Cardiac cellular electrophysiologic actions of adenosine and adenosine triphosphate

Riemenschneider September, 1985

American Heart Journal

other granting agencies. The Standards Committees of our Section of Cardiology, under the effective leadership of Dr. L. Scott, has developed a policy statement on peer review (overwhelmingly approved by vote of the membership) which provides a structure and mechanism to enable programs to perform voluntary internal review annually, and external peer review every 3 years. Through the Northern Great Plains Registry, Dr. J. Moller is developing a computer model for patient data gathering and analysis of results of catheterization and surgery, which will eventually allow us to compare our results with data collected on a nationwide basis. Such a program is needed to ensure that our individual efforts meet accepted standards, but equally as important, to fulfill our responsibility to society to provide the absolute best care to children with heart diseases. Finally, our national organizations can provide opportunities to examine the difficult issues facing us by serving as a focus for national clinical trials of new methods of treatment, for evaluation of new diagnostic and therapeutic technology, and for continuing education programs designed to main- tain and upgrade skills of pediatric cardiologists.

Perhaps as never before, great challenges face us as individuals and in our specialty. We must learn to use our resources more efficiently in the care of

children with heart diseases. Cardiologists must determine and communicate to the public the prop- er balance between quality of care and cost of care. Together we must define the appropriate uses of invasive and noninvasive tests, interventional catheterization techniques, surgery for complex heart defects and heart and heart-lung transplantation. We must determine when and whether resources should be allocated for specific types of care, and clarify the ethical, moral, social, and medico-legal issues associated with our patient care activities. In an era of unprecedented public scrutiny of medicine, we must define for the public realistic expectations for the outcome of our efforts, because, despite recent extraordinary successes in treatment, much of what we do still must be considered as the “art of medicine” rather than the “science.”

As we advance to meet the challenges of the future, we must remember and be guided by the standards and commitments of those who began our specialty in the late 1950s. We owe it to them to continue the work they began; we owe it to society, which has entrusted to us the care of children with heart diseases; and we owe it to the generations of children yet unborn, who will experience a more productive and fulfilling life, if our efforts are successful.

Cardiac cellular electrophysiologic actions of adenosine and adenosine triphosphate

Amir Pelleg, Ph.D. Philadelphia, Pa.

Since the classical observations of Drury and Szent- Gyorgyi in 1929,’ it has been known that adenosine and adenosine triphosphate (ATP) exert pronounced electrophysiologic effects on the mammalian heart. In recent years these effects as well as their clinical implications have attracted growing atten- tion. The electrophysiologic actions of adenosine

From the Lankenau Medical Research Center, Division of Cardiology.

Received for publication March 4, 1985; accepted Apr. 10, 1985.

Reprint requests: Amir Pelleg, Ph.D., The Lankenau Medical Research Center, Division of Cardiology, Lancaster and City Line Aves., Philadel- phia, PA 19151.

and ATP at the organ level and their clinical aspects have been recently reviewed.2-4 The present review focuses on the cellular electrophysiologic actions of adenosine and ATP, an important topic which has not been reviewed heretofore.

Effects on atrial myocardium. Adenosine and ATP have been shown to have a pronounced hyperpolarizing effect in quiescent, spontaneously active and driven myocardial atrial preparations. In 1956, Johnson and McKinnonS studied the effects of adenosine on guinea pig atrial fibers driven at constant rate. They found that adenosine increased the rate of action potential repolarization but it did not

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affect its rate of rise (dV/dt), membrane potential, or conduction velocity. In addition, the action of adenosine was not altered by the muscarinic cholinergic blocker, atropine.5 Similar findings with ATP were reported by Hollander and Webb,6 who studied driven rat atrial preparations. Both ATP and adenosine caused a dose-dependent decrease in action potential duration and only a slight decrease in membrane potential as well as action potential amplitude and overshoot. Atropine did not modify these effects of adenosine and ATP.6 Almost a decade later, DeGubareff and Sleator7 showed that adenosine affected the human atria1 tissue in a similar manner. They reported that the action potential duration of driven human atria1 muscle strips was shortened due to adenosine-induced increase in the rate of membrane repolarization. This action of adenosine, which was not affected by atropine, was antagonized by caffeine.7

Important information concerning the mechanism of the hyperpolarization action of adenosine and ATP has been obtained in more recent studies. Using the frog sinus venous, Hartzella has shown that the similar hyperpolarization effects of adenosine and ATP were competitively antagonized by aminophylline and were not affected by ouabain. In addition, these effects were not altered by atropine but were enhanced in the presence of the adenosine transport blocker, dipyridamole.s Furthermore, high molecular weight analogs of adenosine, which are transported more slowly into the cells, had more pronounced effects than adenosine. HartzelP con- cluded that the electrophysiologic action of adenosine, which does not involve stimulation of the ouabain sensitive electrogenic pump, is mediated by an extracellular P,-purinoceptor.s The possible involvement of intracellular purinoceptors in the mechanism of action of adenosine was proposed by Szentmiklbi et aLlo In congruence with Hartzell’s results, these authors found that aminophylline antagonized the electrophysiologic effects of adenosine in isolated, electrically driven left atria of guinea pig hearts.‘O, *l Their provocative finding was that coformycin, a highly potent and specific inhibitor of the intracellular enzyme adenosine deaminase, significantly enhanced the electrophysiologic action of adenosine. lo However, more studies are required to support this hypothesis before a definite conclusion concerning possible involvement of intracellular P, receptor in the electrophysiologic action of adenosine can be reached.

More recent voltage clamp12~‘” and flux studies13 have indicated that the shortening of the action potential duration and membrane hyperpolarization

caused by adenosine are probably due to activation of potassium conductance. This conclusion is supported by the antagonism between adenosine and bromobenzoyl-methyladamantylamine, a new potassium channel blocker.14

Effects on sinoatrial and atrioventricular nodes. Sur- prisingly, only a few studies attempted to evaluate the cellular electrophysiologic effects of adenosine and ATP on the sinoatrial (SA) and atrioventricular (AV) nodes. Adenosine exerted a dose-dependent depressant effect on the guinea pig SA node automaticity.15, l6 This was associated with diminution of action potential amplitude’” and reduced rate of slow diastolic (phase 4) depolarization.1s~16 Prelimi- nary reports by Pelleg et al.” showed that exposure to adenosine resulted in a pronounced increase in the spontaneous cycle length of the rabbit SA node which was associated with shifts of the maximal diastolic and takeoff potentials toward more nega- tive values. In addition, adenosine caused pronounced augmentation of the vagal induced length- ening of sinus cycle.17 The predominant mechanism of the latter phenomenon appeared to be a decrease in rate of diastolic depolarization, and to a lesser extent, an increase in vagal induced maximal hyperpolarization.‘7 Results of the first systematic and quantitative study of adenosine’s effects in sinus node cells were most recently reported by West and Belardinelli.lR~ lg They showed that adenosine caused a reversible pacemaker shift in isolated perfused rabbit hearts as well as in isolated rabbit sinus node cells.lR In addition, using a preparation that pre- cluded pacemaker shift, it was shown that adenosine caused (1) a significant increase in maximal diastolic potential, (2) a significant increase in rate of rise of the action potential, and (3) a significant decrease in the rate of diastolic depolarization.ls Using various pharmacologic interventions, West and Belardinel- lils found that the hyperpolarization actions of adenosine and acetylcholine involve similar mechanisms (increased potassium conductance) but are mediated by different receptors. They also found that ouabain caused slight nonsignificant enhancement of the hyperpolarizing effect of adenosine.lY Inter- estingly, three decades ago Rand et a1.2n reported that the atrioventricular block produced by adenosine in the guinea pig heart was increased up to 10 times by doses of ouabain, which were otherwise without significant effect.

Applying a patch-clamp method to rabbit AV nodal cells, Kakei and Noma”’ found that in the inside-out patch, application of ATP at the inner surface of the patch membrane reversibly blocked K’ channel activity. Thus, little is known about the

690 Pelleg September, 1985


mechanisms of actions of adenosine and ATP in the SA and AV nodes. There is an urgent need to fill this void, since adenosine could be involved in cardiac arrhythmias and conduction disturbances associated with acute myocardial ischemia (see Discussion in reference 22).

Effects on ventricular myocardium. Early studies by Johnson and McKinnon5 showed that adenosine did not have any significant electrophysiologic effect in guinea pig ventricular myocardium. In concert with these results, Belardinelli and Isenbergz3* 24 found recently that adenosine in concentrations up to 0.2 mM had no significant effect on any of the action potential parameters of isolated bovine and guinea pig ventricular myocytes.

However, adenosine has been reported to affect the electrophysiologic characteristics of stimulated action potentials in quiescent canine right ventricular trabeculae.25 In this preparation, adenosine significantly reduced action potential rate of rise as well as its duration without affecting resting potential and action potential overshoot.25 It should be noted here that the latter results were obtained at a temperature of 25 2 0.1’ C.25 Since the effects of adenosine are inversely related to the temperature,‘sz6 probably due to temperature-dependent adenosine transport,27 a relatively low temperature of 25’ C could have altered the magnitude of adenosine effects.25

Effects on Purkinje fibers. Szentmiklosi et al. reported that adenosine suppressed the automaticity of isolated guinea pig Purkinje fibers by decreas- ing the rate of slow (phase 4) diastolic depolarization.*‘j Similar results were obtained by Rosen et a1.,28 who reported that adenosine, but not 8, y- methylene ATP, a stable active analog of ATP, significantly attenuated the automaticity of canine cardiac Purkinje fibers. However, in a different study with paced canine cardiac Purkinje fibers, adenosine up to 10e4 M produced no effects on action potential characteristics.2g

Membrane stabilizing action. Recent studies have indicated that in addition to its direct electrophysiologic effects, adenosine modulates the electrophysiologic actions of catecholamines in various cardiac tissues. Using right ventricular strips from lo- to l&day-old embryonic chick hearts, Belardinelli et a130 showed that adenosine antagonized the increase in slow action potential amplitude and rate of rise produced by isoproterenol in the presence of tetro- dotoxin (TTX). Similar results were obtained in isolated bovine and guinea pig ventricular myocytes. In these preparations adenosine blunted the prolon- gation of the fast rising action potential duration

and the displacement of the plateau phase to a more positive potential caused by isoproterenolz3 In addition, adenosine also reduced the amplitude of after- depolarization and abolished sustained rhythmic activity induced by isoproterenol.23 These effects of adenosine were probably due to antagonism by adenosine of the isoproterenol-induced increase in maximal calcium conductance (gc,) as well as in the nonactivating component of ica.24 In isolated canine cardiac Purkinje fibers, adenosine blunted the automaticity induced by epinephrine,2s antagonized the action potential shortening induced by isoprotere- no1,2g and increased the catecholamine-shortened escape interval.2g

In at least one study,3l adenosine appeared to mitigate the inhibitory action of acetylcholine on the action potential. Using the voltage clamp technique, Goto et aL3’ found that in the bullfrog atrium, adenosine noncompetitively inhibited the acetylcholine-induced steady current and the delayed outward current. However, in view of the nonphysio- logic doses of adenosine (3 X low3 M) used in this study, interpretation of the results of Goto et al.“’ should be done with great caution.

Effects on slow action potentials. In 1975 Schrader et al.32 and later Rubio et al.33 reported that adenosine and ATP abolished isoproterenol-induced action potentials in potassium depolarized guinea pig atrial muscle fibers. The blockade of the slow action potentials by adenosine could be rapidly reversed by the addition of adenosine deaminase to the bathing medium or by elevation of extracellular calcium ion concentration.32 It was later demonstrat- ed that this effect of adenosine is due to decreased number of functional slow channe1s.34 More recently, it has been shown that adenosine depressed slow action potential induced by agents other than isoproterenol. For example, adenosine blocked slow action potential induced by phosphatidic acid or by phospholipase D in rat atria.35 Furthermore, in a different study, adenosine caused a dose-dependent decrease in the amplitude, rate of rise, and duration of slow action potentials induced by bromobenzoyl- methyladamantylamine, a K’ channel blocker, in guinea pig atrial preparation depolarized with high concentration of extracellular potassium ion.14 Using rat atrial tissue, Rubio et al.36 confirmed the depressant effect of adenosine on slow action potentials. In addition, they found that various molecular size adenosine polymers had different physiologic action, i.e., higher molecular weight polymers decreased the slow action potential duration without affecting their upstroke velocity, while the smallest polymers acted only on the upstroke velocity.“6

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These data were intrepreted by Rubio et a1.36 to suggest that the depressed slow action potential rate of rise and duration due to reduced Ca2+ influx and increased gk+, respectively, are probably mediated by two different adenosine receptors with different degrees of accessibility.

Variable results were obtained when the effects of adenosine on slow channel dependent action potential were studied in ventricular myocardium and Purkinje fibers of various species. Rubio et a1.33 reported that adenosine did not affect isoproterenol- induced slow action potentials of guinea pig ventricular cells depolarized with high extracellular K’. In concert with these results, adenosine had no effect on slow action potentials elicited by intense electrical stimulation in TTX treated right ventricular strips of lo- to l&day-old chick embryonic hearts30 However, Rardon and Baileym have recently reported that in intact canine Purkinje fibers adenosine antagonized isoproterenol-restored calcium-dependent action potentials in 22 mmol/L extracellular K+, but it did not affect slow calcium-dependent action potentials in Na+-free high-Ca2+ (22 mmol/L) so1ution.2g In addition, these authors have observed that adenosine attenuated isoproterenol-restored calcium-dependent action potentials in isolated right ventricular guinea pig papillary muscles (Rar- don and Bailey, unpublished data). A recent study by Isenberg and Belardinelli24 in isolated bovine and guinea pig ventricular myocytes supports the former report. Thus, Isenberg and Belardinelli24 found that adenosine caused a moderate but significant attenuation of slow action potentials enhanced by isoproterenol in 25 mmol/L K+. However, adenosine com- pletely antagonized the isoproterenol-induced increase of slow action potentials obtained in Na+- free medium.24 In another recent study, Knabb et a1.3’ found that exogenous adenosine depressed isoproterenol-induced slow action potential amplitude and rate of rise in potassium depolarized left atrial and ventricular strips of the rat heart. In addition, they found that this action of adenosine in atrial tissue was not dependent on isoproterenol concentration, but in ventricular tissue was manifested only in the presence of small doses of isoproterenol (i.e., <10m6 mol/L). 37* These results are at variance with those of Schneider et al.,38 who reported that adenosine failed to affect slow action potential induced by low concentration of isoproterenol (i.e.,

*Interestingly. similar dose-dependent antagonism by adenosine was also

observed with respect to the positive inotropic effect of norepinephrine in isolated guinea pig right ventricular papillary muscle (Hattori and Levi: J Pharmacol Exp Therap 231:215. 1984).

1W7 mol/L) in potassium depolarized guinea pig ventricular cells. There is no immediate explanation for this discrepancy. It seems, however, that the action of adenosine on the slow action potential in the ventricle depends, at least in part, on the type of tissue (Purkinje fibers versus working myocardium) as well as the mode of induction. Slow channel dependent action potential induced by low concentrations of isoproterenol in high [K.‘]” are probably more vulnerable to the depressant action of adenosine than those induced either with high concentrations of isoproterenol or by increased intensity of electrical stimulation in the presence of TTX.

It is interesting to note here that extracellular or intracellular ATP has a pronounced effect on the slow channels. Schneider and Sperelakis3g found that in the guinea pig perfused heart depolarized with 27 mmol/L K+, the addition of a relatively high concentration of ATP (0.1 mmol/L) to the perfusate rapidly induced slow response. This action of ATP was not blocked by proprano101.3Y More recently it has been reported that intracellular injection of ATP in guinea pig single ventricular cells resulted in increased amplitude of slow inward current4” These effects are probably due to an indirect metabolic action of ATP on the slow channels.41, “’

Different results with respect to the action of adenosine and related compounds on slow action potentials were obtained in the amphibian atrium. Goto et a1.43,44 showed that in frog atria1 tissue ATP and adenosine diphosphate (ADP) augmented slow inward calcium current; this was accompanied by delayed enhancement of outward current. In a similar preparation adenylyl-imidodiphosphate (AMP- PNP), a nonhydrolyzable analog of ATP, caused an immediate increase in overshoot, plateau level, and duration of the action potential without any appre- ciable change in resting membrane potential.45 The electrophysiologic action of ATP was not mediated via &adrenergic receptors, since it was not altered in the presence of propranolol.4” Thus, the actions of adenosine and ATP exhibit marked species variabil- ity; ATP but not adenosine enhances slow inward current in the amphibian heart but both suppress slow channel-dependent action potential in the mammalian heart.

Resemblance of acetylcholine. The electrophysiologic effects of adenine compounds were compared with those of acetylcholine in various experimental models. Similar effects of adenosine and acetylcholine were found in the frog sinus venosusA as well as in guinea pigs, l3 and human7 atria1 fibers. In these studies acetylcholine was much more potent than adenosine. However, using isolated guinea pig atria1

692 Pelleg

cells, Belardinelli and Isenberg’* found that not only the actions of adenosine on membrane K+ conductance were indistinguishable from those of acetylcholine, but also that these effects resulted from similar concentrations and occurred with a similar time course. The equipotency of adenosine and acetylcholine was explained by the lack of significant uptake and deamination of adenosine by the isolated myocytes in contrast to multicellular preparations.12

The electrophysiologic effects of adenosine in the mammalian ventricle also resemble those of acetylcholine (for a review, see reference 46). Thus, the only apparent difference between these two compounds is that the effects of adenosine are blocked by xanthine derivatives and those of acetylcholine are blocked by atropine. Therefore, it seems that both substances activate the same potassium channel population and that this action is mediated by different receptor.12s l3

Physiological role. Adenosine and ATP exert pronounced electrophysiologic effects on the atria1 and ventricular myocardium. In view of the fact that adenosine is released from mammalian myocardial cells during physiologic47 as well as pathophysiologic conditions (e.g., ischemia)4s,4g it can be assumed that adenosine has a physiologic role not only in coronary hemodynamics50 but also in cardiac electrophysiology. These two different actions (i.e., the hemody- namic and electrophysiologic) are apparently mediated via two different purinoceptor subtypes.51 The facts that in the mammalian myocardial tissue in vitro, adenosine and ATP are equipotent and that the effects of both are antagonized and enhanced by aminophylline and dipyridamole respectively, suggest that in the mammalian heart the electrophysiologic action of ATP is not mediated via specific receptors for ATP (P,-purinoceptors). Thus, it seems that the action of ATP depends on its enzy- matic breakdown to adenosine. This hypothesis is supported by the fact that p, y-methylene ATP, a stable analog of ATP, does not have a significant effect on either the SA node, when administered into the SA nodal artery (Pelleg et al., unpublished results), or on Purkinje fibers in vitro.2s Further- more, in dogs with complete autonomic blockade, the electrophysiologic actions of ATP do not differ from those of adenosine and both are influenced in a similar manner by aminophylline and dipyrida- mo1e.52 However, further testing is required before this issue is conclusively resolved.

Conclusions. Both adenosine and ATP alter ion permeabilities to Ca2+ and K+ of myocardial cell membrane and thus modulate transmembrane cur-

September, 1995


rents. In the mammalian atrium, adenosine and ATP suppress inward calcium current and increase outward potassium current. These direct effects on cell membrane result in shortened action potential duration and hyperpolarization of resting membrane potential. In addition, adenosine and ATP antagonize the electrophysiologic action of cathe- cholamines. In the mammalian ventricular myocardium these compounds apparently do not have a direct effect, however, they probably antagonize the electrophysiologic action of catecholamines.* The electrophysiologic actions of adenosine and ATP are similar to those of acetylcholine, but they are mediated, at least in part, via extracellular purinoceptors and not by muscarinic cholinergic receptors. Finally, those effects of ATP which are not dependent on the autonomic nervous system probably result from its rapid breakdown to adenosine by ectoenzymes.

I wish to thank Dr. Todor Mazgalev for fruitful discussions and Rose Marie Wells for secretarial assistance in the preparation of this manuscript.

*Note that evidence against the adenosine-catecholamines antagonism under in viva conditions has recently been reported (Seitelberger et al:Arch Pbarmacol 325234, 1984).

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Cardiac cellular electrophysiologic actions of adenosine and adenosine triphosphate