Loss of Coronary Dilation to N 6 -2-(4-Aminophenyl) Ethyladenosine in Isolated Hearts from Chronic Caffeine-and Nifedipine-Treated Rats (original) (raw)
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Journal of Neurochemistry, 2006
Caffeine, an unspecific antagonist of adenosine receptors, is commonly used to treat the apnea of prematurity. We have defined the effects of caffeine on the carotid body (CB) chemoreceptors, the main peripheral controllers of breathing, and identified the adenosine receptors involved. Caffeine inhibited basal (IC 50 , 210 lM) and low intensity (PO 2 66 mm Hg/30 mM K + ) stimulation-induced release of catecholamines from chemoreceptor cells in intact preparations of rat CB in vitro. Opposite to caffeine, 5¢-(N-ethylcarboxamido) adenosine (NECA; an A 2 agonist) augmented basal and lowintensity hypoxia-induced release. 2-p-(2-Carboxyethyl)phenethyl-amino-5¢-N-ethylcaboxamido-adenosine hydrochloride (CGS21680), 2-hexynyl-NECA (HE-NECA) and SCH58621 (A 2A receptors agents) neither affected catecholamine release nor altered the caffeine effects. The 8-cycle-1,3-dipropylxanthine (DPCPX; an A 1 /A 2B antagonist) and 8-(4-{[(4-cyano-phenyl)carbamoylmethyl]-oxy}phenyl)-1,3-di(n-propyl)xanthine (MRS1754; an A 2B antagonist) mimicking of caffeine indicated that caffeine effects are mediated by A 2B receptors. Immunocytochemical A 2B receptors were located in tyrosine hydroxylase positive chemoreceptor cells. Caffeine reduced by 52% the chemosensory discharges elicited by hypoxia in the carotid sinus nerve. Inhibition had two components with pharmacological analysis indicating that A 2A and A 2B receptors mediate, respectively, the low (17 · 10 )9 M) and high (160 · 10 )6 M) IC 50 effects. It is concluded that endogenous adenosine, via presynaptic A 2B and postsynaptic A 2A receptors, can exert excitatory effects on the overall output of the rat CB chemoreceptors. Fig. 4 Effects of 5¢-(N-ethylcarboxamido)adenosine (NECA), an A 2 Ado receptor agonist, on the release of catecholamines (CA) from rat carotid body. (a) Time courses of the release of [ 3 H]CA from carotid bodies (CBs) incubated with 20 (j, n ¼ 6; normoxic) and 10% O 2 (m, n ¼ 3; hypoxic) solutions. NECA (1 lM) was applied for the period shown in the plot. (b) The percentage increase in the release of [ 3 H]CA elicited by NECA. Data represent means ± SEM. Adenosine and carotid body chemoreception 621
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2004
The aims of this study were (a). to compare absolute myocardial blood flow (MBF) during adenosine triphosphate (ATP) infusion with that after dipyridamole administration without caffeine intake and (b). to evaluate the effect of caffeine intake on the hyperemic flow induced by these coronary vasodilator agents. MBF was quantified with (15)O-labeled water and PET at rest, during ATP infusion (0.16 mg/kg/min for 9 min), and after dipyridamole administration (0.56 mg/kg over 4 min) after a 24-h abstinence from caffeine (baseline evaluation) in 10 healthy volunteers. Within 2 wk, the same PET studies were repeated after caffeine intake to evaluate the effect of caffeine on the hyperemic flow induced by these pharmacologic agents (caffeine study). Myocardial flow reserve (MFR), defined as the ratio of hyperemic to resting blood flow, was also evaluated. Resting MBF in baseline and caffeine studies did not differ significantly (0.79 +/- 0.29 vs. 0.75 +/- 0.31 mL/min/g, P = 0.88). Without ...
Caffeine is a widely consumed methylxanthine drug found naturally in tea, coffee and the cocoa plant, with an average adult consumption of 2.4mg/kg/day (Echeverri et al, 2010). The stimulatory properties of methylxanthine drugs are caused primarily by the non-selective antagonism of Gαi and Gαo protein coupled adenosine A1 and A2A receptors (Hsu et al, 2009). Since, adenosine receptors are involved in the inhibition of neurotransmitter release, the antagonism of these receptors are stimulatory. The antagonism of A1 receptors is known to stimulate heart rate (HR) via ionotropic and chronotropic effects. As a consequence, caffeine has been found to increase HR (Echeverri et al, 2010). The inhibitory effects of A2A receptors is more widely expressed in the cerebral regions that are involved in dopaminergic innervation, including the dorsal striatum, nucleus accumbens (NAc), and olfactory tubercle (Hsu et al, 2009). As a consequence, caffeine is widely regarded to have a large role in the central nervous system, to stimulate neurotransmitter release.
Journal of Alzheimer's Disease, 2010
Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine.
Caffeine's Vascular Mechanisms of Action
International Journal of Vascular Medicine, 2010
Caffeine is the most widely consumed stimulating substance in the world. It is found in coffee, tea, soft drinks, chocolate, and many medications. Caffeine is a xanthine with various effects and mechanisms of action in vascular tissue. In endothelial cells, it increases intracellular calcium stimulating the production of nitric oxide through the expression of the endothelial nitric oxide synthase enzyme. Nitric oxide is diffused to the vascular smooth muscle cell to produce vasodilation. In vascular smooth muscle cells its effect is predominantly a competitive inhibition of phosphodiesterase, producing an accumulation of cAMP and vasodilation. In addition, it blocks the adenosine receptors present in the vascular tissue to produce vasoconstriction. In this paper the main mechanisms of action of caffeine on the vascular tissue are described, in which it is shown that caffeine has some cardiovascular properties and effects which could be considered beneficial.
Brain Research, 2009
Neonatal caffeine treatment (adenosine receptor antagonist, 15 mg/kg/day, between postnatal days 3 and 12) affects respiratory patterns in adult male but not female rats as shown by an increase in the respiratory frequency in the early phase of response to hypoxia and an increase in the tidal volume in the late phase of response. Here, we tested the hypothesis that these changes are correlated with modified expression of adenosine receptors in the chemoreflex pathway. Carotid bodies, nucleus tractus solitarii, and superior cervical ganglia were collected from 3-month-old male and female rats that were either naive (not manipulated during the neonatal period) or treated with caffeine (NCT) or water (NWT) between postnatal days 3 and 12 by gavage. Western blot analysis was used to assess the expression of adenosine A 1 and A 2A receptors and tyrosine hydroxylase, the ratelimiting enzyme for dopamine synthesis. In male rats, there was a 37% increase in the level of A 2A receptor and a 17% decrease in tyrosine hydroxylase in the carotid body of NCT (p < 0.001) as compared to NWT rats. In the nucleus tractus solitarius, we found a 13% and 19% decrease in A 1 receptor expression in NWT and NCT rats (p < 0.01), respectively, compared to naive rats. In the superior cervical ganglion, there was no change in A 1 receptor, A 2A receptor, and tyrosine hydroxylase expression. In female rats, the only changes observed were decreases of 12% and 15% in A 1 receptor levels in the nucleus tractus solitarius of NWT and NCT rats (p < 0.01), respectively, compared to naive rats. We conclude that NCT induces long-term changes in the adenosine receptor system. These changes may partially explain the modifications of the respiratory pattern induced by NCT in adults. The increased expression of the adenosine A 2A receptor (specific to male rats), combined with the decreased tyrosine hydroxylase expression in the carotid body, suggests that NCT affects adenosine-dopamine interactions regulating chemosensory activity.
8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine antagonist in vitro and in vivo
FEBS Letters, 1993
An adenosine antagonist, 8-(3-chlorostyryl)caffeine (CSC), was shown previously to be 520-fold selective for A 2a -adenosine receptors in radioligand binding assays in the rat brain. In reversing agonist effects on adenylate cyclase, CSC was 22-fold selective for A 2d receptors in rat pheochromocy-toma cells (K b 60 nM) vs. A 1 receptors in rat adipocytes (K b 1.3 µM). Administered i.p. in NIH mice at a dose of 1 mg/kg, CSC shifted the curve for locomotor depression elicited by the A 2a -selective agonist APEC to the right (ED 50 , value for APEC shifted from 20 µg/kg i.p. to 190 µg/kg). CSC had no effect on locomotor depression elicited by an ED 50 dose of the A 1 -selective agonist CHA. CSC alone at a dose of 5 mg/kg stimulated locomotor activity by 22% over control values. Coadministration of CSC and the A 1 -selective antagonist CPX, both at non-stimulatory doses, increased activity by 37% (P < 0.001) over CSC alone, suggesting a behavioral synergism of A 1 -and A 2 -antagonist effects in the CNS.
Chronic caffeine consumption increases the number of brain adenosine receptors
Life Sciences, 1983
Caffeine, a potent central stimulant, is known to competitively inhibit the specific binding of both adenosine and benzodiazepine receptor ligands to brain membranes . In mice receiving a diet containing non-toxic doses of caffeine (200 or 400 mg/kg diet) for periods up to 40 days, a dose-related increase in the number of binding sites for [3H]-CHA and [3H] DPX was observed in whole brain membranes without modifications of the receptors' affinity. Furthermore, a transitory increase in the number of [3H]-DZP binding sites was observed. These preliminary data seem to confirm the involvement of the adenosine receptors in the mode of action of caffeine and may be relevant to the development of both tolerance and dependence to some of the central effects of this compound.
Effects of chronic administration of caffeine on adenosine A1 and A2 receptors in rat brain
Brain Research Bulletin, 1988
Chronic administration of caffeine (75 mgikgiday) to rats for 12 days increased [3H]R-PIA binding in the cerebral cortex and cerebellum and [3H]NECA binding to high affinity receptor sites in the striatum. The results indicate that both adenosine A, and A, receptor subtypes possess mechanisms of adaptation to chronic caffeine treatment. In addition, adenosine A, receptor binding shows heterogenous neuroanatomical pattern indicating that the A, response to caffeine treatment presents regional variation in the rat brain.