Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine.
Heart rate (HR), body temperature (Temp), locomotor activity (LA), and oxygen consumption (O(2)C) were studied in awake mice lacking one or both of the adenosine A(1) or A(2A) receptors (A(1)R or A(2A)R, respectively) using telemetry and respirometry, before and after caffeine administration. All parameters were lower during day than night and higher in females than males. When compared with wild-type (WT) littermates, HR was higher in male A(1)R knockout (A(1)RKO) mice but lower in A(2A)RKO mice and intermediate in A(1)-A(2A)R double KO mice. A single dose of an unselective beta-blocker (timolol; 1 mg/kg) abolished the HR differences between these genotypes. Deletion of A(1)Rs had little effect on Temp, whereas deletion of A(2A)Rs increased it in females and decreased it in males. A(1)-A(2A)RKO mice had lower Temp than WT mice. LA was unaltered in A(1)RKO mice and lower in A(2A)RKO and A(1)-A(2A)RKO mice than in WT mice. Caffeine injection increased LA but only in mice expressing A(2A)R. Caffeine ingestion also increased LA in an A(2A)R-dependent manner in male mice. Caffeine ingestion significantly increased O(2)C in WT mice, but less in the different KO mice. Injection of 30 mg/kg caffeine decreased Temp, especially in KO mice, and hence in a manner unrelated to A(1)R or A(2A)R blockade. Selective A(2B) antagonism had little or no effect. Thus A(1)R and A(2A)R influence HR, Temp, LA, and O(2)C in mice in a sex-dependent manner, indicating effects of endogenous adenosine. The A(2A)R plays an important role in the modulation of O(2)C and LA by acute and chronic caffeine administration. There is also evidence for effects of higher doses of caffeine being independent of both A(1)R and A(2A)R.
Yang
Jiang-Ning
JN
Karolinska Institutet, Nanna Svartz väg 2, Stockholm S-171 77 Sweden. Jiangning.Yang@ki.se
Chen
Jiang-Fan
JF
Fredholm
Bertil B
BB
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology*; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012727:Sex Characteristics; D013999:Timolol / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000697:Central Nervous System Stimulants; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D002110:Caffeine; D013999:Timolol