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Influence of Beta-Adrenergic and Vagal Activity on the Effect of Exogenous Adenosine on Supraventricular Tachycardia Termination
Influence of Beta-Adrenergic and Vagal Activity on the Effect of Exogenous Adenosine on Supraventricular Tachycardia Termination Ching-Tai Tai, MD, Shih-Ann Chen, MD, Chern-En Chiang, MD, Shih-Huang Lee, Zu-Chi Wen, MD, Mau-Song Chang, MD, and Sheng-Nan Wu, MD, PhD
MD,
Adenosine, which binds to cell surface receptors and couples with guanosine triphosphate-binding inhibitory proteins (Gi), is potent in terminating supraventricular tachycardia (SVT). However, whether the differences in autonomic tone will influence this effect remains unknown. This study was designed to investigate the role of b-adrenergic and vagal activity on the action of adenosine. Forty patients with clinically documented SVT (22 with atrioventricular node reentrant tachycardia and 18 with atrioventricular reciprocating tachycardia) were divided into 4 groups with 10 patients in each group. In groups 1 and 2, adenosine was intravenously injected during the baseline state and during infusion of isoproterenol (2 and 4 mg/min, respectively). Group 2 patients received atropine (0.04 mg/kg) injection before isoproterenol infusion. In groups 3 and 4, intravenous injection of adenosine was given during the baseline state and after injection of atropine (0.02 and 0.04 mg/kg, respectively). Group 4 patients received propranolol
(0.2 mg/kg) before atropine injection. The minimal dose of adenosine to terminate tachycardia during isoproterenol infusion of 2 mg/min was greater than that during the baseline state in both groups 1 and 2. The minimal dose of adenosine during isoproterenol infusion with 4 mg/min was higher than that with 2 mg/min in group 2, but not in group 1 patients. In both groups 3 and 4, the minimal dose of adenosine required to terminate tachycardia during atropine injection with 0.02 mg/kg was greater than that during the baseline state. The minimal effective dose of adenosine during atropine injection with 0.04 mg/kg was higher than that with 0.02 mg/kg in group 4, but not in group 3 patients. In conclusion, either limb of the autonomic nervous system may modulate the adenosine dosage required for termination of SVT. Patients taking drugs such as b blockers or vagolytic agents may need alterations in the dose of adenosine for therapy. Q 1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;79:1628–1631)
t is known that in supraventricular tissues, adenosine and acetylcholine bind to the different cellIsurface receptors, but elicit the same population of
According to the cellular mechanism of adenosine, we hypothesized that changes in either limb of the autonomic nervous system should modulate the effects of adenosine. Therefore, the goal of the present study was to examine whether alteration in badrenergic and vagal activity might affect the dose of the exogenously injected adenosine required for termination of supraventricular tachycardia.
potassium channels which are referred to as acetylcholine/adenosine-regulated potassium channels, i.e., KACh,Ado channels.1,2 The adenosine- or acetylcholine-induced activation of these channels is coupled to the guanosine triphosphate-binding inhibitory proteins (Gi). When the Gi proteins are activated, the opening probability of KACh,Ado channels can directly be increased or the sympathetic activation can indirectly be attenuated by inhibition of the adenylate cyclase.3,4 Although exogenous adenosine has been used as a diagnostic or therapeutic agent for supraventricular tachycardia, its electrophysiologic effects under the different extent of autonomic tone are not well studied.5 – 9 From the Division of Cardiology, Department of Medicine, National Yang-Ming University, School of Medicine, and Veterans General Hospital, Taipei and Kaohsiung, Taiwan, Republic of China. This study was supported in part by Grants NSC 85-2331-B-075-071, 85-2331-B-010-047, and 85-2331-B-010-048 from the National Science Council, Taipei, Taiwan, Republic of China. Dr. Lee is from Shin-Kong Memorial Hospital, Taipei, Taiwan, Republic of China. Manuscript received November 4, 1996; revised manuscript received and accepted February 20, 1997. Address for reprints: Shih-Ann Chen, MD, Division of Cardiology, Veterans General Hospital-Taipei, 201 Section 2, Shih-Pai Road, Taipei, Taiwan, Republic of China.
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METHODS Patient characteristics: Forty patients (20 men and 20 women, mean age 47 { 12 years [range 20 to 70]) in whom supraventricular tachycardia had been documented were referred to electrophysiologic study and radiofrequency catheter ablation in this institution. Twenty-two patients had atrioventricular (AV) node reentrant tachycardia and 18 had AV reciprocating tachycardia. Baseline electrophysiologic study and electropharmacologic protocols: All patients were in the postab-
sorptive, nonsedated state after being informed about this study and the possible adverse effects. Details of electrophysiologic study were described previously.10,11 In all patients studied, supraventricular tachycardia had been inducible in the baseline state. Patients were divided into 4 separate groups with 10 patients in each group. The clinical and electrophysiologic characteristics summarized
Q1997 by Excerpta Medica, Inc. All rights reserved.
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0002-9149/97/$17.00 PII S0002-9149(97)00211-7
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RESULTS
TABLE I Clinical and Electrophysiologic Characteristics
Effects of adenosine under beta-adrenergic stimulation with isoproterenol:
Group
The lowest doses of adenosine needed to terminate supraventricular tachycardia during the baseline Age (yr) 46 { 13 46 { 10 49 { 13 48 { 14 state, and during 2 and 4 mg/min of Men/women 4/6 5/5 6/4 5/5 isoproterenol infusion were 52 { AVNRT (no.) 5 5 6 6 AVRT (no.) 5 5 4 4 21, 72 { 26, and 67 { 26 mg/kg in Tachycardia cycle length (ms) 319 { 37 320 { 37 332 { 41 332 { 44 group 1, respectively, and 59 { 21, Drugs 78 { 16, and 98 { 13 mg/kg in Isoproterenol / / 0 0 group 2, respectively. Mean tachyAtropine 0 / / / cardia cycle length and mean artePropranolol 0 0 0 / rial blood pressure during the baseAVNRT Å atrioventricular node reentrant tachycardia; AVRT Å atrioventricular reciprocating tachycardia. line state and during 2 and 4 mg/min of isoproterenol infusion were 319 in Table I did not differ significantly among these { 37 ms/92 { 9 mm Hg, 287 { 20 ms/81 { 13 mm 4 groups. In group 1 patients, intravenous bolus Hg, and 277 { 16 ms/76 { 10 mm Hg in group 1, injection of adenosine was given in the absence respectively, and 320 { 37 ms/91 { 7 mm Hg, 269 and presence of isoproterenol infusion (2 and 4 mg/ { 29 ms/78 { 6 mm Hg, and 261 { 25 ms/72 { 5 min, respectively). Group 2 patients underwent the mm Hg in group 2, respectively. The minimal effecsame study protocol as group 1, except that they tive dose of adenosine required to terminate tachyreceived muscarinic receptor blockade with atro- cardia in the presence of isoproterenol (2 mg/min) pine (0.04 mg/kg) before isoproterenol infusion. In infusion was significantly greater than that during the group 3 patients, intravenous bolus injection of baseline state in both groups 1 and 2. However, the adenosine was given during the baseline state and lowest effective dose of adenosine during 4 mg/min after injection of atropine (0.02 and 0.04 mg/kg, of isoproterenol infusion was significantly higher respectively). Group 4 patients underwent the than that during 2 mg/min of isoproterenol infusion same study protocol as group 3, except that they in group 2, but not in group 1 (Figure 1). received b-adrenoceptor blockade with propranoEffects of adenosine under muscarinic blockade with atropine: The lowest doses of adenosine needed to lol (0.2 mg/kg) before atropine injection. The minimum dose of adenosine to reproducibly terminate supraventricular tachycardia during the terminate sustained supraventricular tachycardia was baseline state, and during 0.02 and 0.04 mg/kg of determined. Supraventricular tachycardia was de- atropine injection were 60 { 22, 83 { 20, and 83 fined as sustained if it was maintained for ¢2 { 22 mg/kg in group 3, respectively, and 60 { 22, minutes before intravenous bolus injection of aden- 72 { 20, and 86 { 17 mg/kg in group 4, respecosine. When sustained tachycardia occurred, a rapid tively. Mean tachycardia cycle length and mean arinjection of adenosine was administered through the terial blood pressure during the baseline state and femoral vein followed by a rapid saline flush. In each during 0.02 and 0.04 mg/kg of atropine injection case, the initial dose of adenosine (60 mg/kg) fol- were 332 { 41 ms/91 { 6 mm Hg, 291 { 22 ms/ lowed by a stepwise decrease or increase of 15 mg/ 77 { 6 mm Hg, and 294 { 26 ms/72 { 4 mm Hg kg was given to determine the lowest effective dose in group 3, respectively, and 332 { 44 ms/90 { 6 of adenosine for termination of tachycardia. The mm Hg, 296 { 31 ms/77 { 6 mm Hg, and 290 { minimum adenosine dose was usually given twice to 27 ms/72 { 4 mm Hg in group 4, respectively. The validate its effectiveness. If the response to the sec- lowest dose of adenosine needed to terminate tachyond injection was ineffective, the same dose of aden- cardia during 0.02 mg/kg of atropine injection was osine was given again to determine its effectiveness. significantly higher than that during the baseline Between each dose of adenosine tested, there was a state in both group 3 and 4 patients; however, its 3-minute interruption for the recovery of AV nodal minimal dose during 0.04 mg/kg of atropine injecfunction. tion was significantly higher than that during 0.02 Statistical analysis: Data were expressed as mean mg/kg of atropine injection in group 4, but not in { SD. The minimal effective doses of adenosine group 3 (Figure 2). Effects of adenosine in terminating atrioventricular to terminate tachycardia in the baseline state, and during 2 and 4 mg/min of isoproterenol infusion nodal reentrant tachycardia and atrioventricular recipwere compared by the 2-tailed paired t test in each rocating tachycardia: The minimal effective dose of group 1 and 2 patient. The minimal effective doses adenosine to terminate tachycardia did not signifiof adenosine to terminate tachycardia in the base- cantly differ among the different types of tachycarline state, and during 0.02 and 0.04 mg/kg of at- dia. The mean minimal dose of adenosine in patients ropine injection, were compared by the 2-tailed with AV reciprocating tachycardia was 58 { 21 mg/ paired t test in each group 3 and 4 patient. A p kg (n Å 18), whereas that in patients with AV nodal value õ0.05 was considered statistically signifi- reentrant tachycardia was 57 { 22 mg/kg (n Å 22) cant. (p ú0.05). In patients with AV reciprocating tachy1 (n Å 10)
2 (n Å 10)
3 (n Å 10)
4 (n Å 10)
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FIGURE 1. The minimal effective dose of adenosine required to terminate supraventricular tachycardia in the baseline state and with 2 and 4 mg/min of isoproterenol infusion. A and B, respectively, represent the data points derived from group 1 patients (without atropine injection) and group 2 patients (with atropine injection).
FIGURE 2. The minimal effective dose of adenosine required to terminate supraventricular tachycardia in the baseline state and with 0.02 and 0.04 mg/kg of atropine injection. A and B, respectively, represent the data points derived from group 3 patients (without propranolol injection) and group 4 patients (with propranolol injection).
cardia, the exogenously injected adenosine terminated tachycardia by blocking conduction in the AV node, except for 1 patient in whom the accessory pathway was blocked. In all patients with AV nodal reentrant tachycardia, adenosine terminated tachycardia by blocking conduction on the anterograde slow AV nodal pathway.
DISCUSSION The present study showed that isolation of either limb of autonomic regulation promotes a linear relation between the autonomic limb involved and 1630
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dose of adenosine required to terminate supraventricular tachycardia. A previous study by Lauer et al6 reported that the minimal doses of adenosine required to terminate catecholamine-dependent and catecholamine-independent supraventricular tachycardias were not different, and that the levels of endogenous epinephrine and norepinephrine did not correlate with the minimal effective dose of adenosine. Thus, it was suggested that adenosine exerted its effect on AV nodal conduction primarily through its effects on KACh,Ado channels, irrespecJUNE 15, 1997
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tive of the b-adrenergic system.6,12 In contrast, our study showed that the minimal dose of adenosine required to terminate supraventricular tachycardia was higher with isoproterenol infusion than with the dose used in the control group, although there was no significant difference in the adenosine dose between isoproterenol infusion with 2 and 4 mg/ min. The difference between our study results and those of Lauer et al may be explained by a different patient population. In the study by Lauer et al, catecholamine-dependent supraventricular tachycardia was defined as a tachycardia that could only be induced and sustained with isoproterenol infusion, whereas all patients enrolled in our study had inducible tachycardia in the baseline state. When an atropine injection was administered before the isoproterenol infusion, there was a linear relation between the dose of isoproterenol and the dose of adenosine required for interruption of the tachycardia. Thus, in the absence of atropine, intravenous isoproterenol infusion actually caused an increase in vagal restraint that elicited reflex modification of cholinergic input to the AV node,13 and was different from the condition of exercise that would initiate abrupt withdrawal of the vagal tone, serious increase of the sympathetic tone, and elaborate secretion of catecholamines. With atropine (0.02 and 0.04 mg/kg), the minimal dose of adenosine to terminate tachycardia was significantly elevated. This result suggested that basal vagal activity contributes to the effect of adenosine on termination of supraventricular tachycardia. Furthermore, the reflex sympathetic activity may be increased because of higher heart rate and lower blood pressure when atropine was administered; thus, more adenosine dose was needed to antagonize the effect of b-adrenergic stimulation caused by endogenous catechol-
amines, irrespective of atropine dose. When b-adrenergic blockade with propranolol was given before atropine injection, the minimal adenosine dose under atropine injection of 0.04 mg/kg was significantly greater than that of 0.02 mg/kg. Thus, in the presence of propranolol, there is a more linear relation between muscarinic cholinergic activity and the adenosine dose required for interruption of tachycardia. 1. Kurachi Y, Nakajima T, Sugimoto T. On the mechanism of activation of
muscarinic K/ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins. Pfluegers Arch 1986;407:264–274. 2. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M. Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J 1995;9:359–365. 3. Lerman BB, Belardinelli L. Cardiac electrophysiology of adenosine: basic and clinical concepts. Circulation 1991;83:1499–1509. 4. LaMonica DA, Frohloff N, Dobson JG Jr. Adenosine inhibition of catecholamine-stimulated cardiac membrane adenylate cyclase. Am J Physiol 1985;248:H737–H744. 5. Lai WT, Wu SN, Sung RJ. Negative dromotropism of adenosine under betaadrenergic stimulation with isoproterenol. Am J Cardiol 1992;70:1427–1431. 6. Lauer MR, Young C, Liem LB, Sung RJ. Efficacy of adenosine in terminating catecholamine-dependent supraventricular tachycardia. Am J Cardiol 1994;73:38–42. 7. DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 1983;68:1254–1263. 8. DiMarco JP, Sellers TD, Lerman BB, Greenberg ML, Berne RM, Belardinelli L. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. J Am Coll Cardiol 1985;6:417–425. 9. Griffith MJ, Ward DE, Linker NJ, Camm AJ. Adenosine in the diagnosis of broad complex tachycardia. Lancet 1988;1:672–675. 10. Chen SA, Chiang CE, Yang CJ, Cheng CC, Wu TJ, Wang SP, Chiang BN, Chang MS. Accessory pathway and atrioventricular node reentrant tachycardia in elderly patients: clinical features, electrophysiologic characteristics and results of radiofrequency ablation. J Am Coll Cardiol 1994;23:702–708. 11. Chen SA, Chiang CE, Yang CJ, Cheng CC, Wu TJ, Wang SP, Chiang BN, Chang MS. Sustained atrial tachycardia in adult patients: electrophysiologic characteristics, pharmacologic response, possible mechanism and effects of radiofrequency ablation. Circulation 1994;90:1262–1278. 12. Clemo HF, Belardinelli L. Effect of adenosine on atrioventricular conduction. I. Site and characterization of adenosine action in the guinea pig atrioventricular node. Circ Res 1986;59:427–463. 13. Arnold JMO, McDevitt DG. Vagal activity is increased during intravenous isoprenaline infusion in man. Br J Clin Pharmacol 1984;18:311–316.
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MD,
Adenosine, which binds to cell surface receptors and couples with guanosine triphosphate-binding inhibitory proteins (Gi), is potent in terminating supraventricular tachycardia (SVT). However, whether the differences in autonomic tone will influence this effect remains unknown. This study was designed to investigate the role of b-adrenergic and vagal activity on the action of adenosine. Forty patients with clinically documented SVT (22 with atrioventricular node reentrant tachycardia and 18 with atrioventricular reciprocating tachycardia) were divided into 4 groups with 10 patients in each group. In groups 1 and 2, adenosine was intravenously injected during the baseline state and during infusion of isoproterenol (2 and 4 mg/min, respectively). Group 2 patients received atropine (0.04 mg/kg) injection before isoproterenol infusion. In groups 3 and 4, intravenous injection of adenosine was given during the baseline state and after injection of atropine (0.02 and 0.04 mg/kg, respectively). Group 4 patients received propranolol
(0.2 mg/kg) before atropine injection. The minimal dose of adenosine to terminate tachycardia during isoproterenol infusion of 2 mg/min was greater than that during the baseline state in both groups 1 and 2. The minimal dose of adenosine during isoproterenol infusion with 4 mg/min was higher than that with 2 mg/min in group 2, but not in group 1 patients. In both groups 3 and 4, the minimal dose of adenosine required to terminate tachycardia during atropine injection with 0.02 mg/kg was greater than that during the baseline state. The minimal effective dose of adenosine during atropine injection with 0.04 mg/kg was higher than that with 0.02 mg/kg in group 4, but not in group 3 patients. In conclusion, either limb of the autonomic nervous system may modulate the adenosine dosage required for termination of SVT. Patients taking drugs such as b blockers or vagolytic agents may need alterations in the dose of adenosine for therapy. Q 1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;79:1628–1631)
t is known that in supraventricular tissues, adenosine and acetylcholine bind to the different cellIsurface receptors, but elicit the same population of
According to the cellular mechanism of adenosine, we hypothesized that changes in either limb of the autonomic nervous system should modulate the effects of adenosine. Therefore, the goal of the present study was to examine whether alteration in badrenergic and vagal activity might affect the dose of the exogenously injected adenosine required for termination of supraventricular tachycardia.
potassium channels which are referred to as acetylcholine/adenosine-regulated potassium channels, i.e., KACh,Ado channels.1,2 The adenosine- or acetylcholine-induced activation of these channels is coupled to the guanosine triphosphate-binding inhibitory proteins (Gi). When the Gi proteins are activated, the opening probability of KACh,Ado channels can directly be increased or the sympathetic activation can indirectly be attenuated by inhibition of the adenylate cyclase.3,4 Although exogenous adenosine has been used as a diagnostic or therapeutic agent for supraventricular tachycardia, its electrophysiologic effects under the different extent of autonomic tone are not well studied.5 – 9 From the Division of Cardiology, Department of Medicine, National Yang-Ming University, School of Medicine, and Veterans General Hospital, Taipei and Kaohsiung, Taiwan, Republic of China. This study was supported in part by Grants NSC 85-2331-B-075-071, 85-2331-B-010-047, and 85-2331-B-010-048 from the National Science Council, Taipei, Taiwan, Republic of China. Dr. Lee is from Shin-Kong Memorial Hospital, Taipei, Taiwan, Republic of China. Manuscript received November 4, 1996; revised manuscript received and accepted February 20, 1997. Address for reprints: Shih-Ann Chen, MD, Division of Cardiology, Veterans General Hospital-Taipei, 201 Section 2, Shih-Pai Road, Taipei, Taiwan, Republic of China.
1628
METHODS Patient characteristics: Forty patients (20 men and 20 women, mean age 47 { 12 years [range 20 to 70]) in whom supraventricular tachycardia had been documented were referred to electrophysiologic study and radiofrequency catheter ablation in this institution. Twenty-two patients had atrioventricular (AV) node reentrant tachycardia and 18 had AV reciprocating tachycardia. Baseline electrophysiologic study and electropharmacologic protocols: All patients were in the postab-
sorptive, nonsedated state after being informed about this study and the possible adverse effects. Details of electrophysiologic study were described previously.10,11 In all patients studied, supraventricular tachycardia had been inducible in the baseline state. Patients were divided into 4 separate groups with 10 patients in each group. The clinical and electrophysiologic characteristics summarized
Q1997 by Excerpta Medica, Inc. All rights reserved.
/ 2w24 5044 Mp
1628
Tuesday May 13 06:18 PM
0002-9149/97/$17.00 PII S0002-9149(97)00211-7
EL–AJC (v. 79, no. 12 ’97)
5044
RESULTS
TABLE I Clinical and Electrophysiologic Characteristics
Effects of adenosine under beta-adrenergic stimulation with isoproterenol:
Group
The lowest doses of adenosine needed to terminate supraventricular tachycardia during the baseline Age (yr) 46 { 13 46 { 10 49 { 13 48 { 14 state, and during 2 and 4 mg/min of Men/women 4/6 5/5 6/4 5/5 isoproterenol infusion were 52 { AVNRT (no.) 5 5 6 6 AVRT (no.) 5 5 4 4 21, 72 { 26, and 67 { 26 mg/kg in Tachycardia cycle length (ms) 319 { 37 320 { 37 332 { 41 332 { 44 group 1, respectively, and 59 { 21, Drugs 78 { 16, and 98 { 13 mg/kg in Isoproterenol / / 0 0 group 2, respectively. Mean tachyAtropine 0 / / / cardia cycle length and mean artePropranolol 0 0 0 / rial blood pressure during the baseAVNRT Å atrioventricular node reentrant tachycardia; AVRT Å atrioventricular reciprocating tachycardia. line state and during 2 and 4 mg/min of isoproterenol infusion were 319 in Table I did not differ significantly among these { 37 ms/92 { 9 mm Hg, 287 { 20 ms/81 { 13 mm 4 groups. In group 1 patients, intravenous bolus Hg, and 277 { 16 ms/76 { 10 mm Hg in group 1, injection of adenosine was given in the absence respectively, and 320 { 37 ms/91 { 7 mm Hg, 269 and presence of isoproterenol infusion (2 and 4 mg/ { 29 ms/78 { 6 mm Hg, and 261 { 25 ms/72 { 5 min, respectively). Group 2 patients underwent the mm Hg in group 2, respectively. The minimal effecsame study protocol as group 1, except that they tive dose of adenosine required to terminate tachyreceived muscarinic receptor blockade with atro- cardia in the presence of isoproterenol (2 mg/min) pine (0.04 mg/kg) before isoproterenol infusion. In infusion was significantly greater than that during the group 3 patients, intravenous bolus injection of baseline state in both groups 1 and 2. However, the adenosine was given during the baseline state and lowest effective dose of adenosine during 4 mg/min after injection of atropine (0.02 and 0.04 mg/kg, of isoproterenol infusion was significantly higher respectively). Group 4 patients underwent the than that during 2 mg/min of isoproterenol infusion same study protocol as group 3, except that they in group 2, but not in group 1 (Figure 1). received b-adrenoceptor blockade with propranoEffects of adenosine under muscarinic blockade with atropine: The lowest doses of adenosine needed to lol (0.2 mg/kg) before atropine injection. The minimum dose of adenosine to reproducibly terminate supraventricular tachycardia during the terminate sustained supraventricular tachycardia was baseline state, and during 0.02 and 0.04 mg/kg of determined. Supraventricular tachycardia was de- atropine injection were 60 { 22, 83 { 20, and 83 fined as sustained if it was maintained for ¢2 { 22 mg/kg in group 3, respectively, and 60 { 22, minutes before intravenous bolus injection of aden- 72 { 20, and 86 { 17 mg/kg in group 4, respecosine. When sustained tachycardia occurred, a rapid tively. Mean tachycardia cycle length and mean arinjection of adenosine was administered through the terial blood pressure during the baseline state and femoral vein followed by a rapid saline flush. In each during 0.02 and 0.04 mg/kg of atropine injection case, the initial dose of adenosine (60 mg/kg) fol- were 332 { 41 ms/91 { 6 mm Hg, 291 { 22 ms/ lowed by a stepwise decrease or increase of 15 mg/ 77 { 6 mm Hg, and 294 { 26 ms/72 { 4 mm Hg kg was given to determine the lowest effective dose in group 3, respectively, and 332 { 44 ms/90 { 6 of adenosine for termination of tachycardia. The mm Hg, 296 { 31 ms/77 { 6 mm Hg, and 290 { minimum adenosine dose was usually given twice to 27 ms/72 { 4 mm Hg in group 4, respectively. The validate its effectiveness. If the response to the sec- lowest dose of adenosine needed to terminate tachyond injection was ineffective, the same dose of aden- cardia during 0.02 mg/kg of atropine injection was osine was given again to determine its effectiveness. significantly higher than that during the baseline Between each dose of adenosine tested, there was a state in both group 3 and 4 patients; however, its 3-minute interruption for the recovery of AV nodal minimal dose during 0.04 mg/kg of atropine injecfunction. tion was significantly higher than that during 0.02 Statistical analysis: Data were expressed as mean mg/kg of atropine injection in group 4, but not in { SD. The minimal effective doses of adenosine group 3 (Figure 2). Effects of adenosine in terminating atrioventricular to terminate tachycardia in the baseline state, and during 2 and 4 mg/min of isoproterenol infusion nodal reentrant tachycardia and atrioventricular recipwere compared by the 2-tailed paired t test in each rocating tachycardia: The minimal effective dose of group 1 and 2 patient. The minimal effective doses adenosine to terminate tachycardia did not signifiof adenosine to terminate tachycardia in the base- cantly differ among the different types of tachycarline state, and during 0.02 and 0.04 mg/kg of at- dia. The mean minimal dose of adenosine in patients ropine injection, were compared by the 2-tailed with AV reciprocating tachycardia was 58 { 21 mg/ paired t test in each group 3 and 4 patient. A p kg (n Å 18), whereas that in patients with AV nodal value õ0.05 was considered statistically signifi- reentrant tachycardia was 57 { 22 mg/kg (n Å 22) cant. (p ú0.05). In patients with AV reciprocating tachy1 (n Å 10)
2 (n Å 10)
3 (n Å 10)
4 (n Å 10)
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FIGURE 1. The minimal effective dose of adenosine required to terminate supraventricular tachycardia in the baseline state and with 2 and 4 mg/min of isoproterenol infusion. A and B, respectively, represent the data points derived from group 1 patients (without atropine injection) and group 2 patients (with atropine injection).
FIGURE 2. The minimal effective dose of adenosine required to terminate supraventricular tachycardia in the baseline state and with 0.02 and 0.04 mg/kg of atropine injection. A and B, respectively, represent the data points derived from group 3 patients (without propranolol injection) and group 4 patients (with propranolol injection).
cardia, the exogenously injected adenosine terminated tachycardia by blocking conduction in the AV node, except for 1 patient in whom the accessory pathway was blocked. In all patients with AV nodal reentrant tachycardia, adenosine terminated tachycardia by blocking conduction on the anterograde slow AV nodal pathway.
DISCUSSION The present study showed that isolation of either limb of autonomic regulation promotes a linear relation between the autonomic limb involved and 1630
THE AMERICAN JOURNAL OF CARDIOLOGYT
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dose of adenosine required to terminate supraventricular tachycardia. A previous study by Lauer et al6 reported that the minimal doses of adenosine required to terminate catecholamine-dependent and catecholamine-independent supraventricular tachycardias were not different, and that the levels of endogenous epinephrine and norepinephrine did not correlate with the minimal effective dose of adenosine. Thus, it was suggested that adenosine exerted its effect on AV nodal conduction primarily through its effects on KACh,Ado channels, irrespecJUNE 15, 1997
EL–AJC (v. 79, no. 12 ’97)
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tive of the b-adrenergic system.6,12 In contrast, our study showed that the minimal dose of adenosine required to terminate supraventricular tachycardia was higher with isoproterenol infusion than with the dose used in the control group, although there was no significant difference in the adenosine dose between isoproterenol infusion with 2 and 4 mg/ min. The difference between our study results and those of Lauer et al may be explained by a different patient population. In the study by Lauer et al, catecholamine-dependent supraventricular tachycardia was defined as a tachycardia that could only be induced and sustained with isoproterenol infusion, whereas all patients enrolled in our study had inducible tachycardia in the baseline state. When an atropine injection was administered before the isoproterenol infusion, there was a linear relation between the dose of isoproterenol and the dose of adenosine required for interruption of the tachycardia. Thus, in the absence of atropine, intravenous isoproterenol infusion actually caused an increase in vagal restraint that elicited reflex modification of cholinergic input to the AV node,13 and was different from the condition of exercise that would initiate abrupt withdrawal of the vagal tone, serious increase of the sympathetic tone, and elaborate secretion of catecholamines. With atropine (0.02 and 0.04 mg/kg), the minimal dose of adenosine to terminate tachycardia was significantly elevated. This result suggested that basal vagal activity contributes to the effect of adenosine on termination of supraventricular tachycardia. Furthermore, the reflex sympathetic activity may be increased because of higher heart rate and lower blood pressure when atropine was administered; thus, more adenosine dose was needed to antagonize the effect of b-adrenergic stimulation caused by endogenous catechol-
amines, irrespective of atropine dose. When b-adrenergic blockade with propranolol was given before atropine injection, the minimal adenosine dose under atropine injection of 0.04 mg/kg was significantly greater than that of 0.02 mg/kg. Thus, in the presence of propranolol, there is a more linear relation between muscarinic cholinergic activity and the adenosine dose required for interruption of tachycardia. 1. Kurachi Y, Nakajima T, Sugimoto T. On the mechanism of activation of
muscarinic K/ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins. Pfluegers Arch 1986;407:264–274. 2. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M. Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J 1995;9:359–365. 3. Lerman BB, Belardinelli L. Cardiac electrophysiology of adenosine: basic and clinical concepts. Circulation 1991;83:1499–1509. 4. LaMonica DA, Frohloff N, Dobson JG Jr. Adenosine inhibition of catecholamine-stimulated cardiac membrane adenylate cyclase. Am J Physiol 1985;248:H737–H744. 5. Lai WT, Wu SN, Sung RJ. Negative dromotropism of adenosine under betaadrenergic stimulation with isoproterenol. Am J Cardiol 1992;70:1427–1431. 6. Lauer MR, Young C, Liem LB, Sung RJ. Efficacy of adenosine in terminating catecholamine-dependent supraventricular tachycardia. Am J Cardiol 1994;73:38–42. 7. DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 1983;68:1254–1263. 8. DiMarco JP, Sellers TD, Lerman BB, Greenberg ML, Berne RM, Belardinelli L. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. J Am Coll Cardiol 1985;6:417–425. 9. Griffith MJ, Ward DE, Linker NJ, Camm AJ. Adenosine in the diagnosis of broad complex tachycardia. Lancet 1988;1:672–675. 10. Chen SA, Chiang CE, Yang CJ, Cheng CC, Wu TJ, Wang SP, Chiang BN, Chang MS. Accessory pathway and atrioventricular node reentrant tachycardia in elderly patients: clinical features, electrophysiologic characteristics and results of radiofrequency ablation. J Am Coll Cardiol 1994;23:702–708. 11. Chen SA, Chiang CE, Yang CJ, Cheng CC, Wu TJ, Wang SP, Chiang BN, Chang MS. Sustained atrial tachycardia in adult patients: electrophysiologic characteristics, pharmacologic response, possible mechanism and effects of radiofrequency ablation. Circulation 1994;90:1262–1278. 12. Clemo HF, Belardinelli L. Effect of adenosine on atrioventricular conduction. I. Site and characterization of adenosine action in the guinea pig atrioventricular node. Circ Res 1986;59:427–463. 13. Arnold JMO, McDevitt DG. Vagal activity is increased during intravenous isoprenaline infusion in man. Br J Clin Pharmacol 1984;18:311–316.
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