Evidence That Endogenous Inosine and Adenosine-Mediated Hyperglycaemia During Ischaemia-Reperfusion Through A3 Adenosine Receptors

Auton Autacoid Pharmacol. 2009 Oct;29(4):157-64. doi: 10.1111/j.1474-8665.2009.00443.x.


1 The molecular mechanism underlying stress-induced hyperglycemia has not been comprehensively clarified. Recently, we demonstrated in ischaemia-reperfusion (I-R) stress-subjected liver that inosine and adenosine are mainly responsible for the hyperglycemia observed. 2 We aimed to advance in the knowledge of the role of inosine plus adenosine as mediators of hepatic-induced hyperglycemia detected after I-R in lower limbs. 3 Acute ischaemia was conducted in anesthetized rats by occluding downstream abdominal aorta and cava vein; then, reperfusion was allowed. Blood samples from hepatic or abdominal cava veins were taken throughout the experiments to measure glucose, inosine and adenosine. Antagonists to adenosine (AdoR) and adrenergic receptors (AdrR) were administered during ischaemia to analyze their effect on hepatic glucose release. 4 Ischaemia up to 60 min produced minor increase of glucose and nucleosides blood values, but 5 min of ischaemia followed by 2- (or 10-) min reperfusion increased glucose 23%, and those of inosine or adenosine by 100%. After 60 min of ischaemia and 10 min of reperfusion, glycemia rose 2-fold and blood inosine and adenosine, 3.3- and 2.7-fold, respectively. A linear positive correlation, r(2), as high as 0.839 between glucose and either nucleoside blood values was calculated. The hyperglycemia response to I-R decreased by 0, 25, 33, 45 and 100% after selective inhibition of A(2B) AdoR, A(2A) AdoR, a(1B) AdrR, A(1) AdoR, and A(3) AdoR, respectively. 5 Inosine-adenosine couple through activation of hepatic A(3) AdoR is the main signal for releasing glucose from liver glycogen and for promoting hyperglycemia following experimental injury of I-R from lower limbs.

MeSH terms

  • Adenosine / blood
  • Adenosine / physiology*
  • Adenosine A3 Receptor Antagonists
  • Adenosine Triphosphate / metabolism
  • Animals
  • Blood Glucose / analysis
  • Extremities / blood supply
  • Glucose / metabolism
  • Hyperglycemia / etiology*
  • Inosine / blood
  • Inosine / physiology*
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Wistar
  • Receptor, Adenosine A3 / physiology*
  • Reperfusion Injury / metabolism*


  • Adenosine A3 Receptor Antagonists
  • Blood Glucose
  • Receptor, Adenosine A3
  • Inosine
  • Adenosine Triphosphate
  • Glucose
  • Adenosine