title: Dose and time effects of caffeine intake on human platelet adenosine A(2A) receptors : functional and biochemical aspects.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Ferrara, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Varani
authors.forename: F
authors.initials: F
authors.lastname: Portaluppi
authors.forename: S
authors.initials: S
authors.lastname: Gessi
authors.forename: S
authors.initials: S
authors.lastname: Merighi
authors.forename: E
authors.initials: E
authors.lastname: Ongini
authors.forename: L
authors.initials: L
authors.lastname: Belardinelli
authors.forename: P A
authors.initials: PA
authors.lastname: Borea
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011743:Pyrimidines / Q000378:metabolism; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000097:blood* / Q000502:physiology; D013997:Time Factors; D014230:Triazoles / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D010975:Platelet Aggregation Inhibitors; D058906:Purinergic P1 Receptor Agonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014230:Triazoles; C076864:2-hexynyladenosine-5'-N-ethylcarboxamide; D019830:Adenosine-5'-(N-ethylcarboxamide); D002110:Caffeine; D000242:Cyclic AMP; D002118:Calcium