Physiological roles of A₁ and A_2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

Abstract

Yang JN, Chen JF, Fredholm BB. Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. Am J Physiol Heart Circ Physiol 296: H1141-H1149, 2009. First published February 13, 2009 doi:10.1152/ajpheart.00754.2008.-Heart rate (HR), body temperature (Temp), locomotor activity (LA), and oxygen consumption (O2C) were studied in awake mice lacking one or both of the adenosine A 1 or A2A receptors (A1R or A2AR, 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 1R knockout (A1RKO) mice but lower in A2ARKO mice and intermediate in A1-A2AR double KO mice. A single dose of an unselective ␤-blocker (timolol; 1 mg/kg) abolished the HR differences between these genotypes. Deletion of A 1Rs had little effect on Temp, whereas deletion of A 2ARs increased it in females and decreased it in males. A 1-A2ARKO mice had lower Temp than WT mice. LA was unaltered in A 1RKO mice and lower in A 2ARKO and A1-A2ARKO mice than in WT mice. Caffeine injection increased LA but only in mice expressing A 2AR. Caffeine ingestion also increased LA in an A 2AR-dependent manner in male mice. Caffeine ingestion significantly increased O 2C 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 1R or A 2AR blockade. Selective A2B antagonism had little or no effect. Thus A 1R and A2AR influence HR, Temp, LA, and O2C in mice in a sex-dependent manner, indicating effects of endogenous adenosine. The A2AR plays an important role in the modulation of O2C and LA by acute and chronic caffeine administration. There is also evidence for effects of higher doses of caffeine being independent of both A 1R and A2AR. diurnal rhythm; metabolic rate; locomotor activity; adenosine; telemetry CAFFEINE (1,3,7-trimethylxanthine), the most widely consumed stimulant in the world, acts as a competitive antagonist of adenosine receptors (ARs) (18). It is much more potent on three of the known receptors, A 1 , A 2A , and A 2B (A 1 R, A 2A R, and A 2B R, respectively) than on the fourth, the A 3 R (17). Since a competitive antagonist will have effects only when and where receptors are activated by an agonist, it is relevant that endogenous agonist adenosine is more potent on A 1 R and A 2A R than on A 2B R. The potency of adenosine as an agonist in addition depends on the density of the receptors (16). The levels of adenosine are low under physiological condition but are sufficient to partially activate A 1 R, A 2A R, and A 3 Rs where the receptors are abundantly expressed. For these reasons caffeine is generally believed to act on A 1 R and A 2A R to exert most of its effects, at least when given in lower doses (18). However, a recent study showed that A 2B R knockout (A 2B RKO) mice have e...

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

“…Since then, A 2B knockout mice Hua et al, 2007b), several mice that allow tissue-specific targeting (Scammell et al, 2003;Bastia et al, 2005;Huang et al, 2006), and double knockouts have been described (Yang et al, 2009a). In addition, several mice that are deficient in the enzymes that form or degrade adenosine have been used to characterize the physiological significance of the receptors.…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…Adenosine receptors have been implicated in regulating coronary blood flow and oxygen consumption by cardiac muscle and are present in the brain, most notably in the forebrain [34,35]. CBD (50 μg/kg) inhibits the subsequent ventricular tachycardia following coronary artery occlusion in rats-an effect abolished by 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A 1 receptor antagonist (Table 1).…”

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

“…This sex-dependent phenotypic difference is unlikely attributable to a differential loss of forebrain A 2A Rs between sexes given that Cre expression did not reveal any such sex difference (data not shown). Although the precise origin or mechanism underlying this sex-dependent working memory phenotype in fb-A 2A R KO mice is presently unclear, it is worth noting that global A 2A R knockout has previously been reported to influence other brain-relevant processes in a sexdependent manner, including body temperature regulation (Yang et al 2009) and ethanol sensitivity and consumption (Naassila et al 2002). Interestingly, estrogen has been shown to modify the expression of A 2A R transcript in several different brain regions ); thus, one might venture to speculate a degree of sex hormonal influence over A 2A R-dependent phenotypes.…”