Dose and time effects of caffeine intake on human platelet adenosine A(2A) receptors : functional and biochemical aspects

Circulation. 2000 Jul 18;102(3):285-9. doi: 10.1161/01.cir.102.3.285.


BACKGROUND-We determined whether repeated caffeine administration at different dosages and for different periods of time (400 or 600 mg/d for 1 week or 400 mg/d for 2 weeks) upregulates human platelet adenosine A(2A) receptors and is accompanied by increases in cAMP accumulation and decreases in aggregation and calcium levels after stimulation of A(2A) receptors by the selective agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA). METHODS AND RESULTS-Platelets were obtained from peripheral venous blood of 45 healthy human volunteers at the end of 2 weeks of caffeine abstinence and at 12, 60, and 108 hours after the last dose of caffeine. The lowest dose of caffeine, when given for only 7 days, had no effect. Increasing the total dose, either by giving 400 mg/d for 14 days or giving 600 mg/d, resulted in binding assays performed with the adenosine A(2A) receptor radioligand [(3)H]SCH 58261 [5-amino-7(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1, 5-c]pyrimidine], in the upregulation of A(2A) receptors. Moreover, the potency of HE-NECA to produce antiaggregatory effects, a rise in cAMP accumulation, and a decrease in calcium levels was significantly increased. CONCLUSIONS-Chronic caffeine intake can lead to upregulation of adenosine A(2A) receptors, which is accompanied by sensitization, in a time- and dose-dependent manner, to the actions of the agonist HE-NECA.

MeSH terms

  • Adenosine-5'-(N-ethylcarboxamide) / analogs & derivatives
  • Adenosine-5'-(N-ethylcarboxamide) / pharmacology
  • Adult
  • Blood Platelets / metabolism*
  • Caffeine / pharmacology*
  • Calcium / metabolism
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Middle Aged
  • Myocardium / metabolism
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / pharmacology
  • Purinergic P1 Receptor Agonists
  • Pyrimidines / metabolism
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1 / blood*
  • Receptors, Purinergic P1 / physiology
  • Time Factors
  • Triazoles / metabolism
  • Up-Regulation


  • 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
  • Platelet Aggregation Inhibitors
  • Purinergic P1 Receptor Agonists
  • Pyrimidines
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1
  • Triazoles
  • 2-hexynyladenosine-5'-N-ethylcarboxamide
  • Adenosine-5'-(N-ethylcarboxamide)
  • Caffeine
  • Cyclic AMP
  • Calcium