Tachycardia Caused by A<sub>2A</sub> Adenosine Receptor Agonists Is Mediated by Direct Sympathoexcitation in Awake Rats

Dhalla, Arvinder K.; Wong, May; Wang, Weiqun; Biaggioni, Italo; Belardinelli, Luiz

doi:10.1124/jpet.105.095323

Cited by 105 publications

(89 citation statements)

References 32 publications

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“…Tachycardia can be induced by A2AR agonists and is mediated by direct stimulation of the sympathoexcitation system in awake rats [670]. Caffeine can also induce PSVT [669].…”

Section: Arrhythmiasmentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

120

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This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

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“…Tachycardia can be induced by A2AR agonists and is mediated by direct stimulation of the sympathoexcitation system in awake rats [670]. Caffeine can also induce PSVT [669].…”

Section: Arrhythmiasmentioning

confidence: 99%

Cardiac purinergic signalling in health and disease

Burnstock

Pelleg

2014

Purinergic Signalling

120

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“…5,6 The true mechanism of HR increase, however, is more complicated and involves direct stimulation of the sympathetic nervous system. 7 The administration of adenosine as a bolus, as done for the interruption of supra-ventricular tachycardias, has a negative chronotropic effect on the atrio-ventricular node via stimulation of the A1 receptor. This is in contradistinction to its effect on the A 2A receptor when given as an infusion in stress MPI studies where it induces an increase in HR.…”

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confidence: 99%

Heart rate response during vasodilator stress myocardial perfusion imaging: Mechanisms and implications

Hage

Iskandrian

2010

Journal of Nuclear Cardiology

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See related article, pp. 617-624Myocardial perfusion imaging (MPI) using adenosine, dipyridamole, or regadenoson (a selective A 2A receptor agonist) is an established method for detecting coronary artery disease (CAD) and risk stratification. 1 In high-risk populations, as in those with diabetes mellitus (DM) or chronic kidney disease, MPI has been shown to be a powerful predictor of risk, but nevertheless, patients with normal myocardial perfusion are at higher risk than those without DM or chronic kidney disease. 2,3 Thus, there continues to be a need to extract more useful prognostic data from stress MPI especially in high-risk populations.A blunted heart rate (HR) response to exercise stress has been known to be an independent predictor of poor outcome and is used clinically in conjunction with other prognostic variables such as perfusion defects, left ventricular (LV) ejection fraction (EF) and volumes, exercise time, and symptoms during exercise to derive an overall assessment of risk in a particular patient. 4 In patients undergoing stress testing, for one reason or another, with adenosine or regadenoson (and dipyridamole, which acts indirectly by increasing interstitial levels of endogenous adenosine), there is a modest increase in HR and a modest decrease in blood pressure (BP). The increase in HR has been traditionally attributed to a reflex response to the vasodilatory effect on the systemic circulation and the resultant increase in sympathetic discharge. 5,6 The true mechanism of HR increase, however, is more complicated and involves direct stimulation of the sympathetic nervous system. 7 The administration of adenosine as a bolus, as done for the interruption of supra-ventricular tachycardias, has a negative chronotropic effect on the atrio-ventricular node via stimulation of the A1 receptor. This is in contradistinction to its effect on the A 2A receptor when given as an infusion in stress MPI studies where it induces an increase in HR. 5,8 The development of selective A 2A receptor agonists (such as regadenoson) has allowed for the dissection of the effects of adenosine on the multiple receptors. A well-done pivotal study in rats by Dhalla et al 7 that used regadenoson in combination with a selective A 2A receptor antagonist, B-blocker, a ganglionic blocker (to block the sympathetic nervous system), and a direct vasodilator (nitroprusside) demonstrated the dissociation of tachycardia and hypotension (secondary to peripheral vasodilation) responses to regadenoson. This and other data (reviewed in Ref. 9 ) confirm that A 2A receptor agonists cause a direct stimulation of the autonomic nervous system, which results in sinus tachycardia independent of the baroreflex mechanism. Thus, the change in HR in response to A 2A receptor agonists can be used to evaluate autonomic function.In order to evaluate the HR response to adenosine and regadenoson in relation to DM (since there is a high prevalence of autonomic dysfunction in patients with DM), we used data from the ADenoscan Versus RegAdenosoN Comparativ...

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“…6 This sympathetic stimulatory effect is observed with adenosine and dipyridamole, as well. 7 This presumably causes the brief ''mini-panic attack'' feeling that patients often experience beginning 30-90 seconds after administration of regadenoson or adenosine.…”

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confidence: 79%

When to re-dose regadenoson?

Thomas

Jolly

Safani

2017

Journal of Nuclear Cardiology

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Since FDA approval in 2008, regadenoson, an A2A adenosine receptor agonist, has become the most commonly used pharmacological stress testing agent in the U.S. 1 In this issue of the Journal, Townsend et al 2 address the important question of how to manage redosing of regadenoson if it were to become necessary. This information would be helpful, for example, if the FDA approved 0.4 mg (400 lg) dose of regadenoson were administered intravenously (IV) but the radiotracer became inadvertently unavailable or in the case of an infiltrated IV line resulting in the subcutaneous administration of regadenoson.Townsend et al 2 evaluated the pharmacokinetics (the study of the time course of the drug's absorption, distribution, metabolism, and excretion) and pharmacodynamics (the study of the biochemical and physiological effects of a drug on the body) of different doses of regadenoson administered every 10 minutes (min). To do so, they randomized 36 healthy men and women, mean age 38 years, who were not on any medications, to receive either 3 separate doses of 0.1 mg 10 minutes apart, 3 doses of 0.2 mg 10 minutes apart, 2 doses of 0.4 mg 10 minutes apart or 2 or 3 doses of placebo 10 minutes apart. In addition to measuring plasma concentrations of regadenoson, they studied the pharmacodynamic effect on blood pressure and heart rate as primary endpoints.Work by Lieu et al 3 evaluated the pharmacodynamic effect of escalating doses of regadenoson on coronary velocity using a coronary Doppler flow wire. They found that regadenoson doses of 0.1 mg, 0.3 and 0.4 mg increased peak velocity above baseline by 3.0 ± 0.6 (SD), 3.4 ± 0.8, and 3.1 ± 0.5 times, respectively. As flow increases linearly with velocity, by the formula [Flow = p r 2 (average velocity)(0.5) 9 60] with r equal to vessel radius, peak myocardial blood flow would thus increase to a similar degree with either 0.1 or 0.4 mg of regadenoson. However, the 0.4 mg dose was selected for use with MPI as it produced a sustained velocity 2.5 times above baseline for 2.3 minutes compared to \2 minutes for smaller doses. 3,4 Townsend et al 2 found 0.4 mg of regadenoson to result in mean plasma concentrations of &18 and &9 ngÁmL -1 at 3 and 9 min, respectively. Given earlier findings of Lieu et al 3 that coronary velocity remains C2 times baseline for a mean of 9 minutes, a concentration of 9 ngÁmL -1 would correlate with a &twofold increase in velocity.Using the 0.1 mg dose, which Lieu et al 3 found to increase coronary velocity threefold, Townsend et al 2 found 0.1 mg to result in a mean concentration of &5 ngÁmL -1 measured 3 minutes post dosing. This was the first time of measurement in their study. Correlating this dose with coronary velocity in the study of Lieu et al 3 is difficult, as coronary velocity had decreased to \2 times baseline by 3 minutes with this dose. Nonetheless, the coronary velocity curves Lieu et al 3 observed are consistent with a significant impact on coronary velocity remaining at 3 minutes in relation to a plasma concentration of &5 ngÁmL -1 .Thus, ...

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Tachycardia Caused by A_2A Adenosine Receptor Agonists Is Mediated by Direct Sympathoexcitation in Awake Rats

Cited by 105 publications

References 32 publications

Cardiac purinergic signalling in health and disease

Cardiac purinergic signalling in health and disease

Heart rate response during vasodilator stress myocardial perfusion imaging: Mechanisms and implications

When to re-dose regadenoson?

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Tachycardia Caused by A2A Adenosine Receptor Agonists Is Mediated by Direct Sympathoexcitation in Awake Rats

Cited by 105 publications

References 32 publications

Cardiac purinergic signalling in health and disease

Cardiac purinergic signalling in health and disease

Heart rate response during vasodilator stress myocardial perfusion imaging: Mechanisms and implications

When to re-dose regadenoson?

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Tachycardia Caused by A_2A Adenosine Receptor Agonists Is Mediated by Direct Sympathoexcitation in Awake Rats