adenosine: cellular mechanisms, pathophysiological roles and clinical applications

International Journal of Cardiology, 23 (1989) l-10 Elsevier

IJC 00830

Review

Adenosine: cellular mechanisms, pathophysiological roles and clinical applications

Bernard Clarke r and Michael Coupe ’

Departments of ’ Cardiology and ’ Clinical Pharmacology, Cardiothoracic Institute, Brompton Hospital, London, U.K.

(Received 28 July 1988; accepted 24 September 1988)

Key words: Adenosine; Pathophysiology; Pharmacology

Introduction

In a recent review in the Journal [l], we dis- cussed the relevance of advances in receptor pharmacology to the practice of clinical cardiology, including discussion of the present state of understanding of adenosine receptors. In this article we review the possible roles of adenosine (an endogenous purine nucleoside) in the pathophysiology and treatment of human disease, with particular emphasis on the cardiovascular system.

Historical Perspective

Interest in purine physiology and pharmacology began in 1929 when Drury and Szent-Gyorgi [2] undertook a series of experiments using a tissue extract, the active ingredient of which was identified as adenosine. When injected, adenosine was able to produce slowing of the sinus rate of the heart of several species (guinea pig, rabbit, cat). In addition, conduction through the atrio-

Correspondence to: B. Clarke, Dept. of Cardiology, Cardiothoracic Institute, Brompton Hospital, London SW3 6HP, U.K.

The authors are grateful to the British Heart Foundation for support.

ventricular node in the guinea pig heart was im- paired. Adenosine restored sinus rhythm in the dog when atria1 fibrillation was experimentally induced.

A number of other observations were made by these workers which were later to be of great interest to physiologists and physicians alike. Adenosine had differential effects on the force of contraction of atria1 muscle and ventricular muscle. Coronary blood flow was increased in the dog heart following injection of adenosine and there were effects in other organ systems, including inhibition of small intestinal movements, sedation, and reduction of renal blood flow and urine output.

In the 1930’s, several groups [3,4] showed that adenosine transiently slowed the ventricular rate due to impairment of atrioventricular conduction in patients with chronic atria1 flutter or fibrillation, but was unable to restore sinus rhythm. The doses employed in these studies were considerably greater than are now known to be necessary for the use of adenosine as an antiarrhythmic agent. Subsequently, it was noted that adenosine triphosphate, the parent nucleotide, could also produce bradycardia and hypotension [5].

The investigation of the physiological and bio- chemical aspects of the purines received little attention until 1963, when Robert Beme suggested

0167-5273/89/$03.50 0 1989 Elsevier Science Publishers B.V. (Biomedical Division)

2

that inosine and hypoxanthine, both metabolites of adenosine, were released from the ischaemic myocardium and proposed that adenosine formation was a homeostatic mechanism for matching local tissue flow to local metabolic demand [6].

The concept of adenosine as a “retaliatory metabolite” views adenosine as a controller, equalising local energy requirements with supply [7]. Under circumstances such as hypoxia, break- down of adenosine triphosphate will increase, leading to release of adenosine which, by vasodilatation, increases oxygen delivery and restores tissues towards physiological normality. Whether adenosine has any role in the maintenance of resting coronary vasomotor flow is doubtful [8,9] but exogenous administration of adenosine increases coronary flow in man [lo]. Autoregulation by adenosine of blood flow in the brain [ll]. skeletal muscle [12], and the liver [13] has, as yet, been only partially characterised.

Purine Receptor Pharmacology

The next major step in the understanding of purine physiology occurred when Bumstock proposed that separate pm-me receptors were present in various tissues throughout mammalian organs [14]. These receptors were classified into Pi and Pz variants. These two cell surface purine receptors differ in their affinity for adenosine. The Pi receptor has a preference for adenosine and is competi- tively inhibited by methylxanthines while the P2 receptor has an affinity for adenosine triphosphate. The observation that adenosine may inhibit or activate adenylate cyclase activity leads to the subdivision of the Pi receptor into Ri and R, subtypes [15]. The R nomenclature refers to the ribofuranose ring of the adenosine molecule (Fig. l), which must be intact for agonist activity. This classification has been superseded by that of Van Calker et al. [16], which divides adenosine receptors into A, and A, types based on the potency ratios of a series of adenosine analogues, notably L-phenylisopropyladenosine (PIA), and 5’-N-eth- ylcarboxamide adenosine (NECA), which exhibit relatively greater selectivity for the A, and A, receptors respectively. The definition in terms of agonist potency has some advantages over the

ADENOSINE

NH2 I

N,C,C/N

HA 0 %I

‘N’ LN’

““-yy”>C I

Ah-C H I/’

b” b”

Fig. 1. Structure of the adenosine molecule including the ribofuranose moiety which is essential for agonist activity.

adenylate cyclase classification, as adenosine receptors may be coupled to other second messenger systems [17,18]. Although there has been continuous debate in the literature over the appropriate nomenclature for the definition of adenosine receptors, the A, and A2 classification is established at present. This seems likely to remain so until data concerning protein sequences and analysis of the genetic structure of the receptors allows direct delineation and comparison of the different receptors at the structural level. Both A, and A2 receptors are widely distributed throughout the body; Table 1 illustrates their location and likely function at those sites.

Mechanisms of Action

The mechanisms of action of adenosine on cardiac tissue remain controversial. That adeno-

TABLE 1

Distribution and function of adenosine receptors.

Tissue Physiological effect

A, adenosine receptors Brain Sedation

Inhibition of neurotransmitter release Adipocyte Inhibition of lipolysis Testis Unknown Heart Suppression of contractility

Inhibition of sinoatrial node activity Inhibition of atrioventricular node activity

A, adenosine receptors Brain Modulate neurotransmitter release Platelet Inhibition of aggregation Smooth muscle Relaxation Kidney Vasoconstriction Liver Stimulation of gluconeogenesis

sine acts via modulation of adenylate cyclase activity is clear in both the fat cell [19] (inhibition via A, receptor activation) and the platelet (stimulation via A, receptor activation) [20], but this connection has been difficult to demonstrate in the heart. Various workers have demonstrated an increase [21], a decrease [22], or no change [23] in the rate of isoprenaline stimulated cyclic production of adenosine monophosphate in response to adenosine or its analogues.

A feature of the actions of adenosine on cardiac tissue has been the major species differences observed [24]. Thus, whilst adenosine has pro- found effects of the guinea pig heart [25], it seems to have little effect on the dog [26]. We have studied the effects of adenosine on adenylate cyclase on human heart removed at transplanta- tion, and shown, using a slice preparation, that in both atrium and ventricle the isoprenaline-induced increase in production of cyclic adenosine monophosphate is attenuated by analogues of adenosine [27]. The effects are greater in the atrium than the ventricle and the agonist potency ratio confirms the presence of the A, receptor in both chambers. Little effect is seen on resting tissue.

Thus, it appears that in human heart, the indi- rect actions of adenosine (that is the actions on catecholamine-stimulated tissue) are mediated via changes in activation of adenylate cyclase, whereas the direct actions on resting atria1 myocardium are not. It is likely that the direct actions are mediated by a direct effect of adenosine on the potassium channel [28].

Pathophysiology and Purines

Adenosine may play a role in the pathophysiology of a variety of human diseases. It is a bronchoconstrictor in asthmatics [29] but not in normal subjects. The bronchoconstriction induced is reversed by methylxanthines [30]. Injection of adenosine reproduces the pain of duodenal ulceration in patients with endoscopically proven ulcers [31], and one group has suggested that adenosine may also mimic the pain of angina pectoris in normal individuals [32]. Asphyxia occurs in around 1% of all deliveries and the degree of brain damage which ensues is related to the urinary excretion of

hypoxanthine [33], although to what extent the hypoxanthine is derived from degraded adenosine in such circumstances is not known. The depression of ventilation caused by adenosine may well be responsible for the apnoea associated with hypoxia at birth [34], although, paradoxically, adenosine causes tachypnoea when administered exogenously [35], probably through carotid body chemoreflexes [36]. Indeed, theophylline treatment has been shown to be beneficial in animal models of apnoea [37].

The intriguing suggestions that abnormalities of adenosine feedback or metabolism might play a role in the pathophysiology of cardiovascular diseases as diverse as hypertrophic cardiomyopathy and the “sick sinus” syndrome have yet to receive full investigation. Both adenosine and adenosine triphosphate interact with other neurotransmitters in both the peripheral and central nervous systems [38]. The action of adenosine as a modulator of neurotransmission and hence disease is seen in the brain in three different ways. Firstly, adenosine may influence the amount of neurotransmitter released [39]; secondly, the release of adenosine is dependent on certain neurotransmitters such as noradrenaline [40] and thirdly, as in the heart, effects of neurotransmitters may be regulated [41].

Adenosine may function as the brain’s “natural anticonvulsant” [42] and, in this context, may play a part both in the mechanism of action of anticonvulsant drugs such as phenytoin f43] and in the termination of spontaneous epileptic fits [42]. Other possible roles for adenosine which may have application in clinical cardiology include reduction of superoxide generation in by human neutrophils [44] and reduction in frequency of reperfusion ventricular arrhythmias [45] after coronary arterial occlusion.

Therapeutic Potential

Vasodilator activity

There is a clear distinction to be drawn between the effects of adenosine when given b.y continuous intravenous infusion compared to administration as an intravenous bolus. Adenosine infusion into normal subjects causes reproducible

4

[46] increases in heart rate and systemic vasodilatation, accompanied by minor systemic hypotension unaffected by beta-adrenergic blockade [47], and enhanced by drugs such as dipyridamole, an adenosine uptake inhibitor [48]. The cardiovascular effects of adenosine are antagonised by methylxanthines such as aminophylline [49].

Adenosine infusion has been used to induce and maintain controlled hypotension during neu- rosurgical operations for cerebral artery aneurysms [50], without either tachyphylaxis or rebound hypertension, possibly related to the inhibition by adenosine of renin release [51]. The dose required (200-300 pg/kg/min) is approximately three times the maximum which may be comfortably tolerated by conscious subjects.

Whether adenosine infusion can be used to allow selective pulmonary vasodilatation, an elu- sive goal in the therapy of pulmonary hypertension, remains to be examined. As adenosine is degraded by endothelial cells and blood elements, infusion of adenosine could in theory have a selective effect on the pulmonary vascular bed before saturation of clearance mechanisms leads to systemic spill-over. Certainly, adenosine relaxes human pulmonary vessels in vitro [52] and increases effective pulmonary blood flow (by increasing cardiac output) in normal subjects [53].

In addition, adenosine reduces platelet aggregation in vitro [54] and has been used to reduce platelet consumption during cardiopulmonary bypass in man [55]. This may be of considerable therapeutic importance, as during extracorporeal circulation for open heart surgery, up to 40% of circulating platelets may be lost.

Electrophysiological effects

Adenosine has a variety of differing electrophysiological effects on isolated atria1 and ventricular preparations from animals [56,57] and man [58]. Both voltage clamp [56] and flux studies [59] have shown that adenosine shortens the action potential duration and causes membrane hy- perpolarisation by activation of potassium conductance. This is supported by the finding that bromobenzyl-methyladamantylamine, a potassium-channel blocking agent, antagonises the ef-

fects of adenosine in the guinea pig atrium [60]. The post-receptor intracellular cascade which mediates the electrophysiological effects of adenosine is still not fully understood, with some workers suggesting that purinergic activation of potassium channels in cardiac cell membranes is either mediated via different intracellular mes- sengers, such as phosphatidylinositol phosphate [17] or is independent of such mechanisms [28].

In contrast to its effects on atria1 tissue, adenosine has only limited effects on the ventricular myocardium. In bovine and guinea pig ventricle, adenosine has no direct effect on any action potential parameters [57,61] but antagonises the actions of isoprenaline [62-641. Intracardiac recordings of monophasic action potentials ob- tained by the use of special catheters [65,66] have allowed the repolarisation of myocardial cells to be studied in man. The monophasic action potential duration at 90% of repolarisation is widely used to assess the effect of drug intervention. Adenosine transiently shortens the atria1 action potential in a dose-dependent fashion, but has no significant effect on the ventricular action potential duration in man [67,68]. The difference may be explained by an excess of A, adenosine receptors in the guinea pig atrium compared with the ventricle [69,70].

The regional electrophysiological effects of adenosine and its use as an antiarrhythmic agent have received considerable recent attention [71-731. This is to date the major area of therapeutic importance, as intravenously administered adenosine is useful both for the diagnosis and treatment of cardiac arrhythmias, particularly when the atrioventricular node is involved in their genesis (for example, atrioventricular re-entry tachycardias associated with the Wolff-Parkinson- White syndrome) (Fig. 2; Table 2). Transient preexcitation may be produced by the injection of adenosine both in sinus rhythm (Fig. 3) and after termination of atrioventricular re-entrant tachycardia (Fig. 4), when slowing of atrioventricular nodal conduction allows anterograde conduction over the accessory pathway to become visible on the surface electrocardiogram, suggesting another diagnostic use for adenosine. Slowing of the sinus rate and impairment of atrioventricular nodal con-

Fig. 2. Termination of atrioventricular re-entry tachycardia (AVRT) by adenosine. The R-R intervals are shown in the upper trace (Lead I). The termination of tachycardia is achieved by progressive prolongation of the A-H interval, seen most clearly on the His bundle electrogram (HBE). The paper speed is 100 mm/second. (I, standard lead I; AVF. standard lead AVF; Vl. V6, precordial

surface electrocardiogram; CS, coronary sinus electrogram; HBE. His bundle electrogram).

ADENOSINE 3mg

OF

Fig. 3. Transient appearance of ventricular preexcitation after intravenous injection of adenosine in sinus rhythm. Continuous electrocardiogram recording shows the appearance of a delta wave approximately 10 seconds after injection, with complete

disappearance of the effect within 25 seconds.

b

pm-excitation

Fig. 4. Termination of atrioventricular re-entry tachycardia by adenosine has allowed immediate exaggeration of ventricular preexcitation. This rapidly becomes less obvious disappearing within a few beats. The first complex shown is the first escape beat

after termination of atrioventricular re-entry tachycardia. Paper speed 100 mm/second.

TABLE 2

Effect of adenosine on cardiac arrhythmias.

Antiarrhythmic effecis

Usually terminated Atrioventricular re-entry tachycardia Atrioventricular nodal re-entry tachycardia “Catecholamine-driven” ventricular tachycardia

Sometimes terminated Ectopic atriaf tachycardia

His bundle tachycardia Long RP’ tachycardia

Rarely/never terminated Atria1 fibrillation Atrial flutter Ventricular tachycardia

Proarrhythmic effects of ndenosine Sinus bradycardia Re-initiation of tachycardia Complete heart block Atrial extrasystoles Ventricular extrasystoles Atrial fibrillation

duction means that although adenosine may not terminate arrhythmias of atria1 origin, for example atria1 flutter, it may slow the ventricular response such that an accurate diagnosis of the underlying arrhythmia may be made. The very rapid action and short half-life (less than 15 seconds) [74] of adenosine mean that it may be given repeatedly as required, and it appears to be safe in the clinical setting of paediatric practice [73,75] and in adult patients with a broad complex tachycardia [76]. The shortening of atria1 action potential duration by adenosine could theoretically facilitate the in- duction of atria1 fibrillation, although this has only been observed twice in clinical practice [71,77]. Attempts to deliver adenosine or its analogues by alternative routes, either orally [78] or by nebuliser [79] have so far been unsuccessful.

Recent reports of the termination of “catecholamine mediated” ventricular tachycardia by adenosine [80] raise an interesting therapeutic use for adenosine, but also add weight to the supposi-

tion that the effects of adenosine are mediated by alterations in accumulation of cyclic adenosine monophosphate in the myocardium [27]. Recently, the reversal by aminophylline of atropine resistant atrioventricular block following acute myocardial infarction in man has been reported [81]. Experi- mental work has demonstrated that hypoxia is associated with depressed atrioventricular nodal function, suggesting a possible therapeutic option for atropine-resistant atrioventricular block, namely the use of adenosine antagonists.

Future Developments

There now seems little doubt that adenosine will become established in the treatment of cardiovascular disease. Specific areas will need to be researched, however, before the full therapeutic potential of adenosine can be assessed, even though many theoretical possibilities exist. Dipyridamole is commonly used after coronary artery bypass grafting to inhibit platelet aggregation and the report by Watt and co-workers [82] emphasises that the interaction between adenosine and dipyridamole is important in clinical practice. Di- pyridamole potentiates the degree of atrioventricular block produced by intravenous adenosine approximately 7-fold [82] and so considerable cau- tion is required when adenosine is administered in the postoperative period. Other drugs are also able to potentiate the effect of adenosine, including hexobenidine and lidoflazine, for example [83], and an important interaction which has only recently been recognized is that between verapamil and adenosine [84]. This interaction requires further attention, as adenosine may well be administered to patients presenting with spontaneous supraventricular tachycardia after verapamil has failed where a smaller dose would be appropriate.

The investigation of substances which may modify the cardiovascular effects of adenosine is incomplete. The finding that adenosine reduces left ventricular end systolic dimension without any obvious detrimental change in left ventricular function (B. Clarke, unpublished results) implies that adenosine may be useful in the reduction of afterload in patients with low output states, for example cardiogenic shock, where the peripheral

and coronary vasodilator effects could potentially both be of benefit. In this context the absence of any effect of adenosine on the action potential is reassuring, but further studies are needed to ex- tend knowledge of the effects of adenosine in patients with ischaemic heart disease.

The safety and efficacy of adenosine in the treatment of supraventricular tachycardia is now established. The safety of adenosine in patients with other forms of cardiac conduction disease such as left bundle branch block, bi- and tri-fasic- ular block has not been reported. The negative chronotropic effects of purines may be pro- nounced in patients with sinuatrial disease [85].

The development of long-acting adenosine analogues for the A, and A, receptors has been the subject of scrutiny by pharmacologists for a number of years. A long-acting A, analogue would be useful in the termination and subsequent long-term control of supraventricular tachycardia which can- not be achieved by the use of the parent com- pound, adenosine, alone. It may be difficult to develop organ selective A, analogues; the A, receptor is found in the human kidney, and mediates a reduction in glomerular filtration rate [86] and so this potential hazard, and the theoretical occur- rence of hyperuricaemia, would require careful evaluation. A long-acting A, analogue [87] has been used to terminate experimental ventricular tachycardia, and so a number of exciting therapeutic possibilities are opened by this line of research.

The vasodilator effects of adenosine analogues have as yet received comparatively little attention. The pulmonary and systemic vasodilator effects of adenosine imply that A, analogues could be de- veloped which might allow chronic oral therapy of pulmonary hypertension and angina pectoris, although trials of adenosine analogues in angina have as yet been disappointing [78]. The difficulty which all analogues share is their lack of dis- crimination between adenosine receptors throughout the body: the use of nucleoside transporter inhibitors would provide a rational basis for more specific therapy, as they would only potentiate the effects of adenosine where it is produced, i.e., the potentiation would be only at the (pathological) site of adenosine release.

8

At present few nucleoside transporters are available for human use in vivo, primarily within the cardiovascular system. Although some workers have demonstrated the cardioprotective properties of nucleoside transport inhibitors in animals, pro- ving such benefits in human studies is much more difficult to establish and a great deal of research in this area is presently being undertaken. Cer- tainly an agent which potentiated several aspects of the action of adenosine and produced coronary vasodilatation, inhibited platelet aggregation, was antiarrhythmic, inhibited lipolysis and free radical production could be of enormous benefit.

The other area in which benefits may accrue is in the development of adenosine antagonists which are more specific, and could have a role in blocking pathophysiological responses mediated by adenosine, such as acute atrioventricular block. The pioneering work of Drury and Szent-Gyorgi in 1929 is now approaching fruition and the next few years should see adenosine in clinical use as a first-line antiarrhythmic agent for the treatment of supraventricular tachycardia and the vasodilator effects of the nucleoside exploited further.

Acknowledgements

We wish to thank Professor P.J. Barnes, Dr. P.J. Oldershaw and Dr. E. Rowland for their encouragement and advice during the preparation of this manuscript.

References

Coupe MO, Clarke B. The relevance of advances in receptor pharmacology to clinical cardiology. Int J Cardiol 1988;19:285-301. Drury AN, Szent-Gyorgi A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 1929;68:213-237. Jezer A, Oppenheimer BS, Schwartz SP. The effect of adenosine on cardiac irregularities in man. Am Heart J 1933;9:252-258. Honey RM, Ritchie WT. Thomson WAR. The action of adenosine upon the human heart. Q J Med 1930;23:485- 489. Wayne ET, Goodwin JF, Stoner HB. The effect of adenosine triphosphate on the electrocardiogram of man and animals. Br Heart J 1949;11:55-67. Berne RM. Cardiac nucleotides in hypoxia: possible role in

regulation of coronary blood flow. Am J Physiol 1963;204: 317-322.

7 Newby AC. Adenosine and the concept of retaliatory metabolites. Trends B&hem Sci 1984;9:42-44.

8 Dole WP. Autoregulation of the coronary circulation. Progr Cardiovasc Dis 1987;29:293-323.

9 Kroll K, Feigl EO. Adenosine is unimportant in controlling coronary blood flow in unstressed dog hearts. Am J Physiol H 1985;249:1176-1187.

10 Watt AH. Penny WJ, Singh H, Routledge PA, Henderson

11

12

13

AH. Adenosine causes transient dilatation of coronary arteries. Br J Clin Pharmacol 1987;24:665-668. Winn HR, Mot% S. The role of adenosine in autoregulation of cerebral blood flow. Ann Biomed Eng 1985:13:321-328. Dobson JG. Rubio R, Beme RM. Role of adenine nucleotides, adenosine and inorganic phosphate in the regulation of skeletal muscle blood flow. Circ Res 1971;29:375-384. Ezzat WR, Lautt WW. Hepatic arterial pressure-flow autoregulation is adenosine mediated. Am J Physiol H 1987;252:836-845.

14 Bumstock G. Purinergic nerves. Pharmacol Rev 1972;24: 509-581.

15 Londos C, Cooper DMF, Wolff J. Subclasses of external adenosine receptors. Proc Nat1 Acad Sci USA 1980;77: 2551-2554.

16 Van Calker D, Muller M, Hamprecht B. Adenosine regu- lates via two different types of receptors the accumulation of cyclic AMP in cultured brain cells. J Neurochem 1979;33:999-1005.

17

18

19

20

Rubio R, Bianchi J, Beme RM. Atrial negative inotropic effects of acetylchohne (ACh) and adenosine (ADO) are the result of the initial trigger of a positive inotropic mechanism. Pfliigers Arch 1986;407:S53. Stiles GL. Adenosine receptors: structure, function and regulation. Trends Pharmacol Sci 1986;7:486-470. Ukena D, Furler R, Lohse M, Schwabe U. Labelling of adenosine receptors in rat fat cell membranes with [1251]- N6-hydroxyphenylisopropyladenosine. Naunyn Schmiede- berg’s Arch Pharmacol 1984;326:233-240. Hutteman E. Ukena D, Lenchow V, Schwabe U. Ra adenosine receptors in human platelets: characterisation by 5’.N-ethylcarboxamido [ 3 Hladenosine binding in relation to adenylate cyclase activity. Naunyn Schmiedeberg’s Arch Pharmacol 1984;325:226-233.

21 Huang M, Drummond GI. Effect of adenosine on cyclic AMP accumulation in ventricular myocardium. Biochem Pharmacol 1976;25:2713-2719.

22 Dobson JG. Reduction by adenosine of the isoproterenol induced increase in cyclic adenosine 3,5-monophosphate formation and glycogen phosphorylase activity in rat heart muscle. Circ Res 1978;43:785-792.

23 Bruckner R. Fenner A, Meyer W, Nobis TM, Schmitz W. Scholz H. Cardiac effects of adenosine and adenosine analogs in guinea-pig atria1 and ventricular preparations: evidence against a role of cyclic AMP and cyclic GMP. J Pharmacol Exp Ther 1985;234:766-774.

24 Hopwood AM, Harding SE, Harris P. An antiadrenergic

9

effect of adenosine on guinea pig but not rabbit ventricles. Eur J Pharmacol 1987;137:67-75.

25 Bruns RF. In: Gerlach E, Becker BF, eds. Topics and perspectives in adenosine research. Berlin: Springer-Verlag, 1987;392.

26 Seitelberger R, Shutz W, Schlappack 0, Raberger G. Evi- dence against the adenosine-catecholamine antagonism under in viva conditions. Naunyn-Schmiedeberg’s Arch Pharmacol 1984;325:234-239.

27 Coupe MO, Kioumis I, Yacoub M, Barnes P, Oldershaw P. Adenosine/catecholamine antagonism is mediated by cyclic AMP in the human heart. Eur Heart J 1988;in press.

28 Kurachi Y, Nakajima T, Sugimoto T. On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atria1 cells; involvement of GTP-binding protein. Pfliigers Arch 1986;407:264-274.

29 Cushley MJ, Tattersfield AE, Holgate ST. Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 1983;15:161-165.

30 Dobson JG, Ordway RW, Fenton RA. Endogenous adenosine inhibits catecholamine contractile responses in normoxic hearts. Am J Physiol H 1986;251:455-462.

31 Watt AH, Lewis DJM, Home JJ, Smith PM. Reproduction of epigastric pain of duodenal ulceration by adenosine. Br Med J 1987;294:10-12.

32 Sylven C, Beermann B, Jonzon B, Brandt R. Angina pecto- &-like pain provoked by intravenous adenosine in healthy volunteers. Br Med J 1986;293:227-230.

33 Saugstad 0. Hypoxanthine as a measurement of hypoxia. Pediatr Res 1975;9:158-161.

34 Hedner T, Hedner J, Jonason J, Wessberg P. Effects of theophylline on adenosine induced respiratory depression in the preterm rabbit. Eur J Respir Dis 1984;65:153-156.

35 Fuller RJ, Maxwell DL, Conradson T-B, Dixon CMS. Barnes PJ. Circulatory and respiratory effects of infused adenosine in conscious man. Br J Clin Pharmacol 1987;24:309-317.

36 Watt AH, Reid PC, Stephens MR, Routledge PA. Adeno- sine-induced respiratory stimulation in man depends upon the site of infusion. Evidence for an action on the carotid body. Br J Clin Pharmacol 1987;23:486-490.

37 Lagerkrantz H, Yamamoto Y, Frcdholm BB, Prabhakar N. von Euler C. Adenosine analogues produce apnoea antagonised by theophylline in rabbit neonates. Pediatr Res 1984;18:387-390.

38 Bumstock G. Do some nerve cells release more than one transmitter. Neurosci Lett 1976;1:239-248.

39 Daly JW. Cyclic nucleotides in the nervous system. New York: Plenum, 1977.

40 Hedqvist P, Fredholm BB. Inhibitory effect of adenosine on adrenergic neuroeffector transmission in the rabbit heart. Acta Physiol Stand 1979;105:120-122.

41 Hollingsworth EB, Sears EB. Daly JW. An activator of protein kinase C (phorbol-12-myristate-13-acetate) aug- ments 2-chloroadenosine-elicited accumulation of cyclic AMP in guinea pig cerebral cortical particulate preparations. FEBS Lett 1985;184:339-342.

42 Dragunow M. Adenosine: the brain’s natural anticonvulsant. Trends Pharmacol Sci 1986;7:128-130.

43 Phillis JW. Interactions of the anticonvulsants diphenylhy- dantoin and carbamazepine with adenosine on cerebral cortical neurones. Epilepsia 1984;25:765-772.

44 Cronstein BN, Levin RI, Belanoff J, Weismann G, Hirschom R. A new function for adenosine: protection of vascular endothelial cells from neutrophil-mediated injury. In: Gerlach E, Becker BF, eds. Topics and perspectives in adenosine research. Berlin: Springer-Verlag, 1987;299-307.

45 Parratt JR, Boa&e-An&r G, Kane KA, Wainwright CL. Is adenosine an endogenous antiarrhythmic agent under conditions of myocardial ischaemia. In: Paton DM, ed. Adenosine and adenine nucleotides: physiology and pharmacology. London: Taylor and Francis, 1988;157-166.

46 Clarke B, Conradson T-B. Dixon CMS, Barnes PJ. Repro- ducibility of the heart rate changes during adenosine infusion in man. Eur J Clin Pharmacol 1988, in press.

47 Conradson T-B, Clarke B, Dixon CMS, Barnes PJ. Effects of adenosine on autonomic control of heart rate in man. Acta Physiol Stand 1987; 131:525-531.

48 Conradson T-B, Dixon CMS, Clarke B, Barnes PJ. Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole. Acta Physiol Stand 1987; 129:387-391.

49 Maxwell DL, Fuller RW, Conradson TB. et al. Contrasting effects of two xanthines, theophylline and enprofylline, on the cardiorespiratory stimulation of infused adenosine in man. Acta Physiol Stand 1987;131:459-465.

50 Sollevi A. Lagerkranser M. Irestedt L, Gordon E, Lindquist C. Controlled hypotension with adenosine during cerebral aneurysm surgery. Anesthesiology 1984;61:400-405.

51 Lagerkranser M, Sollevi A, Irestedt L, Tidgren B, Andreen M. Renin release during controlled hypotension with nitroprusside, nitroglycerin and adenosine; a comparative study in the dog. Acta Anaesth Stand 1985;29:45-49.

52 McCormack DC, Clarke BC, Barnes PJ. Characterisation of adenosine receptors in human pulmonary artery. J Phys- iol 1987;396:98.

53 Clarke B, Busst CM, Bush A, Barnes PJ. Effects of adenosine on pulmonary and systemic haemodynamics in man. Eur Heart J 1988;in press.

54 Born GVR. Honour AJ, Michell JRA. Inhibition by adenosine and by 2 chloroadenosine of the formation and embolization of platelet thrombi. Nature (London) 1964;202:761.

55 Sollevi A, Torsell L, Fredholm BB, Settergren G, Blomback M. Adenosine spares platelets during cardiopulmonary bypass in man without causing systemic vasodilatation. Stand J Thorac Cardiovasc Surg 1985;19:155-159.

56 Belardinelli L, Isenberg G. Isolated atria1 myocytes: adenosine and acetylcholine increase potassium conductance. Am J Physiol H 1983;244:734-737.

57 Belardinelli L, Isenberg G. Actions of adenosine and isoproterenol on isolated mammalian ventricular myocytes. Circ Res 1983;53:287-297.

58 Bohm M, Meyer W, Mugge A, Scmitz W, Scholz H. Func-

10

tional evidence for the existence of adenosine receptors in

the human heart. Em J Pharmacol 1985;116:323-326.

59 Jochem G, Nawrath H. Adenosine activates potassium

conductance in guinea pig atrial heart muscle. Experientia

1983;39:1347.

60 Meszaros J, Kelemen K, Kecskemeti V, Szegi J. Antagonism

between adenosine and bromobenzyl-methyladamantyla-

mine, a K+ channel blocker. in the atria1 myocardium of

guinea pig. Em J Pharmacol 1984;98:265.

61 Isenberg G, Belardinelh L. Ionic basis for the antagonism

between adenosine and isoproterenol on isolated mam-

malian ventricular myocytes. Circ Res 1984;55:309-325. 62 Bohm M, Bruckner R, Meyer W, et al. Evidence for

adenosine receptor mediated isoprenaline antagonistic ef-

fects of the adenosine analogs PIA and NECA on force of contraction in guinea pig atria1 and ventricular prepara-

tions. Naunyn-Schmiedeberg’s Arch Pharmacol 1985:331:

131-139.

63 Urthaler F, Woods WT, James TN, Walker AA. Effects of

adenosine on mechanical performance and electrical activ-

ity in the canine heart. J Pharmacol Exp Ther 1981;216:

256-260.

64 Bumstock G, Meghji P. The effect of adenyl compounds on

the rat heart. Br J Pharmacol 1983;79:211-218.

65 Olsson EB, Vamausaka E. Korsgren M. Further improved

method for measuring action potentials of the intact human

heart. J Electrocardiol 1971;4:19-23. 66 Franz M. Long-term recording of monophasic action

potentials from human endocardium. Am J Cardiol 1983;51:1629-634.

67 DiMarco JP, Lerman BB. Kabell G. Belardinelli L.

Adenosine produces different effects on monophasic action

potentials in human atrium and ventricle. J Am Co11 Cardiol

1988;11:A227. 68 Clarke B. The electrophysiological effects of adenosine.

Postgrad Med J 1988;in press.

69 Linden J, Hollen CE, Pate1 A. The mechanism by which

adenosine and choline& agents reduce contractility in rat

myocardium. Circ Res 1985;56:728-735.

70 Coupe M, Clarke B, Oldershaw PJ, Barnes PJ. Differing

physiological responses of atrium and ventricle to adenosine: correlation with receptor densities. Clin Sci 1988;74:61.

71 Munoz A, Leenhardt A, Sassine A, Galley P, Puech P.

Therapeutic use of adenosine for terminating spontaneous

paroxysmal supraventricular tachycardia. Eur Heart J

1984;5:735-738.

72 DiMarco JP, Sellers TD, Beme RM, West GA, Belardinelli

L. Adenosine: electrophysiological effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 1983;68:1254-1263.

73 Clarke B, Till J, Rowland E, Ward DE, Barnes PJ, Shineboume EA. Rapid and safe termination of supra-

ventricular tachycardia in children by adenosine. Lancet 1987;1:299-300.

74 Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 1983;93:

21-26.

75 Overholt ED, Rheuban KS. Gutgesell HP, Lerman BB,

DiMarco JP. Usefulness of adenosine for arrhythmias in

infants and children. Am J Cardiol 1988;61:336-340.

76 Griffith MJ. Linker NJ, Ward DE, Camm AJ. Adenosine

in the diagnosis of broad complex tachycardia. Lancet

1988;1:672-675.

77 DiMarco JP. Sellers TD, Lerman BB, Greenberg ML, Berne

RM, Belardinelli L. Diagnostic and therapeutic use of

adenosine in patients with supraventricular tachyar- rhythmias. J Am Co11 Cardiol 1985;6:417-425.

78 Irshad F. Dagenais GR, Fedor El, Cavanagh JH. Trials

with an adenosine analogue as antianginal medication. Clin

Pharmacol Ther 1977:22:470-474.

79 Coupe MO, Clarke B, Robson A. Oldershaw PJ, Barnes PJ.

Cardiovascular effects of nebulised adenosine. Eur J Clin

Pharmacol 1988; in press.

80 Lerman BB, Belardinelli L. West A, Berne RM, DiMarco

JP. Adenosine sensitive ventricular tachycardia: evidence

suggesting cyclic-AMP mediated triggered activity. Circula-

tion 1986;74:270-280.

81 Wesley RC, Lerman BB, DiMarco JP, Beme RM, Be-

lardinelli L. Mechanism of atropine-resistant attioventricu-

lar block during inferior myocardial infarction: possible

role of adenosine. J Am Co11 Cardiol 1986;8:1232-1234.

82 Watt AH, Bernard MS, Webster J, Passani SL, Stephens

MR. Routledge PA. Intravenous adenosine in the treatment

of supraventricular tachycardia: a dose-ranging study and interaction with dipyridamole. Br J Clin Pharmacol

1986;21:227-230.

83 Van Belle H. In viva effects of inhibitors of adenosine uptake. In: Paton DM ed. Adenosine and adenine nucleo-

tides; physiology and pharmacology. Taylor and Francis:

London, 1988;251-258.

84 Pelleg A, Mitamura H, Mitsuoka T, Mazgalev T, Michelson

EL, Dreifus LS. Interactive negative chronotropic actions

of adenosine and verapamil on the canine sinus node in

viva. In: Pelleg A, Michelson EL. Dreifus LS, eds. Cardiac

electrophysiology and pharmacology of adenosine and ATP: Basic and clinical aspects. New York: Alan Liss, 1987;235

PP. 85 Benedini G. Bolognesi RT, Affotato A, Gal10 G. Renaldini

E. Visioli 0. Value of purinic compounds in assessing sinus

node dysfunction in man: a new diagnostic method. Eur

Heart J 1984;5:394-403.

86 Sollevi A. Cardiovascular effects of adenosine in man: possible clinical implications. Prog Neurobiol 1986;27:

319-349. 87 Constantin L. Miller ML, Martins JB. N6-Rl-phenyl-2-

propyladenosine slows ventricular tachycardia in 24 hour old canine myocardial infarction by prejunctional inhibi-

tion of sympathetic nerves. Circulation 1986;74:11-1376.

adenosine: cellular mechanisms, pathophysiological roles and clinical applications

Documents