Chronic Caffeine Intake Research Articles

Caffeine intake reduces incident atrial fibrillation at a population level.

Background The general belief is that caffeine increases the risk of hyperkinetic arrhythmias, including atrial fibrillation. The aim of this study is to investigate the effect of chronic caffeine intake on incident atrial fibrillation in general population. Design and methods A population cohort of 1475 unselected men and women observed for 12 years and left free to intake food or beverages containing caffeine was studied. Subjects were stratified into tertiles of caffeine intake both in the whole cohort and after genotyping for the -163C > A polymorphism of the CYP1A2 gene, regulating caffeine metabolism. Results In the whole cohort, the 12-year incidence of atrial fibrillation was significantly lower in the third (2.2%) than in the first (10.2%) or second (5.7%) tertile of caffeine intake ( P < 0.001). The same trend was observed in all genotypes; the apparently steeper reduction of atrial fibrillation in slow caffeine metabolisers found at univariate analysis was proved wrong by multivariate Cox analysis. Age, chronic pulmonary disease, history of heart failure and of coronary artery disease, and systolic blood pressure - but not the genotype or the caffeine × CYP1A2 interaction term - were significant confounders of the association between incident atrial fibrillation and being in the third tertile of caffeine intake (hazard ratio 0.249, 95% confidence intervals 0.161-0.458, P < 0.01). Conclusions A higher caffeine intake (>165 mmol/day or > 320 mg/day) is associated with a lower incidence of atrial fibrillation in the 12-year epidemiological prospective setting based on the general population.

Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats

Background/Aims: High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption. Methods: Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay. Results: Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR), and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion. Conclusion: The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats.

OP.1B.04] CAFFEINE INTAKE AND ABSTRACT REASONING AMONG 1,374 UNSELECTED MEN AND WOMEN FROM GENERAL POPULATION. ROLE OF THE –163C>A POLYMORPHISM OF CYP1A2 GENE

Objective: Caffeine is considered to be an enhancer of cognitive performance but its neuroactive effects, particularly those on abstract reasoning, have never been studied in an epidemiological setting, especially in relation to the different genotypes of −163C>A polymorphism of CYP1A2 gene, largely controlling caffeine metabolism. Aim of this study was to ascertain whether free chronic caffeine intake modifies abstract reasoning in a dose-dependent manner, and if this effect is influenced by the above-mentioned polymorphism or modified by other factors. Design and method: We studied 1,374 unselected men and women aged 51 ± 15 years (range 18 to 89) from general population. From a 7-day dietary diary, caffeine deriving from coffee, tea, chocolate or cola was calculated and summed up. Abstract reasoning was measured in the frame of a neuropsychological assessment as the ability to find a concept linking two words indicating objects or actions and explaining how they were connected. Results: In age-schooling-adjusted linear regression, the higher the caffeine intake, the better the abstraction score; the interaction term between caffeine and the −163C>A polymorphism was accepted in linear regression (coefficient 0.0012, standard error 0.0005, p = 0.002). More precisely, abstract reasoning depended on caffeine in the CC homozygous only (“slow” caffeine metabolizers), where it was higher in the 3rd tertile of caffeine intake (Figure 1). Actually, the CC homozygous in the highest tertile were as abstractive as the A-carriers (“fast” caffeine metabolizers, likely prone to consume more caffeine a day in order to avoid abstinence).Conclusions: A direct association between caffeine intake and abstract reasoning exists in general population and is influenced by the −163C>A polymorphism, caffeine intake being the intermediate phenotype; age and ethanol reduce while smoking and schooling enhance this association.

Caffeine intake and abstract reasoning among 1374 unselected men and women from general population. Role of the –163C>A polymorphism of CYP1A2 gene

The possible effect of caffeine as an enhancer of cognitive performance, particularly that on abstract reasoning, has never been studied in an epidemiological setting, especially in relation to -163C>A polymorphism of CYP1A2 gene, largely controlling caffeine metabolism. Aim of this study was to ascertain whether in general population free chronic caffeine intake modifies abstract reasoning, and if this effect is influenced by the above mentioned genotype, by age, schooling, ethanol intake and smoking habits. We studied 1374 unselected men and women aged 51±15 years (range 18-89) from a general population. Daily caffeine intake deriving from coffee, tea, chocolate or cola was calculated from an anamnestic questionnaire and from a 7-day dietary diary. Abstract reasoning was measured in the frame of a neuropsychological assessment as the ability to find a concept linking two words indicating objects or actions and explaining how they were connected. In age-schooling-adjusted linear regression, the higher the caffeine intake, the better the abstraction score. Abstract reasoning depended on caffeine in the -163C>A CC homozygous only (so-called slow metabolizers), where it was higher in the 3rd tertile of caffeine intake. Age and ethanol reduced while smoking and schooling enhanced this association. The interaction term between caffeine and the -163C>A polymorphism was accepted in linear regressions. Caffeine consumption resulted innocuous for the A-carriers (so-called fast metabolizers). In general population, a positive association between caffeine intake and abstract reasoning exists in the CC homozygous of the -163C>A polymorphism of CYP1A2 gene.

Tau hyperphosphorylation in the brain of ob/ob mice is due to hypothermia: Importance of thermoregulation in linking diabetes and Alzheimer's disease

Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM.Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1). We then examined the mechanism of tau hyperphosphorylation and demonstrated that it is mostly due to hypothermia, as ob/ob mice were hypothermic and normothermia restored tau phosphorylation to control levels. As caffeine has been shown to be beneficial for diabetes, obesity and tau phosphorylation, we, therefore, used it as therapeutic treatment. Unexpectedly, chronic caffeine intake exacerbated tau hyperphosphorylation by promoting deeper hypothermia.Our data indicate that tau hyperphosphorylation is predominately due to hypothermia consequent to impaired thermoregulation in ob/ob mice. This study establishes a novel link between diabetes and AD, and reinforces the importance of recording body temperature to better assess the relationship between diabetes and AD.

Synergistic effects of caffeine and catechins on lipid metabolism in chronically fed mice via the AMP-activated protein kinase signaling pathway.

To investigate the mechanistic effects of combined exposure to caffeine and catechins on lipid metabolism in mice. Seventy mice were randomly assigned to seven groups and fed diets containing varying doses of caffeine and catechins for 24weeks. Body weight gain, intraperitoneal adipose tissue (IPAT) weight, serum biochemical parameters, and enzymatic activities, mRNA and protein expression levels of lipid metabolism-related enzymes in the liver and IPAT were analyzed. Following administration of caffeine and catechins, body weight gain, IPAT weight, serum and liver concentrations of total cholesterol and triglyceride were markedly reduced. Lipase activities, including that of AMP-activated protein kinase (AMPK), acyl-CoA oxidase, carnitine acyltransferase, adipose triglyceride lipase, and hormone-sensitive lipase, were significantly upregulated; however, fatty acid synthase (FAS) activity in the liver was suppressed. Combined exposure to caffeine and catechins significantly upregulated mRNA and protein expression levels of lipases while downregulating FAS mRNA expression and protein expression of peroxisome proliferator-activated receptor γ2. The combination of caffeine and catechins regulated the enzymatic activities, mRNA, and protein expression levels of lipid metabolism-related enzymes, resulting in suppression of body weight gain and IPAT weight in mice, potentially through activation of the AMPK signaling pathway. This study indicates that chronic intake of both caffeine and catechins can synergistically contribute to prevention of obesity and lifestyle-related diseases.

Caffeine intake antagonizes salt sensitive hypertension through improvement of renal sodium handling.

High salt intake is a major risk factor for hypertension. Although acute caffeine intake produces moderate diuresis and natriuresis, caffeine increases the blood pressure (BP) through activating sympathetic activity. However, the long-term effects of caffeine on urinary sodium excretion and blood pressure are rarely investigated. Here, we investigated whether chronic caffeine administration antagonizes salt sensitive hypertension by promoting urinary sodium excretion. Dahl salt-sensitive (Dahl-S) rats were fed with high salt diet with or without 0.1% caffeine in drinking water for 15 days. The BP, heart rate and locomotor activity of rats was analyzed and urinary sodium excretion was determined. The renal epithelial Na+ channel (ENaC) expression and function were measured by in vivo and in vitro experiments. Chronic consumption of caffeine attenuates hypertension induced by high salt without affecting sympathetic nerve activity in Dahl-S rats. The renal α-ENaC expression and ENaC activity of rats decreased after chronic caffeine administration. Caffeine increased phosphorylation of AMPK and decrease α-ENaC expression in cortical collecting duct cells. Inhibiting AMPK abolished the effect of caffeine on α-ENaC. Chronic caffeine intake prevented the development of salt-sensitive hypertension through promoting urinary sodium excretion, which was associated with activation of renal AMPK and inhibition of renal tubular ENaC.

High doses of caffeine reduce invivo osteogenic activity in prepubertal rats.

Caffeine adversely affects endochondral ossification during fetal skeletal growth, and results in increased incidence of delayed and abnormal fetal skeletal development. Chronic caffeine intake also decreases growth hormone secretion. Thus, it is conceivable that caffeine may disrupt bone growth during the peripubertal period. This study aimed to investigate the impact of high-caffeine consumption on bone growth throughout puberty. A total of 51 male rats (21days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180mgkg(-1) day(-1) for 4weeks. After death, the final length and weight of leg bones were measured, and the tibia processed for histomorphometric analysis. Caffeine caused a significant decrease in body mass gain. This was accompanied with proportional decreases in lean body mass and body fat. In addition, bone mass and osteogenic activity invivo were assessed using dual-energy X-ray absorptiometry and (18) F-NaF positron emission tomography. The results showed significant decreases of bone mass and invivo osteogenic activity in the caffeine-fed groups. Rats fed with caffeine showed a significantly shorter and lighter tibia and femur and the vertebral column compared with controls. In addition, caffeine does not increase the width of the growth plates (GPs), it slows the rate at which the GP closes due to a slower rate of growth. These results demonstrated that caffeine altered osteogenic activity, leading to delayed peripubertal longitudinal bone growth and maturation. Given that osteogenic cells undergo dynamic changes in metabolic activity and that the pubertal growth spurt is mainly stimulated by growth hormone/insulin-like growth factor-1 and sex steroids during pubertal development, caffeine could suppress ossification by interfering with both physiological changes in hormonal secretion and osteogenic activity during this critical period. Further study will be needed to investigate the cellular/molecular mechanism by which caffeine affects osteogenesis using invitro experimental models.

Cumulative neurobehavioral and physiological effects of chronic caffeine intake: individual differences and implications for the use of caffeinated energy products.

The use of caffeine-containing energy products has increased worldwide in recent years. All of the top-selling energy drinks contain caffeine, which is likely to be the primary psychoactive ingredient in these products. Research shows that caffeine-containing energy products can improve cognitive and physical performance. Presumably, individuals consume caffeine-containing energy products to counteract feelings of low energy in situations causing tiredness, fatigue, and/or reduced alertness. This review discusses the scientific evidence for sleep loss, circadian phase, sleep inertia, and the time-on-task effect as causes of low energy and summarizes research assessing the efficacy of caffeine to counteract decreased alertness and increased fatigue in such situations. The results of a placebo-controlled experiment in healthy adults who had 3 nights of total sleep deprivation (with or without 2-hour naps every 12 hours) are presented to illustrate the physiological and neurobehavioral effects of sustained low-dose caffeine. Individual differences, including genetic factors, in the response to caffeine and to sleep loss are discussed. The review concludes with future directions for research on this important and evolving topic.

Chronic caffeine ingestion causes microglia activation, but not proliferation in the healthy brain.

Caffeine is the most popular psychoactive drug in the world which contributes to behavioral and metabolic changes when ingested. Within the central nervous system (CNS), caffeine has a high affinity for A1 and A2a adenosine receptors. Serving as an antagonist, caffeine affects the ability of adenosine to bind to these receptors. Caffeine has been shown to alter neuronal functioning through increasing spontaneous firing. However, the effects of caffeine on non-neuronal cells in the CNS have not been studied extensively. Microglia are one phenotype of non-neuronal glia within the CNS. Acting as phagocytes, they contribute to the immune defense system of the brain and express A1 and A2a adenosine receptors. Caffeine, therefore, may affect microglia. In order to test this hypothesis, CD-1 mice were randomly placed into one of three groups: control, low caffeine (0.3 g/L water) and high caffeine (1.0 g/L water) and were allowed to drink freely for 30 days. Following 30 days, brain sections were stained to reveal microglia. Morphological reconstructions and density measurements were examined in cortical and subcortical areas including the primary sensory cortex, primary motor cortex and striatum. Results indicate that microglial density throughout the brain is decreased in the caffeine groups as compared to the control. Caffeine also impacted microglia morphology shortening process length and decreasing branching. These results suggest that chronic caffeine ingestion has a systemic impact on microglia density and their activation.

Caffeine intake may modulate inflammation markers in trained rats.

Caffeine is presented in many commercial products and has been proven to induce ergogenic effects in exercise, mainly related to redox status homeostasis, inflammation and oxidative stress-related adaptation mechanisms. However, most studies have mainly focused on muscle adaptations, and the role of caffeine in different tissues during exercise training has not been fully described. The aim of this study was therefore, to analyze the effects of chronic caffeine intake and exercise training on liver mitochondria functioning and plasma inflammation markers. Rats were divided into control, control/caffeine, exercise, and exercise/caffeine groups. Exercise groups underwent four weeks of swimming training and caffeine groups were supplemented with 6 mg/kg/day. Liver mitochondrial swelling and complex I activity, and plasma myeloperoxidase (MPO) and acetylcholinesterase (AChE) activities were measured. An anti-inflammatory effect of exercise was evidenced by reduced plasma MPO activity. Additionally, caffeine intake alone and combined with exercise decreased the plasma AChE and MPO activities. The per se anti-inflammatory effect of caffeine intake should be highlighted considering its widespread use as an ergogenic aid. Therefore, caffeine seems to interfere on exercise-induced adaptations and could also be used in different exercise-related health treatments.

Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology

Tau pathology found in Alzheimer's disease (AD) is crucial in cognitive decline. Epidemiologic evidences support that habitual caffeine intake prevents memory decline during aging and reduces the risk to develop Alzheimer's disease. So far, experimental studies addressed the impact of caffeine in models mimicking the amyloid pathology of AD. However, in vivo effects of caffeine in a model of AD-like tauopathy remain unknown. Here, we evaluated effects of chronic caffeine intake (0.3 g/L through drinking water), given at an early pathologic stage, in the THY-Tau22 transgenic mouse model of progressive AD-like tau pathology. We found that chronic caffeine intake prevents from the development of spatial memory deficits in tau mice. Improved memory was associated with reduced hippocampal tau phosphorylation and proteolytic fragments. Moreover, caffeine treatment mitigated several proinflammatory and oxidative stress markers found upregulated in the hippocampus of THY-Tau22 animals. Together, our data support that moderate caffeine intake is beneficial in a model of AD-like tau pathology, paving the way for future clinical evaluation in AD patients.

Chapter Ten - Adenosine Receptors and Huntington's Disease

Adenosine regulates important pathophysiological functions via four distinct adenosine receptor subtypes (A1, A2A, A2B, and A3). The A1 and A2A adenosine receptors (A1R and A2AR) are major targets of caffeine and have been extensively investigated. Huntington's disease (HD) is a dominant neurodegenerative disease caused by an abnormal CAG expansion in the Huntingtin gene. Since the first genetic HD model was created almost two decades ago, tremendous progress regarding the function of the adenosine receptors in HD has been made. Chronic intake of caffeine was recently shown to be positively associated with the disease onset of HD. Moreover, genetic polymorphism of A2AR is believed to impact the age of onset. Given the importance of adenosine receptors as drug targets for human diseases, this review highlights the recent findings that delineate the roles of adenosine receptors in HD and discusses their potential for serving as drug targets and/or biomarkers for HD. Adenosine is a purine nucleoside that regulates important physiological functions via four different adenosine receptors (A1, A2A, A2B, and A3). These adenosine receptors have seven transmembrane domains and belong to the G protein-coupled receptor family. The functions of the A1 adenosine receptor (A1R) and A2A adenosine receptor (A2AR) have been investigated relative to HD. In this review, we summarize the recent findings regarding the role of adenosine receptors in HD and discuss the potential application of adenosine receptors as drug targets and biomarkers for HD.

Caffeine and Substance Use Disorders

Caffeine and Substance Use Disorders

Effect of the chronic administration of caffeine on adipose mass and lipid profile of Wistar rats

This work aimed at verifying the effect of the chronic ingestion of caffeine on body weight and adiposity of Wistar rats. Sixteen male Wistar rats weighting on average 240 g were divided into two groups, one control and the other caffeine-treated (5 mg kg -1 , orally) for five weeks. At the end, the groups were evaluated for their differences in body weight; weight of the periepididymal, retroperitoneal, subcutaneous and mesenteric fat pads; size of the retroperitoneal adipocytes; liver and heart weight; glycemia and plasma lipids. Statistically significant differences were observed in adipocyte size and total serum cholesterol, while the results for the other parameters were not statistically different. Therefore, this study showed that, using an oral dose of caffeine within acceptable (non toxic) limits, it is possible to reduce the size of adipocytes of non-obese Wistar rats, as well as to reduce the serum cholesterol levels, even in the absence of physical activity or other active compounds.

Safety profile of caffeine and 1,3-dimethylamylamine supplementation in healthy men

Caffeine and 1,3-dimethylamylamine (DMAA) are widely used alone and in combination with dietary supplements. No investigation has determined the safety profile of chronic intake of caffeine or DMAA, alone or in combination, within the same study design. A total of 50 young and healthy men completed 12weeks of daily supplementation with either a placebo (n=11), caffeine at 250mgday(-1) (n=14), DMAA at 50mgday(-1) (n=13), or caffeine at 250mgday(-1)+DMAA at 50mgday(-1) (n=12). Before and after 6 and 12weeks of supplementation, the following variables were measured: body mass/composition, resting respiratory rate, blood pressure, 12-lead electrocardiogram, urinalysis, complete blood count, metabolic panel, lipid panel, and oxidative stress, inflammatory, and cardiac biomarkers. No interaction effects were noted for any variable (p>0.05), with little change occurring across time for subjects in any of the four conditions. With the exception of urinary pH (p=0.05; Pre (6.5±0.1) higher than week 6 (6.1±0.1)) and blood CO2 (p=0.02; week 12 (25.9±0.3mmolL(-1)) higher than week 6 (24.8±0.3mmolL(-1))), no time effect was noted for any other variable (p>0.05). These data indicate that 12weeks of daily supplementation with caffeine and DMAA, alone or in combination, does not result in a statistically significant change in any of the measured outcome variables.

Effects of chronic caffeine intake in a mouse model of amyotrophic lateral sclerosis

Caffeine is a nonselective adenosine receptor antagonist; chronic consumption has proved protective toward neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present study was designed to determine whether caffeine intake affected survival and/or motor performance in a transgenic model of amyotrophic lateral sclerosis (ALS). SOD1(G93A) mice received caffeine through drinking water from 70 days of age until death. Body weight, motor performance and survival were evaluated. Furthermore, the expression of adenosine A(2A) receptors (A(2A) Rs), glial glutamate transporter (GLT1), and glial fibrillar acidic protein (GFAP) were evaluated by Western blotting. The results showed that caffeine intake significantly shortened the survival of SOD1(G93A) mice (log rank test, P = 0.01) and induced a nonsignificant advancing of disease onset. The expression of A(2A) R, GLT1, and GFAP was altered in the spinal cords of ALS mice, but caffeine did not influence their expression in either wild-type or SOD1(G93) mice. These data indicate that adenosine receptors may play an important role in ALS.

Chronic caffeine intake increases androgenic stimuli, epithelial cell proliferation and hyperplasia in rat ventral prostate.

Coffee intake has been associated with a low risk of developing cancer, including prostate cancer, which is one of the most commonly diagnosed cancer in men. However, few studies have evaluated the chronic effects of caffeine, which is the most abundant methylxanthine in coffee, on prostate morphology and physiology. In the present study, we investigated the effects of chronic, low-dose caffeine intake on rat prostate morphology from puberty to adulthood. Five-week-old male Wistar rats were randomized into two experimental groups: caffeine-treated (20ppm in drinking water, n=12) and control (n=12). The ventral and dorsolateral prostates were dissected, weighted and submitted to morphological, morphometrical and immunohistochemical analysis of cellular proliferation, apoptosis and androgen receptor (AR) tissue expression. The testosterone (T) and dihydrotestosterone (DHT) concentrations were measured in the plasma. Our results show that caffeine intake increased the concentrations of T and DHT, organ weight, epithelial cell proliferation and AR tissue expression in the ventral prostatic lobe. All the ventral prostates from the caffeine-treated animals presented various degrees of epithelial and stromal hyperplasia. Our results suggest that chronic caffeine intake from puberty increases androgenic signalling and cell proliferation in the rat prostate gland and can be related to the development of benign prostatic hyperplasia.

Chronic caffeine intake reverses age-induced insulin resistance in the rat: effect on skeletal muscle Glut4 transporters and AMPK activity

The role of caffeine consumption on insulin action is still under debate. The hypothesis that chronic caffeine intake reverses aging-induced insulin resistance in the rat was tested in this work. The mechanism by which caffeine restores insulin sensitivity was also investigated. Six groups of rats were used: 3 months old (3 M), 3 months old caffeine-treated (3MCaf), 12 months old (12 M), 12 months old caffeine-treated (12MCaf), 24 months old (24 M), and 24 months old caffeine-treated (24MCaf). Caffeine was administered in drinking water (1 g/l) during 15 days. Insulin sensitivity was assessed by means of the insulin tolerance test. Blood pressure, body weight, visceral and total fat, fasting glycemia and insulinemia, plasma nonesterified fatty acids (NEFA), total antioxidant capacity (TAC), cortisol, nitric oxide, and catecholamines were monitored. Skeletal muscle Glut4 and 5'-AMP activated protein kinase (AMPK) protein expression and activity were also assessed. Aged rats exhibited diminished insulin sensitivity accompanied by hyperinsulinemia and normoglycemia, increased visceral and total fat, decreased TAC and plasma catecholamines, and also decreased skeletal muscle Glut4 and AMPK protein expression. Chronic caffeine intake restored insulin sensitivity and regularized circulating insulin and NEFA in both aging models. Caffeine neither modified skeletal muscle AMPK expression nor activity in aged rats; however, it decreased visceral and total fat in 12 M rats and it restored skeletal muscle Glut4 expression to control values in 24 M rats. We concluded that chronic caffeine intake reverses aging-induced insulin resistance in rats by decreasing NEFA production and also by increasing Glut4 expression in skeletal muscle.

Chronic Caffeine Intake in Adult Rat Inhibits Carotid Body Sensitization Produced by Chronic Sustained Hypoxia but Maintains Intact Chemoreflex Output

Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing partial pressure of oxygen. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication because it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a nonselective adenosine receptor antagonist, alters CB function and ventilatory responses when administered acutely. Our aim was to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronically hypoxic (12% O₂, 15 days), and caffeine-treated chronically hypoxic rats. Caffeine was administered in drinking water (1 mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Caffeine-treated chronically hypoxic rats exhibited a decrease in the CSN response to acute hypoxia tests but maintained ventilation compared with chronically hypoxic animals. The findings related to CSN neural activity combined with the ventilatory responses indicate that caffeine alters central integration of the CB input to increase the gain of the chemoreflex and that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A(2B)) was down-regulated and that in petrosal ganglion (A(2A)) was up-regulated in caffeine-treated chronically hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells was increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups.