz, R. J.: Isolated hormone receptors; physiologic and clinical implications, N. Engl. J. Med. 288: 1061, 1973.)
receptors; others have only one receptor type. Although the heart contains mostly beta receptors, in this organ beta receptor stimulation results in an excitatory (e.g., increased contractility, rate, etc.) rather than an inhibitory response. These responses are blocked by beta receptor blocking drugs. The identity of the catecholamine beta receptor and how it functions to cause a physiological response when it interacts with catecholamines have been the subject of intense investigation for many years.’ These investigations have suggested that the beta receptor is probably composed of protein binding sites with crucially located sulfhydryl groups, located on the outer surface of the
522
cell membrane. Once norepinephrine is releasec from the nerve terminal, it may bind to the oute; surface of the cell membrane at these binding sites? (Fig. 1). Binding of the neurotransmittel may occur at several distinct points of contact One likely point of attachment is at the catecho ring which might be bound through the two ring hydroxyls.7 Experimental evidence suggests an additional binding site which is specific for and attaches to the ethanolamine side chain of the catecholamine molecule (Fig. 1). No structural alterations of the catecholamine molecule occur consequent to its binding to the cell membrane and it is not consumed by virtue of its reaction with the receptor.’ Beta adrenergic receptors in different tissues may have different properties. The beta receptors in the heart have been designated as beta,, those in other tissues as beta, based in part upon their different susceptibility to blockade by certain beta blocking drugs (see below).” Although this concept is still in the investigative stage, a difference between properties of beta receptors in the heart and beta receptors in other tissues has important clinical implications since it should permit the development of pharmacological agents to specifically stimulate or block the cardiac beta receptor without affecting other tissues. At present there are several agents which show a relatively greater specificity for interacting with beta, receptors than with beta, receptors.!’ Binding of catecholamines to the beta receptor triggers a series of reactions which eventually lead to the physiological response. The exact nature of these reactions is uncertain but it has been suggested that the formation of cyclic adenosine monophosphate (CAMP) may be the link between beta receptor stimulation and the response of the target organ. Studies of a variety of tissues have shown that beta receptor stimulation increases the activity of the membrane bound enzyme, adenylate cyclase. Adenylate cyclase then catalyzes the formation of CAMP from ATP.‘” The sequence of events can be prevented by beta receptor blockade. The exact manner by which the formation of CAMP causes the subsequent physiological reaction is uncertain but some possibilities are discussed in a later section. Caution must still be applied in interpreting the experimental evidence, however, as the increase in cyclic AMP levels which results from beta re-
October,
1975, Vol. 90, No. 4
Electrophysiology and pharmacology of cardiac arrhythmias
Fig. 2. Catecholamine induced spontaneous activity in a canine Purkinje fiber (I-‘anel A) and in a human specialized atria1 fiber (Panel B). Norepinephrine caused the appearance of spontaneous diastolic depolarization in R. J.: Isolated hormone receptors; physiologic and ciinical both fiber types. (Adapted from Lefkowitz, implications, N. Engl. J. Med. 288: 1061, 1973. Reproduced by permission.)
ceptor activation the physiological III. The effects normal cardiac
may not be causally response.
related
of beta-adrenergic stimulation cellular electrophysiology
to on
Cardiac beta adrenergic receptor stimulation either by norepinephrine released from intrinsic cardiac sympathetic nerves, or by exogenously administered catecholamines, elicits a wide variety of electrophysiological responses in different fibers. Such stimulation also results in positive inotropy. Recent studies have also indicated that some electrophysiological responses to catecholamines are mediated by alpha receptor stimulation. However, unless we specifically indicate that a response is due to alpha receptor stimulation, it can be assumed that it results from activation of beta receptors. Sinus node. The action potentials of pacemaker cells within the sinus node show marked spontaneous diastolic (phase 4) depolarization, which proceeds to threshold potential, initiating the regenerative depolarization phase of the action potential. Sympathetic stimulation or catecholamines predominantly increase the slope of phase 4 depolarization (accelerate the decline in membrane potential from maximum diastolic to threshold potential) and thereby shorten the cycle length between spontaneous action potentials. There is little consistent effect on maximum diastolic potential, although it may be increased slightly.“-’ i If this does occur, it probably is not sufficient to affect spontaneous firing rate. The effect of catecholamines on threshold potential of sinus node fibers is also uncertain and does not explain the acceleratory effects of catecholamines on impulse initiation. An increase in rate of rise of phase 0 depolarization and overshoot of the sinus node action potential also occur as a consequence of catecholamine action. It is
American Heart Journal
uncertain whether this represents a direct effect on the magnitude of inward current during the action potential or is secondary to the enhanced phase 4 depolarization; in sinus node fibers, unlike Purkinje fibers, enhancing phase 4 depolarization may increase q,,,,, and amplitude of the action potential upstroke.” An additional effect of symphathetic nerve stimulation is to shift the pacemaker site within the sinus node.‘: This may be a consequence of the uneven distribution of nerve fibers within the node. Sympathetic activation may result in greater increase in local concentration of norepinephrine in some regions of the node more than in others, enhancing phase 4 depolarization more in some nodal fibers than in others, and causing a shift in the pacemaker site to the nodal fibers which have the great,est response. A second possible mechanism for the pacemaker shift is that some sinus node fibers may be more sensitive to t,he actions of catecholamine than others, although this has not been proved. Atrium. Beta adrenergic receptor stimulation has little effect on the action potential of working atria1 myocardium. Catecholamines may accelerate slightly the time course of repolarization in some species (dog, cat), and prolong it in others (rabbit, guinea pig, rat).‘& Part of t,his effect may be due to stimulation of alpha adrenergic receptors. ’ ., Catecholamines in high concentrations accelerate repolarization of normal human working atria1 myocardial cells. When rest,ing membrane potential and Qnlal of phase 0 are within the normal range, catecholamines do not affect these electrophysiological parameters. Catecholamines, and presumably sympathetic stimulation, do have significant effects on “specialized” atria1 fibers located in the crista terminalis. Such fibers have “Purkinje-like” action potentials; there is a significant plateau phase
523
Wit, Hoffman,
and Rosen
CL= l750mmr~c
-1 MOomsk
Fig. 3. Effects of catecholamines on action potentials of cardiac fibers in the mitral valve leaflet of the monkey. The top panel shows control recordings. Only the bottom part of the action potential is displayed. Note that the fiber repolarizes to a membrane potential which is more negative than the membrane potential at which the upstroke is initiated, and then membrane potential gradually declines. The middle panel shows the effects of 1 ag/ml., epinephrine. The catecholamine has elicited a delayed after-depolarization (arrow) which does not result in a regenerative action potential. The bottom panel demonstrates the effects of decreasing stimulus cycle length on the amplitude of the catecholamine induced after depolarization. The stimulus cycle length was abruptly decreased from 2500 msec. (not shown) to 1750 msec. At this stimulus cycle length the amplitude of the after depolarization gradually increased yirst 4 action potentials.) After the fifth stimulated action potential (arrow) the after depolarization reached threshold and continuous spontaneous activity occurred.
during repolarization and these cells may develop spontaneous diastolic depolarization.‘” Betaadrenergic stimulation results in the appearance of spontaneous diastolic depolarization in fibers which do not demonstrate this phenomenon prior to stimulation, or enhances the slope of phase 4 depolarization in fibers in which it is present prior to catecholamine administration (Fig. 2). As a result, these atria1 fibers may spontaneously initiate action potentials and function as pacemaker cells.“’ Catecholamines also enhance pacemaker activity in atria1 fibers in the mitral valve leaflet.” This effect is exerted by a mechanism differing from that which occurs in the atrium or sinus node. Catecholamines initiate a delayed afterdepolarization in mitral valve fibers, the amplitude of which is rate sensitive (Fig. 3). In the presence of catecholamines an increase in the rate at which mitral valve fibers are stimulated results in an increase in the amplitude of the catecholamine 524
induced delayed afterdepolarization until it reaches threshold, at which time spontaneous action potentials occur.‘x The mitral valve leaflets are richly innervated with adrenergic fibers indicating that these effects may occur in situ as well as in vitro.” Atrioventricular (AV) node. Beta adrenergic receptor stimulation improves or speeds impulse conduction through the AV node. The exact cellular effects of catecholamines which cause this response have not been studied in detail due to the technical difficulties of maintaining action potential recordings from single nodal fibers during exposure to catecholamines. Nevertheless, some data are available. Electrophysiologically, the AV node is composed of several different regions, each of which has its characteristic action potentials. Fibers in the upper (AN) region have low maximum diastolic potentials, and action potentials with a slow upstroke which may have several notches, and a low amplitude. Much of October,
1975, Vol. 90, No. 4
Electrophysiology
AC-CC
ZOOO-+G
titCL630--1~
and pharmacology
of cardiac
arrhythmias
tllS%C
4. Catecholamine induced hyperpolarization of a canine Purkinje tiher. Panel A shows the transmembrane action potential recorded from an electrically stimulated Purkinje fiber with a low resting potential tapproximately -6.5 mV.). At this membrane potential the Na carrier system is mostly inactivated and therefore upstroke velocity is low and the cell does not depolarize to positive potentials (top trace = 0 potential). Epinephrine was added to the perfusion fluid between panels A and B at the arrow. In panels B through G resting membrane potential, velocity and amplitude of depolarization all increase as a result of the epinephrine effect. The increase in upstroke velocity is indicated on the bottom trace of panels D to (; hy the height of the differentiated signal of the upstroke velocity. In panel H the rate of electrical stimulation is itrc,reased and in pane/ I t.he Purkinje fiber action potential and the differentiated signal of the upstroke velocity are displayed at a more rapid sweep speed. Epinephrine has restored a normal looking action potential t C’ompcrre panels A and I) From Singer, I). H., Lazzara, R., and Hoffman, B. F.: Interrelationships between automaticity and conduction in Purkinje fiber
