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A study on the mechanism of ventricular arrhythmias induced by adenosine

Gengsheng Yu, Li Zou, Yungru Qian, Wanzhen Li, Xiaomei Li, Jiarong Zhong, Tian Jie

Children's Hospital, Chongqing University of Medical Sciences
Chongqing, P.R China, 400014

Abstract
Introduction
Material and Methods
Results
Discussion
Conclusions
References

Abstract
Objectives: The goal of this study is to discusses how adenosine troposphere (ATP or adenosine) brings electrophysiological effect on the heart that is normal or with triggered activities in order to research on the mechanism of arrhythmias induced by adenosineIt
Method: A Franz 6F catheter was introduced into the left ventricle to record monophasic action potentials (MAPs) using the contact electrode technique to observe the influence to MAPs change of normal heart and with CsCl-induced triggered activities when adenosine is administered as an intravenous bolus.
Result: On one hand adenosine effects little on the amplitude and the maximal upstroke velocity (Vmax) of MAPs to normal heart. But at first the heart rate doesn't slow down evidently and adenosine induces early afterdepolarizations (EADs) that are associated with a prolonged the MAP duration (MAPD90), and the later period heart rate clearly slows and EAD disappears. On the hand it has biphasic effect on delayed after depolarization (DAD) or EAD induced by CsCl. At the initial stage it promotes afterdepolarization (EAD or DAD) temporarily and then abolish it fast.
Conclusion: The effect of adenosine is different to different heart states. It shows the biphasic effects of exciting and repression and it's related to dosage, it is importance to the clinic use adenosine.
[Keywords] Arrhythmia · Action potentials · Cesium · adenosine

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Introduction: Adenosine troposphere(ATP) changes into adenosine in blood after intravenous injection, it inhibits sinoatrial node atrioventricular node shortly and strongly. It is often reported that ATP or Adenosine causes bradyarrhythmias. But it is seldom reported that adenosine induces fatal arrhythmias (1,2), it is unknown about the mechanism of it. Triggered activity is one of the important mechanisms of arrhythmia. It is widely taken seriously. This study discusses the mechanism of adenosine induced-ventricular arrhythmias and the mutral influences of adenosine and triggered activities, using monophasic action potential (MAP) in vivo. It is very helpful to use adenosine in clinic.

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Material and Methods:
1. animals and MAP recording method:
    14 rabbits of both sexes weighing 3-3.8kg were anesthetized with Urethane (20 % 1.0/kg). MAPs were recorded using Franz electrode catheter, which was introduced via neck artery and positioned on left ventricular technique and by pressing a nonpolarizable electrode gently against the endocardium. After a stable recording of MAP was obtained about 5 minutes the medicine was used.

2. groups and injection methods:
    2.1 CsCl group (the model of CsCl-induced triggered activities):
Take rabbit 5 only, after a stable recording of MAPs was obtained, CsCl (1.0 mmol/kg) was administered as an intravenous bolus over 15  second via a catheter positioned in the neck vein. MAPs and the activities from surface ECG were recorded simultaneously at 10, 20, 30 second, 1, 3, 5 min. And every observation parameter's changing, and this procedure (CsCl 0.5 mmol/kg) was repeat every 15 min as long as a stable recording of MAPs could be obtained, and so the model of CsCl-induced triggered activities could be obtained.

    2.2  ATP group (adenosine’ influence on normal heart MAP):
Take rabbit 5 only, after a stable recording of MAPs was obtained, ATP (5mg, 10mg, 15mg/kg) was administered as an intravenous bolus over 3 second via a catheter positioned in the neck vein. MAPs and the activities from surface ECG were recorded simultaneously at 10, 20, 30 second, 1, 3, 5 min. And every observation parameter 's changing.

    2.3  Experimental group (received adenosine influences on CsCl-induced triggered activity).
Taking 4 rabbits after CsCl-induced triggered activities could be obtained, ATP (5mg, 10mg, 15mg/kg) was administered as an intravenous bolus over 3 second via a catheter positioned in the neck vein. MAPs and the activities from surface ECG were recorded simultaneously at 10, 20, 30 second, 1,  3, 5 min. And every observation parameter 's changing.

3.  Measurement.
    3.1 MAP parameters:
* MAP amplitude (MAPA , mV);
*   (2) MAP duration (MAPD, ms): MAPD 5 0 (MAP duration at a repolarization level of 50%) and MAPD 90 (MAP duration at a repolarization level of 90%);
*  The maximal. Upstroke velocity in phase 0 of MAP (Vmax , V/s).

    3.2 After depolarization parameters:
*After depolarization amplitude (EADA or DADA , mV);
*(2) After depolarization amplitude's percentage (EAD% or DAD %).

    3.3 Electrocardiogram parameter:
* Heart rate (H R , times/min);
*  Q - T interval (ms)

4. Statistical analysis
Experimental data are expressed as the mean±SE (X±SE). Mean values were compared by an analysis of variance, and then it was analyzed with the q test. Statistic copes with at PRIMER statistic software. A p<0.05 was considered indicative of statistically significant difference.

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Results:
1. CsCl group:
This group showed the characteristics of the triggered activities Induced by CsCl, Early Afterdepolarizations (EADs) Appeared in the middle-later period of phase 3 in MAP after CsCl; Delayed afterdepolarizations (DADs) could also Be induced by CsCl in the phase 4 of the MAPs in one rabbits. The amplitude of EAD was 6.3 % of total MAP amplitude was 33.8±4.36%. The potential changes of EADs could be divided into three kinds: i.e. the "tail", the "plateau" and "peak" shapes, and trigger arrhythmia. And generations of the triggered arrhythmias were suggested in the "plateau" or "peak" types. A threshold cumulative dose of CsCl-induced sustained VT is 1.6±0.28 mmol/kg. (See appendix table)

2 .ATP group.
This group showed the effect of ATP on the MAP of the endocardium of normal heart, which suggests At the beginning of ATP injection (within five seconds), the heart rate increased slightly, and MAP decreased a little. At the same time, zero phase Vmax decreased, but not significantly different from the situation before using the drugs. MAPD90, which corresponded to phase 3, had significant difference from before using the drugs (P<0.05), and obvious afterdepolarization was produced, mainly of which were DAD, and occurred in phase 3.

Their shapes were mostly "tail" and "plateau", with amplitude reaching 4+ 0.8 mV, EADA% reaching 21.3%+3.5%. And arrhythmias were induced, mainly of which were VPC and ventricular arrhythmias, effective period 1-3 seconds. After that EAD disappeared; the same happened to VPC; MAP shapes returned normal. When reaching the best effect, HR slowed significantly, which had significant difference with the situation before using the drugs (P<0.05); As for MAP, Vmax, MAPD90, they were not significantly changed compared with the situation before using the drugs. Graded doses injection produced the following results: 5mg group, 9 times of injections, 7 times (70%) of which produced EAD and triggered ventricular arrhythmia. 10 mg, 15 mg group, 6 injections, all resulting in triggered ventricular arrhythmia, which suggested that adenosine-induced afterdepolarization was related to its dosage;the larger the dosage, the easier it produces EAD and ventricular arrhythmia. (See appendix table)

3.Experimental group
This group shows the effect of ATP on the endocardium in vivo with the mechanism of triggered activities in existence. The results of the experiment suggested that, after the injection of CsCl, parameters like MAPD 50, MAPA, Vmax did not change significantly, while MAPD90 and Q-T interval prolonged significantly. The application of ATP later shortened MAPD & Q-T interval (reaching the level before using CsCl). What is worth noticing is ATP's effect lasted a short time. Several seconds after, MAPD90 was prolonged again with the accompanying appearance of EAD; Its effect on Vmax MAPA was at first obvious suppressing, then recovered gradually after quite a few seconds.

Application of ATP at the effective peak of CsCl (20-30 seconds) aggravated EAD at the beginning and triggered ventricular arrhythmia; after that, it would suppress EAD and the ventricular arrhythmias it induced. It took effect quickly and lasted shortly. And ATP may make the CsCl-induced EAD appear again. When using ATP to terminate the secondary DAD after CsCl-induced EAD, a transiently aggravated DAD also appeared, and triggered arrhythmias, even ventricular fibrillation; then it would suppress DAD and abolish triggered activities. (See appendix table

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Discussion: ATP-triggered arrhythmias, especially transient sinus bradycardia, SA block, AV block, sinus pause have frequently appeared in reports. ATP, as other anti-arrhythmia agents, also could induce quick arrhythmias. However, they have different mechanism. Knowledge about the latter is especially little(3). MAP as a new technique employed in this experiment to investigate the electrophysiologic features and the mechanism of arrhymias of heart in vivo is a safe and reliable method(4). In recent years, it has gradually entered into the basic and clinic research of cardiovascular disease.

Triggered activities are a transient membrane oscillation after-potential triggered by cardiac depolarization. It always happens after a depolarization, thus also named afterdepolarization. According to the phases of after potential, it is divided into early afterdepolarization (EAD) and delayed afterdepolarization (DAD). Factors that can induce triggered activities include: extracellular hypoklemia, catecholamine, anoxia, ischemic condition, cardiac infarction, etc. Generally, its formation mechanism is related to activated L-type Ca++ current and calcium overloading(5). Triggered activities have already been generally considered be one of the important mechanisms of arrhythmia. CsCl-induced EAD has already been proved to be a stable animal experiment model, because CsCl was able to induce Calcium release in sacroplasmic and to activate L-type Calcium channel. Our research result also suggests that CsCl injection can induce stable EAD model, which would pace the ground for a further study into the occurrence, development, and termination factors of triggered activities.

1.Adenosine's electrophysiologic effects on the MAP of endocardium of normal heart.
We applied 3 dosages of adenosine (5mg, 10mg, 15mg) for bolus injection, and the results were: different dosage has different effect on normal hearts. Lower dosage causes less change in heart compared with heavy dosage. The greater a dosage, the more obvious it would cause changes in heart, the longer the effectiveness would last. This suggests that adenosine dosages in clinic use should increase gradually. Dosages should not be too much. At the beginning of adenosine's taking effects, depolarization usually happens, and usually triggers arrhythmias, including VPC and ventricular tachycardia. Its difference from the research on isolated myocardial cells is probably because the drug mediates the excitation of reflex sympathetic nervous(3). It is once reported that light dosage of adenosine is related to excitation of the ventricular autonomy(12). Researches on isolated myocardial cells have shown that with the existence of catecholamine, afterdepolarization could be produced(7). This suggests that isolated cells differ essentially with hearts in vivo, and that adenosine's effect on hearts should not only be researched at the level of isolated myocardial cells.

2.Adenosine's physiologic effect on existing triggered activities.
Many researchers have investigated the effect of triggered activities, having proved that adenosine can terminate cAMP-mediated triggered activities(10); Researches on isolated myocardial cells proves ATP will promoter the formation of afterdepolarization and triggered activities(7). This experiment suggests: we can establish a model of triggered activities to study ATP's biphasic effects on triggered activities of heart in vivo. On the one hand, at the beginning of its effect, it will increase EAD's original amplitude, and may induce ventricular arrhythmia; On the other hand, at the peak of ATP effect, it will suppress EAD and DAD induced by CsCl. Its mechanism is probably that afterdepolarization is related to calcium overloading. With more inward current of Ca++, ATP will activate the adenosine-sensitive calcium channel in sacroplasmic reticulum, transiently promote the release of Ca++, thus aggravating the overloading of calcium. For this reason, afterdepolarization is increased and induces ventricular arrhythmia, even ventricular fibrillation. Then it will suppress calcium channels, reducing its numbers and decreasing the inward current, thus terminate triggered activities in the end.

Adenosine may induced triggered activities of heart. Its mechanism may be related to the adenosine-sensitive calcium channels in sacroplasmic reticulum activated by adenosine(9). The features of these triggered activities are : 1.occuring at the beginning of bolus intravenous injection, before causing significant heart suppressing; 2. Mainly are EADs, with shapes mostly "tail " or "plateau". 3. At the peak of EAD, ventricular arrhythmias could be triggered ,which occurs more easily when with existing triggered activities. 4. It lasts shortly and disappears quickly. ventricular arrhythmia usually disappears automatically.

From all the above we can conclude that, to both normal hearts and hearts with existing triggered mechanism, adenosine may have biphasic effects, and may induce fatal arrhythmias. So adenosine is not only a kind of heart suppressor, it may also be an excitation of the autonomy of hearts. Adenosine has a different effect on hearts in vitro and hearts in vivo, which suggests that in its clinic use, especially dealing with myocardiopathy, myocardosis, shock, heart failure, digitalis poisoning which may mean a heart with existing triggered mechanism, we should be very cautious in case severe (even fatal) arrhythmias occurs.

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References:

1. Pella J., Strancal B., Komamova et al. Ventricular fibrillation after administration of adenosine. Vnitr Jek. 1995,41,12,832-5
2. Smith JK., Gold Berger JJ., Kadish AH. Adenosine induced polymorphic ventricular tachycardia in adults without structural heart disease. Pacing Clin Etectriphysio1, 1997, 20(3pt1), 743-5
3. Luo Chunyuan, He Gueiping, Gu Yiyi at al. Tachyarrhythmias are induced after adenosine troposphere intravenous bolus injection. Chinese Journal of Circulation. 1993, 5: 287
4. Yuni1m  S., B1omrtrom-Lundgvist, Olsson SB. Monophasic action potential, concept to practical applications. J Cardiovascular Electrophysiol. 1994, 5: 287
5. Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential: II afterdepolarization triggered activity and potentiation. Circulation. 1994, 74(6): 1097-1113
6.Pattereon E, Szado B, Scherlay BJ, et al. Early and delayed afterdepolarization associated with cesium chloride-induced arrhythmias in the dog. J Cardiovascular Pharmacology. 1990,15:323
7.Sony Y, Belardineli L. ATP pronotes development of afterdepolarization and triggered active in cardiac myocytes. Am J physical. 1994,26:2005
8. Zhu Li, Yang Xiangjun, Jiang Wenping. Action and mechanism of Adenosine on cardiac myocytes electrophysiologicalology. Chinese Journal of Cardiol, 1997, 2 5 (2): 8 9
9.Smitti JS, Coronado K, Meissner G Sarcoplusmic reticulum contains adenine nucleotide-activated calcium channels. Nature. 1985, 316:446
10.Lerman BB, Belardinelli L. Cardiac electrophyslology of adenosine: Basic and clinical concepts. Circulation. 1991 83:1499
11.Wesly RC Jr, Turguest P. Toreadesdepointe after intravenous adenosine in the presence of prolonged QT syndrome. Am Heart J. 1992,123:794
12. Hernandez J, Ribeiro JA. Excitatory actions of adenosine on ventricular automatically. Trends Pharmacol Sci .1996, 17(4): 141-4

 

Questions, contributions and commentaries to the Authors: send an e-mail message (up to 15 lines, without attachments) to ARRITMIAS@listserv.rediris.es , written either in English, Spanish, or Portuguese.

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Update
Ene/28/2000