Effect of Caffeine Chronically Consumed During Pregnancy on Adenosine A 1 and A 2A Receptors Signaling in Both Maternal and Fetal Heart from Wistar Rats
Restricted accessResearch articleFirst published online December, 2014
Effect of Caffeine Chronically Consumed During Pregnancy on Adenosine A 1 and A 2A Receptors Signaling in Both Maternal and Fetal Heart from Wistar Rats
Caffeine is the most widely consumed psychoactive substance in the world, even during pregnancy. Its stimulatory effects are mainly due to antagonism of adenosine actions by blocking adenosine A1 and A2A receptors. Previous studies have shown that caffeine can cross the placenta and therefore modulate these receptors not only in the fetal brain but also in the heart.
Methods:
In the present work, the effect of caffeine chronically consumed during pregnancy on A1 and A2A receptors in Wistar rat heart, from both mothers and their fetuses, were studied using radioligand binding, Western-blotting, and adenylyl cyclase activity assays, as well as reverse transcription polymerase chain reaction.
Results:
Caffeine did not significantly alter A1R neither at protein nor at gene expression level in both the maternal and fetal heart. On the contrary, A2AR significantly decreased in the maternal heart, although mRNA was not affected. Gi and Gs proteins were also preserved. Finally, A1R-mediated inhibition of adenylyl cyclase activity did not change in the maternal heart, but A2AR mediated stimulation of this enzymatic activity significantly decreased according to the detected loss of this receptor.
Conclusions:
Opposite to the downregulation and desensitization of the A1R/AC pathway previously reported in the brain, these results show that this pathway is not affected in rat heart after caffeine exposure during pregnancy. In addition, A2AR is downregulated and desensitized in the maternal heart, suggesting a differential modulation of these receptor-mediated pathways by caffeine.
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References
1.
NehligA, DavalJL, DebryG. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev, 1992; 17:139–170.
2.
FredholmBB, APIJ, JacobsonKA, LindenJ, MullerCE. International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors—an update. Pharmacol Rev, 2011; 63:1–34.
3.
LindenJ. Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection. Annu Rev Pharmacol Toxicol, 2001; 41:775–787.
4.
RalevicV, BurnstockG. Involvement of purinergic signaling in cardiovascular diseases. Drug News Perspect, 2003; 16:133–140.
5.
FredholmBB, BattigK, HolmenJ, NehligA, ZvartauEE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev, 1999; 51:83–133.
6.
HeadrickJP, PeartJN, ReicheltME, HaselerLJ. Adenosine and its receptors in the heart: regulation, retaliation and adaptation. Biochim Biophys Acta, 2011; 1808:1413–1428.
RomanoFD, DobsonJGJr. Adenosine modulates beta-adrenergic signal transduction in guinea-pig heart ventricular membranes. J Mol Cell Cardiol, 1990; 22:1359–1370.
9.
LorbarM, ChungES, NabiA, et al.Receptors subtypes involved in adenosine-mediated modulation of norepinephrine release from cardiac nerve terminals. Can J Physiol Pharmacol, 2004; 82:1026–1031.
10.
BurgdorfC, RichardtD, KurzT, et al.Adenosine inhibits norepinephrine release in the postischemic rat heart: the mechanism of neuronal stunning. Cardiovasc Res, 2001; 49:713–720.
11.
McIntoshVJ, LasleyRD. Adenosine receptor-mediated cardioprotection: are all 4 subtypes required or redundant?. J Cardiovasc Pharmacol Ther, 2012; 17:21–33.
12.
BonneyS, HughesK, EckleT. Anesthetic cardioprotection: the role of adenosine. Curr Pharm Des, 2014Feb3. [Epub ahead of print]
13.
Dominguez-RodriguezA, Abreu-GonzalezP, ReiterRJ. Cardioprotection and pharmacological therapies in acute myocardial infarction: challenges in the current era. World J Cardiol, 2014; 6:100–106.
14.
JahanfarS, JaafarSH. Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome. Cochrane Database Syst Rev, 2013; 2:CD006965.
15.
McCallAL, MillingtonWR, WurtmanRJ. Blood–brain barrier transport of caffeine: dose-related restriction of adenine transport. Life Sci, 1982; 31:2709–2715.
16.
DumasM, GouyonJB, TenenbaumD, et al.Systematic determination of caffeine plasma concentrations at birth in preterm and full-term infants. Dev Pharmacol Ther, 1982; 4:S182–186.
17.
LeonD, AlbasanzJL, RuizMA, FernandezM, MartinM. Adenosine A1 receptor down-regulation in mothers and fetal brain after caffeine and theophylline treatments to pregnant rats. J Neurochem, 2002; 82:625–634.
18.
Ballesteros-YanezI, CastilloCA, Amo-SalasM, AlbasanzJL, MartinM. Differential effect of caffeine consumption on diverse brain areas of pregnant rats. J Caffeine Res, 2012; 2:90–98.
19.
LeonD, AlbasanzJL, RuizMA, MartinM. Chronic caffeine or theophylline intake during pregnancy inhibits A1 receptor function in the rat brain. Neuroscience, 2005; 131:481–489.
20.
LorenzoAM, LeonD, CastilloCA, et al.Maternal caffeine intake during gestation and lactation down-regulates adenosine A1 receptor in rat brain from mothers and neonates. J Neurosci Res, 2010; 88:1252–1261.
21.
RivkeesSA. The ontogeny of cardiac and neural A1 adenosine receptor expression in rats. Brain Res Dev Brain Res, 1995; 89:202–213.
22.
IglesiasI, LeonD, RuizMA, AlbasanzJL, MartinM. Chronic intake of caffeine during gestation down regulates metabotropic glutamate receptors in maternal and fetal rat heart. Amino Acids, 2006; 30:257–266.
23.
Reagan-ShawS, NihalM, AhmadN. Dose translation from animal to human studies revisited. Faseb J, 2008; 22:659–661.
24.
AsadifarM, YazdaniM, SadeghpourR, et al.Combined effects of caffeine and malnutrition on the newborn rat's myocardium. Food Chem Toxicol, 2005; 43:451–456.
25.
FlatenV, LaurentC, CoelhoJE, et al.From epidemiology to pathophysiology: what about caffeine in Alzheimer's disease?. Biochem Soc Trans, 2014; 42:587–592.
26.
Rivera-OliverM, Diaz-RiosM. Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review. Life Sci, 2014; 101:1–9.
27.
RibeiroJA, SebastiaoAM. Caffeine and adenosine. J Alzheimers Dis, 2010; 20:S3–15.
28.
SudanoI, BinggeliC, SpiekerL, et al.Cardiovascular effects of coffee: is it a risk factor?. Prog Cardiovasc Nurs, 2005; 20:65–69.
29.
PatilH, LavieCJ, O'KeefeJH. Cuppa joe: friend or foe? Effects of chronic coffee consumption on cardiovascular and brain health. Mo Med, 2011; 108:431–438.
30.
HartleyTR, LovalloWR, WhitsettTL. Cardiovascular effects of caffeine in men and women. Am J Cardiol, 2004; 93:1022–1026.
31.
JamesJE, GreggME. Hemodynamic effects of dietary caffeine, sleep restriction, and laboratory stress. Psychophysiology, 2004; 41:914–923.
32.
VlachopoulosC, PanagiotakosD, IoakeimidisN, DimaI, StefanadisC. Chronic coffee consumption has a detrimental effect on aortic stiffness and wave reflections. Am J Clin Nutr, 2005; 81:1307–1312.
33.
BalasubramaniamR, ChawlaS, GraceAA, HuangCL. Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca(2+) homeostasis. Am J Physiol Heart Circ Physiol, 2005; 289:H1584–1593.
34.
DunwiddieTV, MasinoSA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci, 2001; 24:31–55.
35.
LewingtonS, ClarkeR, QizilbashN, PetoR, CollinsR. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet, 2002; 360:1903–1913.
36.
NawrotP, JordanS, EastwoodJ, et al.Effects of caffeine on human health. Food Addit Contam, 2003; 20:1–30.
37.
BrowneML. Maternal exposure to caffeine and risk of congenital anomalies: a systematic review. Epidemiology, 2006; 17:324–331.
38.
BrentRL, ChristianMS, DienerRM. Evaluation of the reproductive and developmental risks of caffeine. Birth Defects Res B Dev Reprod Toxicol., 2011; 92:152–187.
39.
BrowneML, BellEM, DruschelCM, et al.Maternal caffeine consumption and risk of cardiovascular malformations. Birth Defects Res A Clin Mol Teratol, 2007; 79:533–543.
40.
RivkeesSA, WendlerCC. Regulation of cardiovascular development by adenosine and adenosine-mediated embryo protection. Arterioscler Thromb Vasc Biol, 2011; 32:851–855.
41.
CnattingiusS, EkbomA, GranathF, RaneA. Caffeine intake and the risk of spontaneous abortion. Food Chem Toxicol, 2003; 41:1202; author reply 1203.
42.
HoytAT, BrowneM, RichardsonS, RomittiP, DruschelC. Maternal caffeine consumption and small for gestational age births: results from a population-based case-control study. Matern Child Health J, 2014; 18:1540–1551.
43.
WendlerCC, Busovsky-McNealM, GhatpandeS, et al.Embryonic caffeine exposure induces adverse effects in adulthood. Faseb J, 2009; 23:1272–1278.
44.
BuscariolloDL, BreuerGA, WendlerCC, RivkeesSA. Caffeine acts via A1 adenosine receptors to disrupt embryonic cardiac function. PLoS One, 2011; 6:e28296.
45.
IkedaGJ, SapienzaPP, McGinnisML, et al.Blood levels of caffeine and results of fetal examination after oral administration of caffeine to pregnant rats. J Appl Toxicol, 1982; 2:307–314.
46.
OhnishiA, BranchRA, JacksonK, et al.Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats. J Clin Invest, 1986; 78:1045–1050.
47.
NakamotoT, JosephFJr, YazdaniM, HartmanAD. Effects of different levels of caffeine supplemented to the maternal diet on the brains of newborn rats and their dams. Toxicol Lett, 1988; 44:167–175.
48.
AuchampachJA, BolliR. Adenosine receptor subtypes in the heart: therapeutic opportunities and challenges. Am J Physiol, 1999; 276:H1113–1116.
49.
FunayaH, KitakazeM, NodeK, et al.Plasma adenosine levels increase in patients with chronic heart failure. Circulation, 1997; 95:1363–1365.
50.
KitakazeM, MinaminoT, NodeK, et al.Elevation of plasma adenosine levels may attenuate the severity of chronic heart failure. Cardiovasc Drugs Ther, 1998; 12:307–309.
51.
MustafaSJ, MorrisonRR, TengB, PellegA. Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology. Handb Exp Pharmacol, 2009; 161–188.
52.
WendlerCC, AmatyaS, McClaskeyC, et al.A1 adenosine receptors play an essential role in protecting the embryo against hypoxia. Proc Natl Acad Sci U S A, 2007; 104:9697–9702.
53.
WendlerCC, PoulsenRR, GhatpandeS, GreeneRW, RivkeesSA. Identification of the heart as the critical site of adenosine mediated embryo protection. BMC Dev Biol, 2010; 10:57.
54.
GhatpandeSK, BillingtonCJJr, RivkeesSA, WendlerCC. Hypoxia induces cardiac malformations via A1 adenosine receptor activation in chicken embryos. Birth Defects Res A Clin Mol Teratol, 2008; 82:121–130.
55.
XiangF, HuangYS, ZhangDX, et al.Adenosine A1 receptor activation reduces opening of mitochondrial permeability transition pores in hypoxic cardiomyocytes. Clin Exp Pharmacol Physiol, 2010; 37:343–349.
56.
FloodAJ, WillemsL, HeadrickJP. Coronary function and adenosine receptor-mediated responses in ischemic-reperfused mouse heart. Cardiovasc Res., 2002; 55:161–170.
AndresenBT, GillespieDG, MiZ, DubeyRK, JacksonEK. Role of adenosine A(1) receptors in modulating extracellular adenosine levels. J Pharmacol Exp Ther, 1999; 291:76–80.
59.
SchindlerCW, Karcz-KubichaM, ThorndikeEB, et al.Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists. Br J Pharmacol, 2005; 144:642–650.
60.
WeeS, JennerT, Rose'meyerRB. Loss of coronary dilation to N6-2-(4-aminophenyl) ethyladenosine in isolated hearts from chronic caffeine- and nifedipine-treated rats. J Caffeine Res, 2011; 1:49–57.
61.
WhitePJ, NguyenTT. Chronic caffeine treatment causes changes in cardiac adenosine receptor function in rats. Pharmacology, 2002; 65:129–135.
62.
RongenGA, LendersJW, LambrouJ, et al.Presynaptic inhibition of norepinephrine release from sympathetic nerve endings by endogenous adenosine. Hypertension, 1996; 27:933–938.
63.
BarracoRA, Clough-HelfmanC, GoodwinBP, AndersonGF. Evidence for presynaptic adenosine A2a receptors associated with norepinephrine release and their desensitization in the rat nucleus tractus solitarius. J Neurochem, 1995; 65:1604–1611.
64.
DonosoMV, AedoF, Huidobro-ToroJP. The role of adenosine A2A and A3 receptors on the differential modulation of norepinephrine and neuropeptide Y release from peripheral sympathetic nerve terminals. J Neurochem, 2006; 96:1680–1695.
65.
MinanaMD, GrisoliaS. Caffeine ingestion by rats increases noradrenaline turnover and results in self-biting. J Neurochem, 1986; 47:728–732.
66.
DhallaAK, ShryockJC, ShreeniwasR, BelardinelliL. Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Curr Top Med Chem, 2003; 3:369–385.
67.
StrickbergerSA, ManKC, DaoudEG, et al.Adenosine-induced atrial arrhythmia: a prospective analysis. Ann Intern Med, 1997; 127:417–422.
