18
Subject Review Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology WIN-KUANG SHEN, M.D., AND YOSHIHISA KURACHI, M.D., PH.D. Objective: To provide insights into the molecular mechanisms of adenosine-mediated cardiac cellular electrophysiology and how information about these mechanisms can be used to facilitate diagnostic and therapeutic approaches to various clinical arrhythmias. Design: A review of (1) adenosine metabolism and receptors in the cardiac system, (2) adenosine- mediated signal transduction pathways in the regula- tion of cellular electrophysiology in various cardiac cell types, and (3) the clinical usefulness of adenosine in cardiac electrophysiology is presented. Results: The effects of adenosine on cardiac electrophysiologic properties are consequences of complex interactions among the specific cardiac tar- get structures, the density and type of adenosine re- ceptors, and the effector systems. The easy applica- tion of adenosine and its short half-life, favorable side- effects profile, and electrophysiologic properties make Adenosine, a natural metabolic substance, is ubiquitous in all living cells. Under physiologic and pathophysiologic condi- tions, adenosine is released from cells, and it interacts with specific cell membrane receptors to modulate cell function in an autocrine or paracrine manner.'? The events that are modulated include heart rate and contractility, smooth muscle tone, sedation, release of neurotransmitters, glycoly- sis, and lipolysis as well as renal, platelet, leukocyte, and endothelial cell functions. During the past decade, major advances have been made in understanding the underlying mechanisms of adenosine-mediated cell functions. In the cardiac system, adenosine decreases spontaneous depolarization (that is, pacemaker activity) in the sinus node and conduction velocity in the atrioventricular node.' Its direct negative chronotropic and dromotropic properties are the basis for its wide diagnostic and therapeutic application From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. W.-K. Shen, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. it an excellent diagnostic and therapeutic tool for the initial assessment of various tachyarrhythmias. Conclusion: The direct adenosine-activated K ACh (potassium acetylcholine) channel signal transduction system explains the effects of adenosine on the sinus node, atrioventricular node, and atrial myocardium. The indirect adenosine-inhibited adenylate cyclase system accounts for its negative inotropic effects on the catecholamine-entrained contractility in atrial and ventricular myocardium. Because of the recent purification and cloning of adenosine receptors and subunits of G proteins, additional adenosine-mediated electrophysiologic mechanisms can be explored. (Mayo Clin Proc 1995; 70:274-291) AMP = adenosine monophosphate; ATP = adenosine triphos- phate; GDP = guanosine diphosphate; GTP = guanosine trio phosphate; lea and I K =calcium current and potassium current; K and K ACh = potassium and potassium acetylcholine; PTX = pertussis toxin; SAH =S-adenosyl homocystine in patients with supraventricular tachycardia.V In atrial tissue, adenosine produces a negative inotropic effect by activating the adenosine-sensitive potassium (K) channel under basal conditions" as well as by attenuating catechol- amine-stimulated contractility and cyclic adenosine mono- phosphate (AMP) accumulation under enhanced autonomic conditions."!' In ventricular tissue, adenosine minimally affects the ventricular inotropic state under basal condi- tions;'? however, it negates the catecholamine-enhanced contractility and decreases catecholamine-induced triggered activity by inhibiting adenylate cyclase activity and cyclic AMP production. 13-16 These complex physiologic responses result from different adenosine-modulated receptor-effector pathways. Herein our review focuses on the molecular mechanisms of adenosine-regulated cardiac cellular electrophysiologic activities and how information about these mechanisms can be applied to facilitate the diagnostic and therapeutic ap- proaches to various clinical arrhythmias. First, we discuss adenosine metabolism and receptors in the cardiac system. Second, we provide details about adenosine-mediated signal transduction pathways in various cardiac cell types. Third, Mayo Clin Proc 1995; 70:274-291 274 © 1995 Mayo Foundation for Medical Education and Research For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology

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Page 1: Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology

Subject Review

Mechanisms of Adenosine-Mediated Actions on Cellular andClinical Cardiac Electrophysiology

WIN-KUANG SHEN, M.D., AND YOSHIHISA KURACHI, M.D., PH.D.

• Objective: To provide insights into the molecularmechanisms of adenosine-mediated cardiac cellularelectrophysiology and how information about thesemechanisms can be used to facilitate diagnostic andtherapeutic approaches to various clinicalarrhythmias.

• Design: A review of (1) adenosine metabolismand receptors in the cardiac system, (2) adenosine­mediated signal transduction pathways in the regula­tion of cellular electrophysiology in various cardiaccell types, and (3) the clinical usefulness of adenosinein cardiac electrophysiology is presented.

• Results: The effects of adenosine on cardiacelectrophysiologic properties are consequences ofcomplex interactions among the specific cardiac tar­get structures, the density and type of adenosine re­ceptors, and the effector systems. The easy applica­tion of adenosine and its short half-life, favorable side­effects profile, and electrophysiologic properties make

Adenosine, a natural metabolic substance, is ubiquitous in allliving cells. Under physiologic and pathophysiologic condi­tions, adenosine is released from cells, and it interacts withspecific cell membrane receptors to modulate cell function inan autocrine or paracrine manner.'? The events that aremodulated include heart rate and contractility, smoothmuscle tone, sedation, release of neurotransmitters, glycoly­sis, and lipolysis as well as renal, platelet, leukocyte, andendothelial cell functions. During the past decade, majoradvances have been made in understanding the underlyingmechanisms of adenosine-mediated cell functions.

In the cardiac system, adenosine decreases spontaneousdepolarization (that is, pacemaker activity) in the sinus nodeand conduction velocity in the atrioventricular node.' Itsdirect negative chronotropic and dromotropic properties arethe basis for its wide diagnostic and therapeutic application

From the Division of Cardiovascular Diseases and Internal Medicine, MayoClinic Rochester, Rochester, Minnesota.

Address reprint requests to Dr. W.-K. Shen, Division of CardiovascularDiseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN55905.

it an excellent diagnostic and therapeutic tool for theinitial assessment of various tachyarrhythmias.

• Conclusion: The direct adenosine-activated KACh

(potassium acetylcholine) channel signal transductionsystem explains the effects of adenosine on the sinusnode, atrioventricular node, and atrial myocardium.The indirect adenosine-inhibited adenylate cyclasesystem accounts for its negative inotropic effects onthe catecholamine-entrained contractility in atrialand ventricular myocardium. Because of the recentpurification and cloning of adenosine receptors andsubunits of G proteins, additional adenosine-mediatedelectrophysiologic mechanisms can be explored.

(Mayo Clin Proc 1995; 70:274-291)

AMP =adenosine monophosphate; ATP =adenosine triphos­phate; GDP = guanosine diphosphate; GTP = guanosine triophosphate; lea and IK =calcium current and potassium current;K and K ACh =potassium and potassium acetylcholine; PTX =pertussis toxin; SAH =S-adenosyl homocystine

in patients with supraventricular tachycardia.V In atrialtissue, adenosine produces a negative inotropic effect byactivating the adenosine-sensitive potassium (K) channelunder basal conditions" as well as by attenuating catechol­amine-stimulated contractility and cyclic adenosine mono­phosphate (AMP) accumulation under enhanced autonomicconditions."!' In ventricular tissue, adenosine minimallyaffects the ventricular inotropic state under basal condi­tions;'? however, it negates the catecholamine-enhancedcontractility and decreases catecholamine-induced triggeredactivity by inhibiting adenylate cyclase activity and cyclicAMP production. 13-16 These complex physiologic responsesresult from different adenosine-modulated receptor-effectorpathways.

Herein our review focuses on the molecular mechanismsof adenosine-regulated cardiac cellular electrophysiologicactivities and how information about these mechanisms canbe applied to facilitate the diagnostic and therapeutic ap­proaches to various clinical arrhythmias. First, we discussadenosine metabolism and receptors in the cardiac system.Second, we provide details about adenosine-mediated signaltransduction pathways in various cardiac cell types. Third,

Mayo Clin Proc 1995; 70:274-291 274 © 1995 Mayo Foundation for Medical Education and Research

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Page 2: Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology

Mayo Clin Proc, March 1995, Vol 70 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION 275

Fig. 1. Adenosine metabolism. ADP = adenosine diphosphate;AMP =adenosine monophosphate; ATP =adenosine triphosphate;SAH =S-adenosyl homocystine.

AMP AMP-ADP-ATP

5'-nUCI80ljd~ ~jn.....(dePhosphoryla:n)", ,;(p~horylaljOn)

Adenosine

Hydrolaselionl / '- /.?.~aminase(lran,methyla,/, ~.minatiOn)

SAH lnosine-Hypoxanthine-Uric acid

(ATP) and adenosine diphosphate. " The adenosine recep­tors (PI type) on the cellular membrane can be subdividedfurther into at least two subtypes on the basis of their differ­ential selectivity for adenosine analogues and their action onadenylate cyclase." Ligand binding to Al receptors inhibitsadenylate cyclase, but binding to A

2receptors stimulates

adenylate cyclase. In addition to the adenosine receptors onthe surface of the cell membrane, an intracellular binding site(P site) is also present and is functionally linked to adenylatecyclase inhibition." The heart contains predominantly AIadenosine receptors; A

2receptors are present on endothelial

cells and vascular smooth muscle cells.' Methylxanthines,caffeine, and theophylline are nonspecific competitive an­tagonists to adenosine receptors .

N;Y~~)l-N

"'-~.HO OH

3' 2'

Adenosine

----, InosineDeaminase

(deaminallon)

AMP

5'-nUcleolida~(dephosPhorylalliln) ""-

Adenosine

LIGAND-RECEPTOR-EFFECTOR COUPLINGIn addition to adenylate cyclase, AI receptors couple othereffector systems.i" The effector systems are strongly spe­cies dependent and tissue dependent. In the heart, the mostcomprehensively studied effector is adenylate cyclase. Thatadenosine activates the muscarinic K acetylcholine (K

ACh)

channels in sinoatrial and atrioventricular nodal cells and inatrial cells but not in ventricular cells (except in ferret) iswell known.

Direct Adenosine Action: Adenosine and AcetylcholineActivate the Muscarinic K Channel Through GuanosineTriphosphate-Binding Proteins in Cardiac Atrial Cells.­The similarity between the effects of adenosine and acetyl­choline on cardiac membrane potential has been knownsince the 1950s. Later, investigators demonstrated in patch­clamp experiments with single atrial myocytes that K chan-

ADENOSINE RECEPTORSAfter adenosine is released, it can activate adenosine recep­tors, which in tum regulate a diverse set of physiologicfunctions in cardiac tissue. On the basis of natural ligandrecognition, purinoreceptors are classified as two generaltypes: PI receptors preferentially bind adenosine and AMP,whereas P

2receptors recognize adenosine triphosphate

ADENOSINE METABOLISMAdenosine metabolism is shown in Figure 1. Adenosine isthe product of the enzymatic hydrolysis of two substrates:AMP and S-adenosyl homocystine (SAH).17 The mainmechanism for the production of adenosine in cardiacmyocytes is the dephosphorylation of AMP by 5'-nucleotid­ase located in the cytosol.P:'? Some 5' -nucleotidase activityis associated with the plasma membrane, and its active site isalso available to substrates in the extracellular fluid.20

•21 The

possible sources for extracellular AMP include AMP re­leased from platelets, neurons, cardiac myocytes , and endo­thelial cells. The formation of adenosine from SAH, a prod­uct of S-adenosylmethionine-dependent transmethylationreaction, is catalyzed by SAH hydrolase. The quantitativeimportance of this cytosolic pathway in comparison with the5'-nucleotidase pathways in the heart has not been clari­fied.22•24 Hypoxia, ischemia, catecholamines, calcium, andsympathetic nerve activation (among other factors) increaseadenosine formation .F:"

Adenosine is transported across the cell membrane by acombination of simple diffusion and facilitated diffusion.P"Facilitated diffusion is carrier mediated, nonconcentrative(that is, the transported solute moves down a concentrationgradient but at a faster rate than simple diffusion), anddirectionally symmetric, with similar kinetics. The adeno­sine transport system has a large capacity and is effective.Release and uptake of adenosine are probably regulated bythe concentration-not the saturation-of the transporter.Several 6-aralkylthiopurine ribosides" and dipyridamole"are blockers of this transport system.

The two catabolic pathways for adenosine are deamina­tion to inosine by adenosine deaminase and reincorporationinto the adenine nucleotide pool by adenosine kinase-medi­ated phosphorylation." -" Degradation of adenosine occursboth intracellularly and extracellularly because adenosinedeaminase is present in the cytosol as well as on the exteriorsurface of the cell membrane (that is, the ecto- form ofthe enzyme) of cardiac and endothelial cells. Because ofthe rapid transport and metabolism of adenosine, its half-lifein human plasma has been estimated to be as brief as 0.6 to1.5 S.34

we review the clinical usefulness of adenosine in cardiacelectrophysiology.

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276 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION Mayo Clio Proc, March 1995, Vol 70

nels activated by adenosine and acetylcholine have the sameconductance and gating kinetic properties" (Fig. 2). Theunitary channel conductance and prominent inward rectifi­cation of this K channel are similar under the influence ofadenosine and acetylcholine. Both agonists increase thefrequency of bursts of channel openings with similar ki­netics. The effects of adenosine and acetylcholine are se­lectively antagonized by theophylline and atropine, re­spectively. These observations suggest that adenosine andacetylcholine regulate the same K channel-the K

AChchan­

nel in cardiac atrial cells-by activating different membranereceptors (that is, Al purinergic receptors by adenosine andM

2muscarinic cholinergic receptors by acetylcholine).

The signal transduction system for adenosine activationof K

AChchannels in cardiac atrial myocytes has been eluci­

dated further by the inside-out patch-clamp experiments.tv"In the presence of either acetylcholine or adenosine in theextracellular site of the membrane, K

AChchannels are acti­

vated by intracellular guanosine triphosphate (GTP). Thisagonist-dependent GTP-induced K

AChchannel activation is

blocked by pertussis toxin (PTX). Because PTX specificallypromotes adenosine diphosphate ribosylation and inhibitsthe function of a family of guanine nucleotide-binding pro­teins (inhibitory G proteins, G, and G), these observationsstrongly indicate that Al purinergic and M

2muscarinic re­

ceptors are linked to the KACh

channels through PTX-sensi­tive G proteins (GK) in the cell membrane with no obligatoryinvolvement of intracellular second messengers (Fig. 3).Consistent with this model, GTP in the absence of an agonist(adenosine or acetylcholine) failed to activate the channel,but GTPyS and GppNHp, nonhydrolyzable GTP analogues,gradually increased the frequency of K

AChchannel openings.

AIF4

- , an activator ofG proteins, also activates the channel inthe absence of an agonist." Intracellular magnesium isessential for GTP activation of K

AChchannels." On the basis

of these results, a simplified model was proposed for themolecular mechanism underlying GKactivation of the K

ACh

channel with analogues of G protein regulation of adenylatecyclase (Fig. 4).42 In the absence of an agonist, GKremains ina trimeric complex composed of GKa and GK~Y' and the K ACh

ACh300t

200~~i 135ms

100l I

; 1\ ,..\°b--- - '~s___10inS

c

"pP

to •+ '........... ,'1. raJ

ACh

20 mM K'o

Er; -SOmV

Ado

"

-20

.20

-60

-40

.100mV'---­.80•60.40

A

Fig. 2. Conductance and kinetic properties of adenosine- and acetylcholine-regulatedchannel activity. A, Adenosine (Ado)- and acetylcholine (ACh)-regulated channelcurrents recorded from guinea pig atrial myocytes at various membrane potentials incell-attached patch-clamp configuration. Pipettes contained Ado (10 11M) or ACh (5.5/lM). All records were low-pass filtered at I kHz (-3 dB). Arrowhead (each trace) =zero current level. B, Current-voltage relationships of Ado- (closed circles) and ACh(open circles)-regulated channels. In this example, slope conductance of unitary currentwas 46 pS. C, Open time histograms of Ado- and ACh-regulated channels at Er. Bothdistributions were fitted by single exponential curve with time constant indicated ineach graph. (From Kurachi and associates." By permission.)

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

Page 4: Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology

Mayo CIiD Proc, March 1995, Vol 70 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION 277

K channel

Fig. 3. Scheme of purinergic and muscarinic activation of Kchannel in atrial cell membrane. In cardiac atrial cell membrane,two membrane receptors (P}-purinergic and muscarinic [M] acetyl­choline [ACh] receptors) are linked to K channel through guanosinetriphosphate (GTP)-binding proteins (GK)' Quantitative relation­ships between components are not represented in scheme. Ado =adenosine; GDP = guanosine diphosphate; Pi = phosphate. (Modi­fied from Kurachi and associates." By permission.)

channel is closed (state 1). In this state, guanosine diphos­phate (GDP) may be bound to G

K• When an agonist (either

adenosine or acetylcholine) binds to the membrane receptor,a signal is transmitted to G

K(state 2). If magnesium is

present on the intracellular side of the membrane, GTP bindsto G

Ka, probably in exchange for GDP, and activates the K

ACh

channel (state 3). During activation, GK

may be dissociatedinto its subunits (Ga-GTP and G~), and either subunit poten­tially may activate the K

AChchannel. When GTP, which is

bound to GKa

, is hydrolyzed to GDP, GK

is deactivated and

1

returns to state 1 or state 2. Because GTPyS and GppNHpare not hydrolyzed to GDP, G

K, which is activated by GTPyS

or GppNHp, may stay in state 3, and the openings of the KACh

channel are continuously stimulated. GTP-dependent chan­nel activation and AIF

4--dependentactivation require mag­

nesium, whereas G-protein subunit activation of the channelrequires no intracellular magnesium. These observations areconsistent with the notion that dissociation of the trimer intoGa and GIJ'y is magnesium dependent."

G-Protein Subunit Activation of the KACh

Channel.­Studies of G proteins initially focused on Ga subunits, about20 of which have been identified in mammals." These Gaproteins are responsible for nucleotide binding and hydroly­sis and are thought to be the sole regulator of G-protein­mediated actions.r':" The first strong indication that G~1

could regulate effectors directly or indirectly was in a studyby Logothetis and associates," who used G-protein subunitspurified from brain. Activation of the K

AChchannel was

observed under the influence of nanomolar concentrations ofG~1' In contrast, Yatani and colleagues" and Codina andcoworkers" reported that only Gia-GTPyS (picomolar range)activated the channel. They also reported that G

a 40from

human erythrocytes (probably Gi3a) is much more potentthan Gil or G2a and Goa' Moreover, Yatani and associates"demonstrated that recombinant Gias (Gila' Gi2a, and Gi3) areequally potent in activating K

AChchannels.

Codina and colleagues" and Kirsch and coworkers'? pro­posed that the effects of G~1 on the K

AChchannel are due to

2

3

Fig. 4. Scheme of activation of K+ channel regulated by guanosine triphosphate (GTP)­binding protein in atrial cell membrane. A = agonist (acetylcholine or adenosine); a, /3,and Y= subunits of GTP-binding protein; GDP = guanosine diphosphate; Pi = phos­phate; R = membrane receptor (muscarinic or AI receptor). Scheme does not representany quantitative relationships and does not exclude possibility of several states otherthan 1,2, and 3, as shown. (Modified from Kurachi and associates." By permission.)

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Page 5: Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology

278 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION Mayo Clio Proc, March 1995, Vol 70

either contaminating Gu-GTP'ySin the GIJ'y preparation or thedetergent CHAPS (cholamidopropyldiethyl ammonio­propane sulfonate), which was used to suspend the G~y

preparation. Kim and associates" proposed that GIJ'y activa­tion of the KACh channel was indirectly caused by arachidonicacid metabolites released by G~y activation of phospholipaseA

2and that the physiologic functional subunit of GKto the

KAc h

channel was GKU' Additional observations, however,further supported that the activating effect of G~y on the KACh

channel was directly or in a membrane-delimited mannerattributed to the function of the G~y protein itself.52-59 Bycomparing the effects of G-protein subunits on the ATP­sensitive K (K

ATP) channel and the K

Ac hchannel (see subse­

quent discussion), GK~y is apparently the functional arm ofGKresponsible for activation of K

Ac hchannels.

Logothetis and colleagues'" showed that exogenous GU41­GDP blocked exogenous G~y activation of the KAc h channel.They also demonstrated that Gu41-GDP blocked GTPyS­induced activation of the K

Ac hchannel. In our Mayo lab­

oratory, we recently found that the GDP-bound form oftransdusine (T) ex subunit irreversibly inhibited the agonist­mediated and GTP-induced or GTPyS-induced K

Ac hchan­

nel activity.F-" This inhibition was restored only by T~y orG~f These results strongly support the notion that GK~y

is the physiologic subunit of GK that activates the KAc h

channel.Adenosine Activation of the ATP-Sensitive K Chan­

net-Since the initial reports that G proteins might be in­volved in the regulation of K

ATPchannels in pancreatic P

cells" and skeletal muscle cells," G proteins have also beenfound to activate K

ATPchannels in cardiac myocytes. 52,63-65

We found that GTPyS-bound GiUor Gzu of PTX-sensitive Gproteins purified from bovine brain activated K

ATPchannels

in the guinea pig ventricular cell membrane. G~y inhibitedthe adenosine-dependent and GTP-induced activation ofK

ATPchannels." These results indicate that ex subunits of the

PTX-sensitive G proteins activate KATP

channels in the ven­tricular cell membrane.

In atrial cell membrane where both KATP

and KAc h

chan­nels are expressed, Gi1U-GTPyS clearly activated the K

ATP

channel, and G~y substantially increased the openings of theKAc h channel in the same membrane patch. The GiIU-GTPyS­induced channel openings were inhibited, whereas the G~y­

induced channel openings were unaffected by glyburide, aK

ATP-channel-specific inhibitor.

From these results, we proposed that, after stimulation ofAl purinergic or M

2muscarinic receptors, PTX-sensitive G

proteins would be dissociated into Gu-GTP and G~f Gu-GTPactivates the K

ATPchannel, and G~y activates the K

Ac hchannel

(Fig. 5); however, whether the G protein coupled to the KAc h

channel is identical to the one coupled to the KATP

channel isunknown. The former mechanism exists in both ventricular

AChAdenosine «

a ACh Channel

~~

Fig.5. Proposed mechanism forpertussis toxin-sensitive G-proteinsubunitactivation of potassium adenosine triphosphate (K

ATP) and

potassium acetylcholine (KAc h

) channelsin cardiaccell membrane.After stimulation of receptors (R) by adenosine or acetylcholine(ACh), pertussis toxin-sensitive G proteins may be functionallydissociated into G,,-guanosine triphosphate (GTP) and G~y' G,,­GTPmayactivate KATP channel, andG~ mayactivate KAc h channel.Former mechanism exists in both ventricular and atrial cells, andlatter may exist in atrial but not in ventricular cells. Scheme doesnot represent any quantitative relationship between each compo­nent and doesnot considerall possible intermediate stepsbetweencomponents. a, p, and r = subunits of GTP-binding protein.(Modified from ito and associates." By permission.)

and atrial cells, but the latter may exist in atrial cells and notin ventricular cells.

Because cardiac myocytes contain millimole concentra­tions of ATP, adenosine activation of K

ATPchannels may not

operate under physiologic conditions. This mechanism,however, may be one of the important components of theadenosine-mediated protection of cardiomyocytes duringischemia.v"

Indirect Adenosine Action: CyclicAMP-DependentAc­tion of Adenosine.-Adenosine antagonizes the electro­physiologic and biochemical effects of p-adrenergic agonistson the heart, a situation that is related to the regulation ofintracellular cyclic AMP and is observed only when the heartis pretreated with p-adrenergic agonists. ' 3,69-71 The antago­nistic effects of adenosine on p-agonist action can be ex­plained by the dual control of adenylate cyclase activity bystimulatory and inhibitory G proteins." The molecularmechanism for the antagonistic effect of adenosine to p­adrenergic agonist action on the L-type calcium channelcurrent has been demonstrated by several investigators. 13.69.70

The mechanism seems to be identical to the muscarinicantagonism to p-agonists. 73

In the absence of /3-agonists, adenosine does not affect theventricular action potential or the calcium current (I

Ca) '

When the lea is augmented by isoproterenol, adenosine de­creases the inward current to the values in basal conditions.This phenomenon is explained by a dual control mechanismof adenylate cyclase activity by G proteins (Fig. 6)-that is,by Al purinergic receptors coupled to cardiac adenylate cy­clase through the inhibitory G protein (G, probably G

i2) and

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Page 6: Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology

Mayo Clio Proc, March 1995, Vol 70 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION 279

L·typeCachannel

Fig. 6. Signal transduction mechanisms responsible for direct and indirect effects ofadenosine in cardiac myocytes. A J = adenosine receptor; AC = adenylate cyclase;AMP = adenosine monophosphate; ATP = adenosine triphosphate; f3

I= adrenergic

receptor; cAMP =cyclic AMP; cGMP =cyclic guanosine monophosphate; G;=inhibi­tory G protein; GK = guanosine triphosphate-binding proteins; G, = stimulatory Gprotein; K

ACh=potassium acetylcholine; M

2=muscarinic receptor; PDE =phosphodi­

esterase; PKA =protein kinase A; P04=phosphorylation; R =receptor.

f3-adrenergic receptors coupled to adenylate cyclase throughthe stimulatory G proteins (GJ Under f3-adrenergic stimula­tion, activated G, promote adenylate cyclase activity, a situa­tion that results in the formation of cyclic AMP. CyclicAMP activates a specific protein kinase that phosphorylatescalcium channels. Thus, the cardiac I

Cais augmented by 13­

adrenergic stimulation." Under this condition, activation ofG

jby adenosine inhibits G,-stimulated adenylate cyclase

activity and decreases cyclic AMP to control levels. Thephosphorylated calcium channels cannot be maintainedwithout continuous generation of cyclic AMP, and its activ­ity decreases to control levels. In the absence of f3-adrener­gic stimulation, intracellular cyclic AMP in cardiac myo­cytes may be minimal. Thus, even when adenylate cyclaseactivity is suppressed by activation of G, with adenosine, theintracellular cyclic AMP level and Ica are unaffected byadenosine. Because cardiac sodium channels and the de­layed outward K channels are also regulated by intracellularcyclic AMP-dependent protein kinase.I':" similar antagonis­tic regulation by adenosine also may exist for these channels.

Although the regulation of adenylate cyclase by G-pro­tein subunits is more complicated than previously pro­posed," adenylate cyclases expressed in the heart (type 5 andtype 6) seem to be unaffected by G~y when preactivated byGsa-GTPyS.78 The precise mechanism underlying antag­onistic interaction of subunits of G and G. has not been

S I

determined.Adenosine may also suppress adenylate cyclase activity

through the P site by increasing intracellular AMP.23,78 The

contribution of this pathway to the antagonism of adenosineto [3-adrenergic stimulation is unclear, however.

ADENOSINE AND CARDIACELECTROPHYSIOLOGYThe effects of adenosine on cardiac electrophysiologic prop­erties are a function of the specific cardiac target structure,the density of the adenosine receptors, and the effector sys­tem. Distribution of adenosine receptors within the heart isheterogeneous and species dependent.' Most of our knowl­edge of the adenosine-mediated basic electrophysiologic ef­fects is from in vitro studies on rodent hearts. Some uncer­tainties exist about the extent that in vitro observations inanimal models can translate into physiologic function regu­lated by adenosine in human hearts.

The predominant effector systems in the various cardiacstructures are summarized in Table 1. Although the belief isthat adenosine receptors (primarily the Al type) are presentthroughout cardiac tissue, their relative distribution is un­clear. The density of adenosine receptors in the heart isconsiderably less (at least 2 orders of magnitude) than that inthe brain, a factor that makes quantification of these recep­tors difficult.Y'"

Sinus Node.-Adenosine directly inhibits sinus node ac­tivity in intact and isolated preparations.!" These effects aremediated by the adenosine- KACh effector system, as shown instudies of single pacemaker cells.81,82 The activation of theoutward K

AChcurrent shortens the duration of the action

potential and hyperpolarizes the resting membrane potential.

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Page 7: Mechanisms of Adenosine-Mediated Actions on Cellular and Clinical Cardiac Electrophysiology

280 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION Mayo Clin Proc, March 1995, Vol 70

Table I.-Adenosine Effector Systems and Electrophysiologic Effects on the Heart*

ActionAdenylate potential Resting Rhythm, conduction,

Site KACh

KATP

cyclase duration potential or refractoriness

Sinus node Present ? Present] Decrease Hyper- Sinus bradycardiapolarization

AVN Present ? Present] Decrease Hyper- Atrioventricular delay/block; terminates SVTpolarization and necessitates AVN as an obligatory

component of the reentrant circuitHis-Purkinje Absenr] ? Present] :j: § May transiently suppress junctional tachy-

system cardiaAtrium Present Present Present Decreased § May transiently suppress automatic tachy-

cardiaVentricle Absent Present Present :j: § Terminates VT of triggered mechanismsAccessory ? ? ? ? ? Enhances preexcitation due to AVN blockade;

pathway may shorten anterograde refractoriness

*AVN = atrioventricular node; KACh

and KATP

= potassium acetylcholine and potassium adenosine triphosphate; SVT = supraventriculartachycardia; VT = ventricular tachycardia.

[Indirect observation.:j:Adenosinenegates catecholamine-induced prolongation of action potential duration.§Adenosine inhibits catecholamine-induced spontaneous depolarization.

This hyperpolarization can account for the slowing of sinusrate.83-87 Under basal conditions, adenosine has no pro­nounced effect on I

Caor on the pacemaker current.81,82 With

the challenge of isoproterenol, adenosine attenuates both theIca and the pacemaker current, an outcome that suggests thatthe indirect adenosine-adenylate cyclase effector systemmay be involved.

After a bolus injection of adenosine in conscious subjects,a paradoxical sinus tachycardia has been reported. Thisobservation can be explained on the basis of reflux sympa­thetic activation due to adenosine-mediated vasodilatation"or to direct activation of cardiac sympathetic afferentnerves" (Shen W-K, Hammill SC, Munger TM, Stanton MS,Packer DL, Osborn MJ, et al. Unpublished data) or to bothmechanisms. The changes in sinus rate in response to aden­osine are the net result of direct electrophysiologic suppres­sion, indirect compensatory reflux sympathetic activation,and direct cardiac sympathetic afferent activation.

Atrioventricular Node.-The effects of adenosine onatrioventricular conduction were first reported by Drury andSzent-Gyorgi'" in studies on animals and by Honey, Ritchie,and Thomson" in studies on human hearts. The depressanteffect of adenosine, which causes atrioventricular block, hasbeen confirmed in several species.v":" The effect of adeno­sine on atrioventricular conduction in a normal subject isshown in Figure 7. After a bolus injection of adenosine (6mg), a transient prolongation of the A-H interval (upperatrioventricular junction conduction time including the atrio­ventricular node) was observed, but the H-V interval (Hisbundle to ventricular conduction) was unaffected. This ob­servation suggests that adenosine acts on the proximal por-

tion of the atrioventricular junction. In animal models, theresults of multiple simultaneous recordings suggest that thespecific target for adenosine is the nodal cells." The depres­sant effect of adenosine on nodal cells correlates with theprolongation of the A-H interval and the conduction timebetween the nodal zone of the atrioventricular node and theHis bundle. The precise identity of the effector system in theatrioventricular node has not been determined. Becauseacetylcholine increases single K channel currents in atrio­ventricular nodal cells'?" and elicits responses from the si­noatrial node and atrial cells similar to those for adenosine, ithas been proposed that the KACh channel is the effector in theatrioventricular node. In contrast to the effect on the si­noatrial node, adenosine also depresses the upstroke of theaction potential (phase 0).99 The ionic mechanism for thisaction on the atrioventricular node is unclear; a possibleeffect on Ica cannot be excluded. 1

His-Purkinje System.-Under basal conditions, the di­rect effect of adenosine on the His-Purkinje system is mini­mal. Conduction time from the His bundle to the ventricularmyocardium (the H-V interval) is not significantly pro­longed, even with high concentrations of adenosine, in eitheranimal'"10I or human!" studies. In guinea pig103 and ca­nine'?' hearts, adenosine inhibits spontaneous depolarization(automaticity) in the His-Purkinje system under basal condi­tions. This observation has not been confirmed in humanstudies.l'" Under enhanced adrenergic conditions, however,adenosine attenuates the effects of catecholamine stimula­tion. As shown in patients with complete heart block, aden­osine reverses isoproterenol-induced acceleration of the His­Purkinje escape rate.'?' The effector in the His-Purkinje

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Mayo Clin Proc, March 1995, Vol 70 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION 281

"I'' ''01 11 '1'' '''' '' '1'"''''''1'''''11"I'"''' ''' 1'' '' '' ''' 1'""""1"''' '" '1''"11111]" "'''''I '' '' ""'j""'"III'""" "",,,,,1"""' ''1'''''' '''1'' '' ''" '1''' '' '' ''1'' '''' ' '']''''' ''''1'''''' '''1'' ''"," ~"""" 'l ""'" ''1'"''""J'""""I'

BASELINE ADENOSIN E

VI VI -~----. ~--------"\

A-H !56H-V43

""'4HRA --J~·l r--..,r~--l HRA----"I,---.,r----,II,r---..I'--I

A-H90H-V 43

RV ----1\,...--------'1:.---1 RV,

"1""",.,1._, ,,.11,1,,•.,,,,,1,,,,,,,,,111,,,,,,,1,,,....,,1,,.1111,,1.,,,,,,"1•."",,,I,,,,,."':,,,·..·.I,l,..,.•.,,1,,.,,,, "".""1""",,,1,,,,,,,,,1,,,,,,,.,1,,,,,,,,,1,,,,,,,,,1,,,,,,,,,1,,,,,,,,,1"""",1",,,.,,.111,,..,,,1,,,,,,,,,1,,,,,,,,,1,

Fig. 7. Effects of adenosine (15 s after intravenous injection) on atrioventricularnodal conduction. Top two tracings are from surface electrocardiogram leads I andVI" All numbers are in milliseconds . A-H = upper atrioventricular junction conduc-

. tion time including atrioventricular node; HBE = His-bundle electrogram ; H-V = Hisbundle to ventricular conduction ; HRA = high right atrial intracardiac recording;RV = right ventricular intracardiac recording.

conduction system has not been elucidated. Experimentalobservations suggest that adenylate cyclase is the main ef­fector pathway.

Atrium.-Adenosine produces a negative inotropic effectin atrial myocardium."!' Two distinct mechanisms accountfor this effect. Under basal conditions, adenosine shortensthe duration of the action potential and decreases contractil­ity.?·9.?9.to6-to9 This action is mediated by the KACh channeleffector system. With increased adrenergic stimulation,adenosine attenuates the catecholamine-stimulated contrac­tility and cyclic AMP accumulation.!?:'! This action ismediated by the adenylate cyclase effector system.Pharmacologic and radioligand binding studies suggest thatthese actions are mediated by AIreceptors .?9.80.11o-1 13 Becauseof the presence of the two distinct effector systems, theelectrophysiologic effects of adenosine on the atrium aremultiple. Activation of the KAChchannel shortens the dura­tion of the action potential. I.? In humans, this decrease in theduration of the action potential has been correlated with adecrease in atrial refractoriness.114 With enhanced adrener­gic activity , adenosine attenuate s both catecholamine-acti­vated outward I

Kand inward Ica' presumabl y by the inhibi­

tion of phosphorylation of these channels, because adenosineinhibits adenylate cyclase activity and decreases the genera­tion of cyclic AMP. The net electrophysiologic effect is theresult of the direct adenosine-mediated activation of KAChchannels and the indirect adenosine-mediated inhibition ofIcaand I

K•

Ventricle.-In the absence of catecholamine stimulation,adenosine minimally affects the ventricular inotropic state"or the amplitude and duration of ventricular action poten­tials." The lack of any electrophysiologic effect in ventricu­lar myocytes under basal conditions is likely explained bythe absence of KACh channels. Ventricular myocardium issensitive only to adenosine under enhanced adrenergic con­ditions. Adenosine reverses the catecholamine-induced ac­cumulation of cyclic AMP, prolongation of action potentials,and augmentation of contractile forces by the adenylate cy­clase effector cascade. 10.1 1.109.115·119 In the presence of cat­echolamines, adenosine attenuates an outward I

Kand inward

ICa' presumably by inhibiting the phosphorylation of thesechannels. P"!"

The precise physiologi c role of the adenosine-KATPeffec­tor system in ventricular myocytes has not been confirmed.Clearly, adenosine activates KATPchannels in isolated mem­brane patches from guinea pig heart.52.63-65 In contrast, aden­osine elicits minimal changes in the action potentials inintact cells. 13 One suggestion is that, in animal models,activation of KATPchannel s by adenosine may contribute tothe protective mechanism s during ischemia. Whether KATPchannels are responsible for the adenosine-modulated myo­cardial protection from ischemic injury in humans necessi­tates further investigation.

Accessory Pathway.-Determining the effects of adeno­sine on the accessory pathway has been difficult because ofthe transient nature of adenosine action and the frequent

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282 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION Mayo Clio Proc, March 1995, Vol 70

interaction between the accessory pathway and normal atrio­ventricular conduction in humans. On a therapeutic basis,one speculation is that adenosine should have a minimal orno effect on accessory pathway conduction because the elec­trophysiologic properties of the accessory pathway are gen­erally similar to those of the atrial myocardium. Nonethe­less, investigators have demonstrated that adenosine inhibitsconduction in the accessory pathway with decremental prop­erties, including permanent junctional reciprocating tachy­cardia.!" and in Mahaim fibers.!" Other investigators havereported that the accessory pathway is occasionally sensitiveto ATP. 124,125 The actions of ATP are thought to be mediatedprimarily by hydrolysis to adenosine.P<!" but its actions arenot entirely equivalent to those of adenosine because of theadditional ATP-activated vagal effects."? One study re­ported that adenosine shortens the anterograde refractorinessof the accessory pathway.!" Possible explanations for thisoutcome include reflex sympathetic activation, transientwithdrawal of vagal tone, or a direct effect of the K

ATP

channel in the accessory pathway. The effector of adeno­sine-mediated action on the accessory pathway is unknown.

ADENOSINE AND CLINICAL ARRHYTHMIASIn addition to a thorough understanding of the adenosine­mediated actions on basic cardiac electrophysiology, an ac­curate identification of the clinical tachyarrhythmias is thekey to using adenosine appropriately in diagnostic and thera­peutic situations. Of note, ATP instead of adenosine hasbeen used clinically in Europe I29-131 and Canada. 125,132 Theelectrophysiologic effects of ATP are thought to be due tothe breakdown product adenosine. 102,126 In addition, ATP hasa vagal component to its action."? Tachyarrhythmias can bedistinguished by mechanisms, anatomic sites, andelectrophysiologic features (Table 2).

On the basis of electrophysiologic and pharmacologicresponses, mechanisms of tachyarrhythmias can be classi­fied as abnormal automaticity, triggered activity, and reen­try.133-135 Abnormal automaticity is a manifestation of en­hanced spontaneous depolarization. Triggered activity iscaused by afterdepolarization before (early) or after (de­layed) repolarization (or both). A substrate for reentry canbe created when abnormal conduction or refractoriness (orboth) is present.

Tachyarrhythmias also can be categorized on the basis ofanatomic sites. 133,134 Supraventricular tachycardia can origi­nate in the sinoatrial node, atrial myocardium, or atrioven­tricular junction. Ventricular tachycardia can involve theanterior and posterior fascicles ("fascicular tachycardia"),left and right bundle branches ("bundle branch reentranttachycardia"), and the ventricular myocardium. Reentranttachyarrhythmias in patients with the Wolff-Parkinson­White syndrome involve the accessory pathway and atrio-

Table 2.-Classification of Tachyarrhythmias*

MechanismReentryAutomaticityTriggered activity

Anatomic siteSupraventricular

SinusnodeAtrialmyocardiumAtrioventricular node

VentricularFascicularBundle branchVentricular myocardium

Accessory pathwayElectrocardiography

Narrow complex tachycardiaSupraventricular

SinustachycardiaAtrialtachycardiaMultifocal atrial tachycardiaAtrialfibrillationAtrialflutterJunctional tachycardiaAVNRTAVRT(orthodromic reentrant tachycardia/WPW)

VentricularFascicular tachycardia

Widecomplex tachycardiaSVT withaberrationVentricular tachycardiaAVRT(antidromic reentrant tachycardia/WPW)

*AVNRT=atrioventricular node reentranttachycardia; AVRT =atrioventricular reentrant tachycardia; SVT = supraventriculartachycardia; WPW= Wolff-Parkinson-White syndrome,

ventricular node as well as the atrial and ventricular myocar­dium as obligatory components of the tachycardia circuit("atrioventricular reentrant tachycardia").

Perhaps the most practical classification of the tachy­arrhythmias is obtained from the l2-lead electrocardiogram.Tachyarrhythmias can be categorized as either narrow (QRSduration, less than 120 ms) or wide (QRS duration, 120 msor more) complex tachyarrhythmias. In general, narrowcomplex tachyarrhythmias are supraventricular in origin,although the QRS duration of the fascicular ventriculartachycardia can be less than 120 ms in duration. A differen­tial diagnosis for wide complex tachycardia is not extensive.Tachyarrhythmias with a wide QRS complex include ven­tricular tachycardia, supraventricular tachycardia with aber­rant atrioventricular conduction, and supraventricular tachy­cardia with anterograde accessory pathway conduction.

Therapeutic Applications.-The clinical response toadenosine is a net result of complex interactions of (1) localconcentration of adenosine, (2) receptor density and func­tion, (3) underlying electrophysiologic substrates, and (4)

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Mayo Clio Proc, March 1995, Vol 70

A I I. , I I , ~ .~ r~

1" I I "1 I I I I 1'1

J - I ~ I I

II I II " II'

I I I ' I IJ

'. , "

MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION 283

Fig. 8. A, Twelve-lead electrocardiogram, showing narrow complex tachycardia at rate of about 200 beats/min, B, Duringelectrophysiologic testing, narrow complex tachycardia was induced during atrial-programmed stimulation consistent with atrioventricu­lar (AV) nodal reentrant tachycardia and terminated by injection of 6 mg of adenosine. Top two tracings are from surface electrocardio­gram leads I and V I' AV nodal reentry tachycardia was terminated with retrograde atrial recording (fast pathway conduction) and blockedin slow pathway in anterograde direction above His bundle, First QRS complex after termination of tachycardia is fusion beat. Afterinjection of adenosine, premature ventricular contractions are common (see text for discussion). Presence of accessory pathway wasexcluded during electrophysiologic testing, HBE = intracardiac His-bundle electrogram; HRA = high right atrium intracardiac recording;RVA = intracardiac recording from right ventricular apex.

autonomic tone. The local concentration of adenosine is afunction of the rate and dose of adenosine administered andthe site. Determining the local concentration of adenosine isdifficult because of its rapid metabolism. In addition, thereceptor density and the regulation of membrane signalingsystems are dynamic and complex processes, The functionof the receptor is subject to change by up- or down-regula­tion, rate of transcription or translation, alteration in thequantity of G proteins, and covalent modification of thereceptor by phospnorylation.v's!" The response to adeno­sine also depends on the electrophysiologic substrate. Forexample, activation of K

AChchannels in the atrial myocar­

dium can be antiarrhythmic or proarrhythmic. Decreasingthe duration of the action potential and hyperpolarization ofthe resting membrane potential through K

AChactivation sup­

press triggered activity and abnormal automaticity; however,decreasing the duration of the action potential reduces re­fractoriness, which potentially promotes arrhythmias of thereentrant type. Finally, the indirect adenylate cyclase effec­tor system may be effective in suppressing catecholamine­induced arrhythmias.

Supraventricular Tachycardia.-Adenosine is highlyeffective in converting paroxysmal supraventriculartachycardia to sinus rhythm because of its negativechronotropic and dromotropic actions.v!" Most paroxysmalsupraventricular tachyarrhythmias respond to adenosine be­cause they have a reentrant mechanism that includes theatrioventricular node in the circuit.F'-"? Josephson andWellens"? reviewed the data on 708 consecutive patientsadmitted to two university hospitals for assessment of supra­ventricular tachycardia; 50% had atrioventricular nodal re-

entrant tachycardia, 35% had atrioventricular reentranttachycardia involving the accessory pathway, and 15% hadother types of atrial tachycardia. In the setting of atrioven­tricular nodal reentrant tachycardia, the substrate of dualpathways is present in the atrioventricular nodal region.':"During a typical atrioventricular nodal reentrant tachycardia,a slow pathway maintains anterograde conduction, and a fastpathway maintains retrograde conduction. Adenosine canterminate atrioventricular nodal reentrant tachycardia at ei­ther limb of the atrioventricular node, although the site oftermination occurs most frequently in the anterograde slowpathway (Fig. 8). In the setting of atrioventricular reentranttachycardia, the reentry circuit involves the normal atrioven­tricular conduction system, the extranodal accessory path­way, and the atrial and ventricular myocardium. Termina­tion of tachycardia usually occurs in response to adenosine(Fig. 9).130,142,143 The efficacy of adenosine in terminatingatrioventricular nodal reentrant tachycardia or atrioventricu­lar reentry tachycardia has been reported to be between 80and 100% (mean success rate for more than 600 events,93%).138

Generally, adenosine is not effective in terminating mostother types of supraventricular arrhythmias that do not in­volve the atrioventricular node as an obligatory componentof the tachycardia circuit. 130,142,144 In a study of 15 patientswith intra-atrial reentrant tachycardia, atrial flutter, atrialfibrillation, and sinus node reentrant tachycardia, adenosinedid not terminate tachycardia in any of the patients. 142 Otherstudies and case reports have shown that adenosine or ATPmay slow or terminate sinus node reentrant tachycardia'P'!"and automatic intra-atrial tachycardia. ' 29, ' 32, ' 46 These two

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284 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION Mayo Clin Proc, March 1995, Vol 70

lU~

r I r

J-Uuill lULlHili- J-LLLWJ

c ORntoDROMIC REfJI,'TRANT TACiIYCARDIAl~&""I),----- ,,----'"'- V- v----

VI ....... ------I -1\-

.,,- ...--"

.1v

"v A

I I V "Hl'~ ~

U' of~ , ,

I't---------~·ll---

----~t--

....

Fig. 9. A, Base 12-lead electrocardiogram, showing preexcitationconsistent with diagnosis of Wolff-Parkinson-White syndrome. B,Twelve-lead electrocardiogram, showing narrow complextachycardia consistent with orthodromic atrioventriculartachycardia. C, Recordings from electrophysiologic testing; toptwo tracings are from surface electrocardiogram leads I and VI'Activation sequence during tachycardia is consistent with left-sidedaccessory pathway. Adenosine terminated tachycardia (atrial re­cording). Block occurred at atrioventricular node above His bundle(absence of His-bundle signal). DCS, MCS, and PCS = recordingsfrom distal, mid, and proximal coronary sinus electrodes, respec­tively. HBE =His-bundle recording; HRA =intracardiac recordingfrom high right atrium; RVA = right ventricular apex recording.

types of supraventricular tachycardia are relatively uncom­mon. The response of automatic atrial tachycardia toadenosine as the ectopic pacemaker (inverted P wave) tran-

siently slowed after administration of adenosine is shown inFigure 10. Sinus node function (upright P wave) brieflyappeared before the ectopic rhythm resumed. As previouslydiscussed, different clinical responses of various types ofatrial arrhythmias to adenosine could be explained byadenosine-mediated cellular mechanisms. Atrial fibrillation,atrial flutter, and intra-atrial reentrant tachycardia are notexpected to respond to adenosine because of their reentrantmechanism and site. Transient suppression of an automaticintra-atrial tachycardia is expected to occur; however, theresponse may vary on the basis ofthe local concentration ofadenosine, receptor density, and function. The suppressanteffect of adenosine on the sinus node usually results intransient slowing or termination of tachycardia that origi­nated in the sinus node.

Ventricular Tachycardia.-Most ventricular tachy­arrhythmias are insensitive to adenosine. Adenosine seemsto have no effect on ventricular tachycardia due to eithermicroreentrant or macroreentrant tachycardia (bundlebranch reentrant tachycardia) or enhanced automatic­ity.14,15,130,147 These observations can be explained by theabsence of the K

ACheffector system on the ventricular myo­

cardium. Under basal conditions, adenosine has no signifi­cant effect on the action potential of ventricular myocytes;however, one type of ventricular tachycardia seems to behighly sensitive to adenosine.I':" Exercise-induced ven­tricular tachycardia that originates in the right ventricularoutflow tract is a relatively uncommon type of ventriculartachycardia that usually is associated with a structurallynormal heart .!" Generally, this tachycardia is inducible bycatecholamine stimulation-catecholamine activates theadenylate cyclase system and promotes cyclic AMP produc­tion. Increased cyclic AMP concentration activates proteinkinase and promotes phosphorylation of calcium channels, asituation that leads to increased cytosolic concentration ofcalcium. Such an increase promotes afterdepolarization andtriggered activity, which are thought to be the underlyingmechanisms of exercise- or catecholamine-induced ven­tricular tachycardia. Adenosine inhibits catecholamine-acti­vated adenylate cyclase through the inhibitory G protein and,therefore, suppresses catecholamine-sensitive ventriculartachycardia of the triggered type. An example of exercise­induced ventricular tachycardia and its response to adeno­sine are shown in Figure II.

Diagnostic Applications.-The easy application ofadenosine and its short half-life, favorable side-effects pro­file, and electrophysiologic properties make it an excellentdiagnostic tool for the initial evaluation of various tachyar­rhythmias (Fig. 12). In the setting of narrow complex tachy­cardia, adenosine is effective in terminating atrioventricularnodal reentrant tachycardia and atrioventricular reentranttachycardia that involve the atrioventricular node. Usually,

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Mayo Clio Proc, March 1995, Vol 70 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION 285

Fig. 10. Responseof ectopic atrial tachycardia(automatic) to adenosine. Recordingsare from surfaceelectrocardiogram leads I, II, andIII. A, P-wavemorphology in leads II andIII suggestsatrialectopicfocus (invertedP wave). After 12 mg of adenosinewasadministered,ectopicfocus was transientlysuppressed, and sinus node activitywas apparent(uprightP wave). B, Effect of adenosinewas transient, asshownby return of ectopic focus shortly after adenosineinjection.

the transient slowing or temporary termination occurs intachycardias of the automatic type that originate in the si­noatrial node or atrial myocardium. Because of its strongatrioventricular nodal blocking effect, adenosine frequentlyunmasks atrial activity during atrial fibrillation, flutter, orintra-atrial reentrant tachycardia and facilitates a correct di­agnosis (Fig. 10). Although the sensitivity and specificity ofresponses to adenosine are imperfect,130,138,142,149 adenosine isan excellent drug for diagnosis and treatment during theinitial manifestation of any narrow complex tachycardia.

In the case of wide complex tachycardia, the usefulness ofadenosine for the diagnosis is less certain, mainly because ofsafety issues and because most wide complex tachycardias inan un selected patient population are ventriculartachycardias."? Ventricular tachycardia, except for the rightventricular outflow tract type (triggered), usually is insensi­tive to adenosine. 130,151-153 Further hemodynamic compro­mise, even transient, may cause deterioration of the patient'scondition. Despite these concerns, several small studieshave shown that responses to adenosine or ATP have a highpositive predictive value (more than 90%) in distinguishingsupraventricular tachycardia with aberrant conduction fromventricular tachycardia. 130,132,152,154 Of more importance, nopatient had pronounced hemodynamic deterioration in thesetting of regular wide complex tachycardia after adenosineor ATP was administered.

Of note, adenosine should be used with extreme cautionin the setting of irregular wide complex tachycardia whenatrial fibrillation with preexcitation (Wolff-Parkinson-Whitesyndrome) is part of the differential diagnosis. Because ofthe atrioventricular nodal blocking effects, ventricular ratesfrequently increase after the administration of adenosine andcould cause hemodynamic deterioration (Fig. 13), Garratt

and associates!" reported that the shortest R-R interval dur­ing the preexcited atrial fibrillation was transiently de­creased after the administration of adenosine, but the aver­age R-R interval was unchanged during electrophysiologictesting. They concluded that the risk associated with adeno­sine was small.

A

C'J II I II " I ,III,; It" l

"

B

Fig. 11. A, Twelve-leadelectrocardiogram of youngmanwithwidecomplex tachycardia, which began during basketballgame. Typi­cally, this tachycardia has left bundle branch block morphologywith inferior axis. B, Single-lead electrocardiogram, showingtachycardiawas terminatedafter intravenous injectionof adenosine(6 mg). This tachycardia was subsequently induced duringelectrophysiologic testingwith isoproterenol challenge(3 ug/min),

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286 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION Mayo Clio Proc, March 1995, Vol 70

•Hemodynamicallystable

Suspect SVTNo heart disease

Inconclusive(adenosine) I

JTerminatestachycardia

•AVNRT ·AVRTSNRTAutomatic AT'

•Unmasksatrial activity

•Atrial flutterAtrial tachycardia

No effect

•VT

Fig. 12. Use of adenosine in diagnosis of and therapy for tachyarrhythmias (see text for discussion). AFiblWPW =atrial fibrillation/Wolff-Parkinson-White syndrome; AT = atrial tachycardia; AVNRT :: atrioventricular nodalreentrant tachycardia; AVRT :: atrioventricular reentrant tachycardia; ECG =electrocardiographic; Hx =history;la drugs > disopyramide, procainamide, and quinidine; lc drugs = propafenone and flecainide; RVOT = rightventricular outflow tract; SNRT = sinus node reentrant tachycardia; SVT = supraventricular tachycardia; VT =ventricular tachycardia; * ::transient suppression.

Several criteria have been established for the differentialdiagnosis of regular wide complex tachycardia} 5o.I55-157 Inaddition to the electrocardiographic features , Akhtar andcolleagues!" found that a history of myocardial infarctionhad a positive predictive value for ventricular tachycardia of98% and that a history of structural heart disease had apositive predictive value of 95%. Our opinion is that, whenthe diagnosis of ventricular tachycardia is highly suspectedon the basis of established criteria, the use of adenosine is notindicated. Other antiarrhythmic agents, such asprocainamide hydrochloride administered intravenously, ordirect current cardioversion should be considered to restoresinus rhythm. When the diagnosis is uncertain , adenosinecan be used with caution in patients with a stable hemody­namic condition. In the setting of irregular wide complextachycardia, the usefulness of adenosine for diagnosis ortreatment is limited.

Side Effects.-Transient side effects are common after anintravenous bolus injection of adenosine.6.142-144.149.153.158 Thefrequency and severity of the symptoms are usually doserelated. The most common symptoms are diaphore sis, light­headedness, chest pain, and dyspnea .130.142 Nausea, vomit­ing, headache, and anxiety can also occur. Inhalation ofadenosine may produce bronchocon striction in patients withasthma.!" Bronchospasm was reported in one patient afterintravenous bolus injection of adenosine. 160 Despite thepotential for adverse effects , most symptoms related toadenosine are brief and are tolerated by patients. In situa­tions of prolonged adenosine-induced chest pain in patients

with ischemic heart disease , administration of theophyllinemay alleviate symptoms of chest pain.

Proarrhythmic responses are also common after a bolusinjection of adenosine.130.142.143 Premature atrial and ven­tricular beats are most common. Nonsustained polymorphicventricular tachycardia'" and atrial fibrillation'F:"! havebeen reported. Episodes of transient asystole and heart blockare frequently observed, but these are usually short lived andresolve spontaneously without intervention. Extra precau­tion should be used when adenosine is administered to pa­tients taking dipyridamole or to those with sinus node orconduction system disease.

CONCLUSIONCardiac electroph ysiologic effects of adenosine exemplifythe critical importance of cellular mechanisms in clinicalmedicine . The direct adenosine-activated K

AChchannel sig­

nal transduction system explains the effects of adenosine onthe sinus node, atrioventricul ar node, and atrial myocardium.The indirect adenosine-inh ibited adenylate cyclase systemaccounts for its negative inotrop ic effects on the catechol­amine-entrained contractility in atrial and ventricular myo­cardium . With the recent purification and cloning of adeno­sine receptors and subunits of G proteins, we can begin toexplore additional adenosine-mediated electrophysiologicmechanisms. Undoubtedly, the regulatory mechanisms ofthe adenosine-K

ATPchannel effector system in cardiac tissue

will be defined soon.

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Mayo Clio Proc, March 1995, Vol 70 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION 287

I r III

J , •

\,.~ - ..I · ·v

II'I

..

co'

>• r

I I f I I II I' " I I I I II

I , , I

. ",

I I I

"~'v

I

j • •. .)

I I

t I I./'j I

B

c

Fig. 13. Twelve-lead electrocardiogram (A) showing atrial fibrillation with preexcitation (Wolff-Parkinson-White syndrome). Ventricularrate was increased substantially after 6 mg (B) and 12 mg (C) of adenosine was injected intravenously.

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288 MOLECULAR DISSECTION OF ADENOSINE-MEDIATED ACTION

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Rev 1990; 70:761-8453. Sparks HV Jr, Bardenheuer H. Regulation of adenosine formation

by the heart. Circ Res 1986; 58:193-2014. Belardinelli L, West A, Crampton R, Berne RM. Chronotropic and

dromotropic action of adenosine. In: Berne RM, Rall TW, RubioR, editors. Regulatory Function of Adenosine. The Hague:Martinus Nijhoff Publishers, 1983: 378-398

5. Camm AJ, Garratt CL Adenosine and supraventriculartachycardia. N Engl J Med 1991; 325:1621-1629

6. DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L.Adenosine: electrophysiologic effects and therapeutic use for ter­minating paroxysmal supraventricular tachycardia. Circulation1983; 68:1254-1263

7. Belardinelli L, Isenberg G. Isolated atrial myocytes: adenosineand acetylcholine increase potassium conductance. Am J Physiol1983; 244:H734-H737

8. Nawrath H, Jochem G, Sack U. Ionotropic effect of adenosine inguinea pig myocardium. In: Stefanovich V, Rudolphi K, SchubertP, editors. Adenosine: Receptors and Modulation of Cell Function.Oxford (England): IRL, 1985: 323-340

9. Bruckner R, Fenner A, Meyer W, Nobis T-M, Schmitz W, ScholzH. Cardiac effects of adenosine and adenosine analogs in guinea­pig atrial and ventricular preparations: evidence against a role ofcyclic AMP and cyclic GMP. J Pharmacol Exp Ther 1985;234:766-774

10. Dobson JG Jr. Adenosine reduces catecholamine contractile re­sponses in oxygenated and hypoxic atria. Am J Physiol 1983;245:H468-H474

II. Dobson JG Jr. Mechanism of adenosine inhibition of catechol­amine-induced responses in heart. Circ Res 1983; 52:151-160

12. Raberger G, Kraupp 0, Stiihlinger W, Nell G, Chirikdjian JJ. Theeffects of an intracoronary infusion of adenosine on cardiac perfor­mance, blood supply and on myocardial metabolism in dogs.Pflugers Arch 1970; 317:20-34

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