Adenosinergic System and Neuroendocrine Syncope: What Is the Link?

Abstract

Although very common, the precise mechanisms that explain the symptomatology of neuroendocrine syncope (NES) remain poorly understood. This disease, which can be very incapacitating, manifests itself as a drop in blood pressure secondary to vasodilation and/or extreme slowing of heart rate. As studies continue, the involvement of the adenosinergic system is becoming increasingly evident. Adenosine, which is an ATP derivative, may be involved in a large number of cases. Adenosine acts on G protein-coupled receptors with seven transmembrane domains. A₁ and A_2A adenosine receptor dysfunction seem to be particularly implicated since the activation leads to severe bradycardia or vasodilation, respectively, two cardinal symptoms of NES. This mini-review aims to shed light on the links between dysfunction of the adenosinergic system and NHS. In particular, signal transduction pathways through the modulation of cAMP production and ion channels in relation to effects on the cardiovascular system are addressed. A better understanding of these mechanisms could guide the pharmacological development of new therapeutic approaches.

Keywords: adenosine; ionic channels; neuroendocrine syncope; receptor reserve.

Figure 1

Main source of adenosine.

Figure 2

Main consequences of A₁ R activation on excitable cells.

Figure 3

Main consequences of A_2A R activation on excitable cells.

Figure 4

Physiological effects of the activation of adenosine receptors on the cardiovascular system. The main adenosine receptors implicated in NES are the A₁ and A₂ subtypes. Activation of A₁ receptors (A₁ R) leads to the inhibition of cAMP production (indirect effects), but also to the activation of the inward rectifying K⁺ current (I_{. kado/Ach}). This current is also activated by acetylcholine (Ach). A₁ R activation also leads to the inhibition of L-Type calcium channels (LTCC [16]). The main effect secondary to the activation of A1R is a post-synaptic membrane hyperpolarization of the sinus node (SN) and atrio-ventricular node (AVN) cells, leading to negative chronotropy and dromotropy. These effects are similar to those observed during activation of muscarinic receptors (M2R) and G protein-coupled inwardly rectifying K⁺ channels (GIRK) following vagal stimulation. In the myocardium, activation of adenosine A2 receptors (A2R) leads to inotropy, mostly via indirect (cAMP-dependent) effects. In the vessels, activation of KATP and KV channels and inhibition of voltage-dependent calcium channels (VDCC) leads to smooth cell relaxation and vasodilation.

Figure 5

The vicious circle of A2A R.

Figure 6

In the absence of adenosine receptor reserve (spare, A) maximal biological effects (cAMP production) occur when all the receptors of a target cell are occupied by adenosine (Ado). In the presence of spare receptors; (B) maximal biological effects occur even if a weak fraction of adenosine receptors are occupied.

Figure 7

Main consequences of the pharmacological profile of adenosine receptors on the biological and clinical manifestations of NES/. (A): In VVS, (left panel) the basal adenosine plasma level (APL) is upper than the EC 50 value, while in sudden syncope (low adenosine level, left panel) APL in basal condition is under the EC50 value. (B): During an increase in APL that occurs as an example during the HUT, the number of activated receptors increase in VVS (left panel) while in the case of the presence of spare receptors (right panel) No additional receptors are activated in spite of the increase in APL. Consequently, (C) the production of cAMP increases as a function of activated receptors (left panel) but remains unchanged in the presence of spare receptors (right panel). Finally, (D) the decrease in SBP occurs progressively during the prodrome period (left panel) but is more dramatic in the presence of spare receptors (right panel). The presence of spare receptors seems to be an adaptive mechanism to low APL, low receptor number or both.

Figure 8

Consequences of the presence of spare A₁ R or A_2A R.

Figure 9

In the absence of reserve receptors (spare receptors, panel A), adenosine receptor antagonists competitively displace adenosine from its site and decrease the effects of adenosine on the cardiovascular system in a dose-dependent manner. In the presence of spare receptors (panel B), a very small proportion of receptors occupied by adenosine is sufficient to produce maximal biological effects (vasodilation and/or bradycardia). In patients where adenosinemia is low, receptor expression level is low or both, a very small increase in adenosinemia is sufficient to occupy the active fraction of the receptors causing an abrupt drop in blood pressure without prodromes. In these cases, the use of adenosine receptor antagonists such as theophylline or caffeine will be ineffective. Indeed, the concentration of the antagonist would have to displace all the adenosine molecules from its receptors, which requires a very high concentration of the antagonist with side effects that are not tolerated by the patients.