Is Sick Sinus Syndrome an Adenosine—Mediated Disease?: Effects of Intravenous Aminophylline on Sick Sinus Node Function after Pharmacologic Autonomic Blockade

doi:10.1378/chest.99.4.887

Chest

Volume 99, Issue 4, April 1991, Pages 887-891

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To assess the effects of intravenous aminophylline on the sinus node, 12 patients with clinical and Holter monitor-documented sick sinus syndrome were studied (1) during the control state, (2) after pharmacologic autonomic blockade and (3) 5 min after intravenous administration of aminophylline. The effects of aminophylline on sinus node function were compared with those after pharmacologic autonomic blockade. No significant improvement of sinus node function was found after intravenous aminophylline administration with a mean sinus cycle length and a mean maximum CSRT of 968 ± 218 and 1832 ± 1036 ms, respectively. The mean serum theophylline level was 10.9 ± 1.7 μg/ml. Since aminophylline is an adenosine receptor antagonist, these findings suggest that intrinsic adenosine may not play an important role in pathogenesis in patients with chronic and advanced sick sinus syndrome.

Section snippets

Study Patients

Twelve patients with the diagnosis of sick sinus syndrome were enrolled in this study. There were six men and six women ranging in age from 40 to 78 years (mean, 59.9 ± 10.0 years). The diagnosis of sick sinus syndrome was based on the presence of sinus bradycardia, sinus arrest and the bradytachycardia syndrome documented in the 24-h ambulatory electrocardiographic Holter recordings. None of the patients had glaucoma, urinary retention or contraindications to using beta-blockers. After

Definitions

Maximum sinus node recovery time was defined as the longest interval from the last paced high right atrial electrogram to the first spontaneous sinus atrial electrogram after termination of any rate of pacing.

Maximum corrected SNRT was calculated by subtracting the mean sinus cycle length from the maximum SNRT.

Sinoatrial conduction time was estimated by a continuous pacing method as proposed by Narula et al.²¹ The high right atrium was paced for eight beats at a cycle length slightly shorter

Control Measurements

During the control state, the mean sinus cycle length was 1,012.9 ± 208.1 ms (range 680 to 1,390 ms [Table 1]). The mean maximum SNRT and mean maximum corrected SNRT were 2,392 ± 817 and 1,379 ± 703 ms, respectively. The maximum corrected SNRT was abnormal (>525 ms) in 11 of 12 patients. The SACT was abnormal (>125 ms) in 9 of 12 patients with a mean SACT of 156 ± 66 ms.

Autonomic Blockade

After administration of pharmacologic autonomic blockade, the mean sinus cycle length was 953 ± 175 ms, corresponding to the

Discussion

If adenosine played a role in the pathogenesis of sick sinus syndrome, intravenous aminophylline would improve the sinus node function by competitively antagonizing the adenosine effect through extracellular adenosine receptors.¹⁶ In this study, intravenous aminophylline in a dosage of 5 mg/kg did not improve sinus node function as shown by clinical electrophysiologic measurements in patients with sick sinus syndrome. These results indicate that intrinsic adenosine may not play an important

Conclusion

Thus, intravenous aminophylline after pharmacologic autonomic blockade cannot improve the sinus node function in patients with chronic and advanced sick sinus syndrome. Endogenous adenosine may not play an important role in the pathogenesis of advanced sick sinus syndrome. Clinically, aminophylline does not increase the intrinsic heart rate in patients with advanced sick sinus syndrome and pacemaker therapy is still the first choice for patients with symptomatic sick sinus syndrome.

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Cited by (7)

Adenosine and its receptors in the heart: Regulation, retaliation and adaptation
2011, Biochimica et Biophysica Acta - Biomembranes
Citation Excerpt :
The actions of adenosine are also consistent with a role in sick sinus syndrome [70], though mechanistic involvement is yet to be fully established. The poorly selective AR antagonists aminophylline and theophylline do suppress symptoms in aged patients with this disorder [71,72]. Decay of ventricular fibrillation is accelerated by A1AR antagonism in a swine model [73], though this effect of endogenous adenosine does not impact on short-term outcomes [74].
The purine nucleoside adenosine is an important regulator within the cardiovascular system, and throughout the body. Released in response to perturbations in energy state, among other stimuli, local adenosine interacts with 4 adenosine receptor sub-types on constituent cardiac and vascular cells: A₁, A_2A, A_2B, and A₃ARs. These G-protein coupled receptors mediate varied responses, from modulation of coronary flow, heart rate and contraction, to cardioprotection, inflammatory regulation, and control of cell growth and tissue remodeling. Research also unveils an increasingly complex interplay between members of the adenosine receptor family, and with other receptor groups. Given generally favorable effects of adenosine receptor activity (e.g. improving the balance between myocardial energy utilization and supply, limiting injury and adverse remodeling, suppressing inflammation), the adenosine receptor system is an attractive target for therapeutic manipulation. Cardiovascular adenosine receptor-based therapies are already in place, and trials of new treatments underway. Although the complex interplay between adenosine receptors and other receptors, and their wide distribution and functions, pose challenges to implementation of site/target specific cardiovascular therapy, the potential of adenosinergic pharmacotherapy can be more fully realized with greater understanding of the roles of adenosine receptors under physiological and pathological conditions. This review addresses some of the major known and proposed actions of adenosine and adenosine receptors in the heart and vessels, focusing on the ability of the adenosine receptor system to regulate cell function, retaliate against injurious stressors, and mediate longer-term adaptive responses.
Effects of oral theophylline on sick sinus syndrome
1993, Journal of the American College of Cardiology
Objectives. We sought to determine the effect of theophylline on cardiac pauses in sick sinus syndrome.
Background. Sick sinus syndrome, a relatively benign condition, is usually treated with pacemaker implantation without any proved effectiveness. Thus, an appropriate pharmacologic therapy would be useful.
Methods. Theophylline (200 to 400 mg/day for 1 month) was initially administered orally to 17 patients with sick sinus syndrome, which is manifested by sinus pauses of > 2.5 s. Eleven of the 17 patients subsequently received theophylline for an additional 8 to 37 months. Twenty-four-hour Holter recordings were obtained before treatment, at the end of 1 month of treatment and then at 6-month intervals.
Results. Theophylline decreased the frequency of sinus pauses from 256 ± 230 to 23 ± 62 pauses per 24 h and decreased the duration of the longest pauses from 4.7 ± 1.8 to 2.2 ± 0.97 s after 1 month of treatment Subjective symptoms associated with cardiac pauses disappeared in 16 of 17 patients. Ventricular premature beats increased in frequency but did not last longer than two beats. Three patients experienced adverse effects. Nine of the 11 patients receiving long-term treatment had a good outcome, but 2 patients required a pacemaker because of the resppearance of long sinus pauses.
Conclusions. The results suggest that oral theophylline may be beneficial for the treatment of patients with sick sinus syndrome.
Comparison of the electrophysiologic effects of oral sustained-release and intravenous verapamil in patients with paroxysmal supraventricular tachycardia
1993, The American Journal of Cardiology
The electrophysiologic effects of intravenous verapamil (0.15 mg/kg) and oral sustained-release verapamil (verapamil-SR) (240 mg once daily for 7 days) were studied in 17 patients with paroxysmal supraventricular tachycardia (SVT). Ten patients had atrioventricular (AV) nodal reentrant tachycardia and 7 had AV reciprocating tachycardia involving an accessory AV pathway. Both preparations significantly prolonged anterograde effective refractory period of the AV node and depressed the retrograde AV nodal conduction system. The sinus cycle length, and atrial and ventricular effective refractory periods were prolonged after oral verapamil-SR. Furthermore, oral verapamil-SR depressed retrograde accessory pathway conduction which was not interfered with by intravenous verapamil. Intravenous verapamil and oral verapamil-SR prevented induction of sustained SVT in 12 of 17 (71%) and 10 of 17 (59%) patients, respectively. Follow-up study with oral verapamil-SR 240 mg once daily in 15 patients for 19 ± 6 months revealed that among the 8 patients without induction of sustained SVT, 7 have been free of symptomatic arrhythmia; only 1 patient had occasional SVT attacks. For the 7 patients with induction of sustained SVT, 3 patients failed to respond to oral verapamil-SR, 1 patient became symptom free, and the remaining 3 patients had less frequent SVT attacks. Thus, immediate intravenous verapamil testing predicts the electrophysiologic results of oral verapamil-SR therapy, and oral verapamil-SR once daily may be used for long-term prophylaxis of SVT with better patient compliance.
Negative dromotropism of adenosine under beta-adrenergic stimulation with isoproterenol
1992, The American Journal of Cardiology
Adenosine depresses atrioventricular (AV) nodal function by binding to specific A₁ receptors which activate the acetylcholine, adenosine-regulated potassium current. In addition, adenosine can act to antagonize the effects of β-adrenergic stimulation on AV nodal function. To assess the negative dromotropic effects of adenosine under β-adrenergic stimulation, 15 patients were studied during clinical electrophysiologic study. During high right atrial pacing at a cycle length of 400 to 600 ms, adenosine was injected intravenously at an initial dose of 0.5 mg followed by a stepwise increment of 0.5 or 1.0 mg given at 5-minute intervals until a maximal dose of 12 mg was achieved or AV block developed. Intravenous isoproterenol (1 to 3 μg/min) was then infused to accelerate sinus rate by 20 to 30% during which intravenous injection of incremental doses of adenosine as described was repeated. The AV nodal conduction time (AH interval) was measured at each dose of adenosine. Dose-response curves of AV nodal conduction time (expressed as percent increase in AH interval) were studied during the control state and during isoproterenol infusion. The dose of adenosine required to produce AV nodal Wenckebach block, the increase in the AH interval by 50% (ED₅₀) and the maximal response (E_max) were 3.4 ± 0.9 mg, 1.8 ± 0.9 mg and 60 ± 4%, respectively, in the control state, and 3.7 ± 0.8 mg, 2.0 ± 0.7 mg and 56 ± 4%, respectively, during isoproterenol infusion. No significant changes in ED₅₀, E_max and the dose of adenosine yielding AV nodal Wenckebach block could be demonstrated between the control state and during isoproterenol infusion. Thus, the negative dromotropic effects of adenosine on AV nodal conduction remained unchanged with β-adrenergic stimulation. These findings suggest that adenosine may remain efficacious in terminating catecholamine-sensitive supraventricular tachycardia involving the AV node as part of the reentrant circuit.
Unmasking adenosine: The purinergic signalling molecule critical to arrhythmia pathophysiology and management
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Electrophysiology study: A comprehensive review
2001, American Journal of Critical Care

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: Manuscript received June 21; revision accepted September 14.

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Chest

Clinical InvestigationsIs Sick Sinus Syndrome an Adenosine—Mediated Disease?: Effects of Intravenous Aminophylline on Sick Sinus Node Function after Pharmacologic Autonomic Blockade

Section snippets

Study Patients

Definitions

Control Measurements

Autonomic Blockade

Discussion

Conclusion

Am J Cardiol

Prog Cardiovasc Dis

Am J Cardiol

Lancet

Trends Pharm Sci

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Trends Biochem Sci

Am J Cardiol

Syncopal attacks associated with prolonged arrest of the whole heart

Quart J Med

The sick sinus syndrome

Circulation

Junctional pacemakers in man: response to overdrive suppression with and without parasympathetic blockade

Circulation

The sinus node as a servomechanism

Circ Res

Studies on the mechanism of sinus node dysfunction in the sick sinus syndrome

Circulation

The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart

J Physiol

Clinical Investigations
Is Sick Sinus Syndrome an Adenosine—Mediated Disease?: Effects of Intravenous Aminophylline on Sick Sinus Node Function after Pharmacologic Autonomic Blockade