DESCRIPTION

• Adenosine is an endogenous purine derived from high-energy adenosine phosphates (ATP, ADP, and AMP):
  • Intracellular adenosine can cross the cell membrane and diffuse to the extracellular space, where it may act as an autocoid (ie, it can exert its effects on adjacent cells).
  • Adenosine also can be generated in the extracellular space by the ectonucleotidase metabolism of plasma ATP that is released from vascular cells, thrombocytes, and sympathetic nerves during ischemia.
  • In the interstitial space, adenosine has a very short half-life. The cell actively reuptakes adenosine, by either simple or facilitated diffusion via a nucleoside transport system that can be pharmacologically inhibited (eg, by dipyridamole).
• Adenosine receptors:
  • The physiologic effects of adenosine are mediated by specific G protein-coupled receptors (also known as purinergic P1 receptors) that belong to the family of the seven transmembrane domain receptors:
  • At present, four adenosine receptors have been characterized: A1, A2a, A2b, and A3:
    • The Al and the A3 receptors both couple to inhibitory Gi/o G proteins (hence causing an inhibition of adenyl cyclase), can activate phospholipase C via G protein subunits, and can activate protein kinase C.
    • The high-affinity A2a and the low-affinity A2b receptors both couple to Gs, but the A2b receptor also can couple to Gq/11 to mobilize calcium.
• Adenosine cardiovascular effects:
  • Vascular tone:
    • Coronary vasodilation (the A2a receptor mainly at the level of resistance vessels and the A2b receptor at the level of conductance vessels), via both KATP channel and NO-mediated mechanisms
    • Renal vasoconstriction (A1)
    • Peripheral vasodilation (A2)
  • Electrophysiology:
    • Negative chronotropic effect (sinoatrial node, A1)
    • Negative dromotropic effect [atrioventricular (AV) node, A1]
    • Depression of automaticity (A1)
  • Mechanical performance:
    • Negative inotropic effect (atrial myocardium, A1)
    • Direct positive inotropic effect (A2a receptor, via cyclic AMP (cAMP)-dependent and -independent effects).
    • Indirect negative inotropic effect, by attenuating the cardiac responsiveness to -adrenergic stimulation
    • A2-mediated modulation of A1 receptor activity
  • Adrenergic responsivity: A1 receptor stimulation attenuates the responsiveness by reducing the -adrenergic-mediated increase in cAMP (A1):
    • Presynaptic nerve endings: Adenosine attenuates the release of norepinephrine caused by adrenergic nerve stimulation (A1).
    • Myocardial metabolism: Attenuation of the metabolic effects of -adrenergic stimulation
    • Endothelial cells: Proliferation (and angiogenesis)
• Adenosine as a retaliatory metabolite:
  • Adenosine acts as a negative feedback modulator of -adrenoceptor-mediated responses in the heart and as a negative feedback regulator that inhibits norepinephrine release from the sympathetic nerve endings. These effects are already present at physiologic adenosine interstitial concentrations.
  • In several pathophysiologic conditions, adenosine concentrations in the intracellular space may increase significantly (eg, during -adrenergic catecholamine stimulation, cardiac ischemia, cardiac hypoxia, increased cardiac workload caused by volume or pressure overload). In these situations, characterized by an unfavorable oxygen supply-demand ratio, adenosine can induce coronary vasodilation, attenuate the metabolic and inotropic response to -adrenergic stimulation, and modulate the release of norepinephrine from the sympathetic nerve endings.
• Cardioprotection against the ischemic/reperfusion injury:
  • During ischemia, the antiadrenergic effect of adenosine reduces the norepinephrine available for stimulating the flow-deprived heart and reduces the metabolic and inotropic effects of -adrenergic receptor stimulation. At the same time, adenosine is a potent coronary vasodilator.
  • Adenosine can therefore protect against ischemia-induced cell death and against reperfusion injury. Moreover, adenosine attenuates ischemia-induced myocardial stunning and decreases the incidence of arrhythmias.
• Ischemic preconditioning:
  • Adenosine plays an important role in triggering and mediating the cardioprotective effect of ischemic preconditioning, via the activation of A1 and A3 adenosine receptors. By mechanisms yet to be completely elucidated, adenosine release during an ischemic episode interacts with KATP channels to induce a protective effect against subsequent periods of acute ischemia. Adenosine-induced protein kinase C activation may be involved as well.
• Cardiovascular diagnosis: Arrhythmias:
  • The cardiac electrophysiologic actions of adenosine are mediated by the A1 receptor and are either cAMP independent (at the level of nodal or atrial tissue) or cAMP dependent, that is, mediated by the inhibition of the stimulatory effects of adenylyl cyclase (at the level of atrial and ventricular myocytes).
  • Due to these electrophysiologic effects, adenosine can be used in the electrophysiology laboratory as a diagnostic tool:
    • Adenosine may transiently suppress (but not terminate) automatic atrial tachycardia.
    • Because adenosine may transiently block AV nodal conduction, it plays an important role in the diagnosis of reentrant arrhythmias in which the AV node is a critical component of the tachycardia circuit.
    • Adenosine causes transient suppression of adrenergically mediated automatic arrhythmias.
    • Adenosine is useful to identify ventricular arrhythmias due to triggered activity.
    • Adenosine may be used to diagnose latent preexcitation, to localize the region of the accessory pathway, and to assess the immediate efficacy of accessory pathway ablation.
• Ischemic heart disease:
  • In the setting of coronary atherosclerosis artery disease, adenosine-induced coronary vasodilation may induce acute regional ischemia due to flow maldistribution (coronary steal in the myocardial area perfused by a stenotic artery). This paradoxical effect of coronary vasodilation can be exploited as a diagnostic tool by allowing the evaluation of the consequences of acute inducible ischemia. To this end, endogenous adenosine accumulation induced by dipyridamole infusion is used as a pharmacologic stress test in combination with 2-dimensional echo or radionuclide perfusion scans. The former will allow the identification of wall motion abnormalities induced by regional ischemia, whereas the latter will assess the relative flow heterogeneity caused by dipyridamole in the presence of coronary artery disease.
  • The short-lasting effect of dipyridamole, which acts by blocking the reuptake of adenosine by the cells, and the availability of the antidote theophylline, which blocks adenosine receptors, make dipyridamole stress testing a safe and effective choice for cardiac imaging in ischemic heart disease.
• Possible role in cardiovascular therapy arrhythmias:
  • Adenosine can terminate sinus node reentry, paroxysmal reciprocating atrial tachycardia, nodal reciprocating tachycardia, and effort-related ventricular tachycardia due to triggered activity. Dipyridamole-induced increase in endogenous adenosine may slow or terminate AV nodal reentrant tachycardia and AV reciprocating tachycardia.
  • Adenosine receptor blockade by theophylline may be effective in treating bradycardia in patients with sick sinus syndrome, in increasing the ventricular response rate in patients with atrial fibrillation, and in reversing complete heart block in the setting of acute MI.
  • Adenosine administration may cause atrial flutter and/or fibrillation, AV block, sinus bradycardia, and sinus pauses.
• Myocardial cardioprotection
• Adenosine is a potentially beneficial additive to cardioplegic solutions during open heart surgery, and it is used to control blood pressure in the setting of postoperative systemic and pulmonary HTN. Its possible role in protecting the ischemic myocardium during coronary angioplasty and in acute MI is under extensive clinical evaluation.

CODES

ICD9

• 411.89 Other acute and subacute forms of ischemic heart disease, other
• 427.9 Cardiac dysrhythmia, unspecified

SNOMED

• 44808001 conduction disorder of the heart (disorder)
• 414545008 ischemic heart disease (disorder)

Stefano Perlini

Gerard P. Aurigemma