Adenosine and Adenosine Receptors: Advances in Atrial Fibrillation

Figures

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  Figure 1. Adenosine metabolism. The sources of intracellular adenosine (ADO) come partly from the methionine cycle by the hydrolysis of S-adenosylhomocysteine (SAH) and mainly from the ATP dephosphorylation cascade when cellular energy requirement increases. Massive extracellular release of ATP produces adenosine by the consecutive actions of ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5’-nucleotidase (CD73). Adenosine can bind to adenosine receptors (ARs), but it is also reuptake by equilibrative nucleoside transporters (ENT1–2) and rephosphorylated by adenosine kinase (ADK). Adenosine is catabolized by adenosine deaminase (ADA) into inosine (Ino) and, finally, joins uric acid metabolism. Hypoxia and inflammation increase the expression of adenosine receptors and the production of extracellular adenosine: HIF promotes the transcription of adenosine receptors and CD73 and NF-kB genes and represses ENT and ADK genes; NF-κB promotes the transcription of adenosine receptors and HIF genes. ATP: adenosine triphosphate; ADP: adenosine diphosphate; AMP: adenosine monophosphate; HCY: homocysteine; HIFs: hypoxia-inducible transcription factors; MC-ADA: mononuclear cell ADA;…

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  Figure 2. Cardioprotective effects of adenosine A1 receptors’ activation. Stimulation of the A1 receptors induces bradycardia (negative chronotropy) on a sinoatrial node (SA node), atrioventricular conduction slowing (negative dromotropy) on an atrioventricular node (AV node) and reduced atrial cardiomyocyte contractility (negative inotropy).

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  Figure 3. Adenosine receptors signaling (right: A1R; left: A2AR). Prejunctional A1R activation limits the norepinephrine release. Complementarily, A1Rs reduce the increased adrenergic-induced cAMP elevation and the cAMP-dependent currents (I funny, ICa,L). The main effect of A1R activation is mediated through GIRK-induced outward K+ current (IK,Ado). A2AR activation increases cAMP and, consequently, activates the PKA. PKA phosphorylates L-type Ca2+ channels (LTCC) inducing an inward Ca2+ current (ICa,L). Ryanodine receptors’ (RyR2) phosphorylation by the PKA allows for the Ca2+-induced Ca2+ release from the sarcoplasmic reticulum. Cardiac troponin I phosphorylation and cytosolic Ca2+ sparks trigger the myofibrils’ contraction during systole. During diastole, the phosphorylation of phospholamban (PLN) permits the SERCA to pump Ca2+ into the sarcoplasmic reticulum. The Na+: Ca2+ exchanger extrudes Ca2+ allowing for diastolic relaxation. AC: adenylyl cyclase; cTnI: cardiac troponin I; PKA: protein kinase A.

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  Figure 4. Illustrations of the effects of adenosine on action potential in a sinoatrial cell (A) and atrial cardiomyocyte (B). In a sinoatrial node, adenosine increases the outward IK,Ado current, which induces hyperpolarization and reduces the slope of the diastolic depolarization. Complementarily, adenosine reduces indirectly the inward Na+ pacemaker current (If) and the inward Ca2+-dependent depolarization through L-type Ca2+ channels (ICa,L). Adenosine incudes negative chronotropy. On an atrial working myocardium, adenosine increases the outward K+ current (IK,Ado) and shortens the action potential duration and the refractoriness, thereby adenosine can reduce atrial contractility. Dotted arrows correspond to the corresponding RR intervals. Solid arrows correspond to the corresponding action potential refractory period.

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  Figure 5. Schematic illustration of differences between action potentials (APs) in atrial cardiomyocytes and in pulmonary vein (PV) cardiomyocytes. Action potential of PV cardiomyocytes have a more depolarized resting membrane potential, a lower AP amplitude, a smaller maximum phase 0 upstroke velocity and a shorter action potential duration compared to atrial AP.

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  Figure 6. Formation of a functional reentrant circuit due to the heterogeneity of the atrial potential duration at the pulmonary vein (PV) entrance. The delay after depolarization in area no. ① initiates a PV ectopy within the PV sleeve, where the action potential duration (APD) is shorter, with a subsequently shorter effective refractory period (ERP) and propagates toward the PV junction where the APD is longer. The ectopic beat blocks are in area no. ② because of the refractory tissue. However, the impulse propagation continues laterally until the APD tissue is out of the refractory time (area no. ③.). Finally, the PV ectopic beats move around the functional refractory area and then across the previous refractory region of the block in area no. ④, which is now out of the refractory time. The dotted line represents the functional unidirectional refractory area, the solid arrows represent the propagation of the action potential and the star represents the initiation of the ectopic focus.

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  Figure 7. Effects of A1R activation by adenosine on pulmonary vein (PV) action potential (AP). AP: action potential; ERP: effective refractory period; PV: pulmonary vein. In PV sleeves of AF patients, A1R activation opens GIRK channels, which are responsible for an outward potassium current (IK,ADO). This current shortens the atrial AP duration and effective refractory period (ERP). This enhanced PV firing follows PV ectopy. Furthermore, the outward potassium current is also responsible for a resting membrane potential hyperpolarization which reactivates the If current, increasing PV automaticity.

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  Figure 8. Remodeling of the calcium handling associated with A2AR overexpression in AF. Atrial remodeling in atrial fibrillation is associated with the overexpression of A2AR. This is responsible for an increased phosphorylation state of ryanodine receptors into dyads, which can induce diastolic Ca2+ leaks without modulating the L-type Ca2+ current. In parallel, the cytosolic Ca2+ overload activates the Na+-Ca2+ antiporter exchanger to remove Ca2+ from cells with an accepted stoichiometry of 3Na+:1Ca2+. Consequently, the associated cytosolic Ca2+ diastolic overload and the increased cation inward currents can induce delayed afterdepolarizations, which can be sufficient to meet the threshold cell membrane voltage and to trigger an action potential.