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PubMed1998

The effect of caffeine on ambulatory blood pressure in hypertensive patients.

Because the potential impact of habitual caffeine intake on blood pressure is a controversial issue, a study was carried out to explore the relationship between caffeine and various humoral factors that could account for a coffee-induced rise in blood pressure. Twenty-three hypertensive patients who refrained from caffeine for 2 to 3 weeks were given 250 mg oral caffeine powder dissolved in water. Blood pressure was recorded every 15 min by blood pressure monitor. Caffeine blood level, renin and endothelin were measured before and 1, 2, 3, and 6 h after caffeine intake. Urinary electrolytes and catecholamines were measured under caffeine influence (period I), and for the next 6 h (period II). A significant increase in systolic (P = .017) and diastolic blood pressure (P = .023) occurred in 13 subjects who were 58 +/- 10.4 years old. Nonresponders were younger (44.5 +/- 15.8 years). A statistically significant decrease in heart rate was seen during the first hour after caffeine intake in both responders (P = .008) and nonresponders (P = .004). Marked diuresis and natriuresis were observed during period I in both groups. Renin and endothelin levels were unchanged. Although chronic studies point to development of tolerance to long-term caffeine ingestion, acute studies like the one described are essential to obtain data on the immediate effects that can be of practical importance, especially in the elderly.

Adult↗
PubMed2004

Effect of caffeine on meiotic maturation of porcine oocytes.

This study was conducted to evaluate the effect of caffeine on the meiotic maturation of porcine oocytes. Oocyte-cumulus complexes were collected from slaughterhouse-derived ovaries and cultured for 24, 32 or 48 h in medium 199 supplemented with 10% fetal calf serum, 10 microg/ml FSH, 50 microg/ml sodium pyruvate and 50 microg/ml gentamicin in the presence or absence of 2.5 mM caffeine. Caffeine inhibited the meiotic resumption of pig oocytes effectively after 24 h of culture, and 95.5% of oocytes were arrested at the germinal vesicle (GV) stage (control 17.8%, p < 0.05). Prolonged culture with caffeine up to 32 h or 48 h, however, resulted in a significant decrease in the inhibitory effect (GV: 13.8% and 8.2%). The number of oocytes at metaphase II after 48 h of culture in the presence of caffeine was significantly lower than that in the control medium (65.3% vs 94.7%, p < 0.05). The withdrawal of caffeine after 24 h of culture resulted in the resumption of meiotic maturation, and the oocytes reached metaphase II after 48 h. However, the ability of caffeine-treated oocytes to develop to blastocysts after artificial activation was lower than that of the control (5.5% vs 9.1%, p < 0.05). Caffeine treatment significantly increased cAMP levels in the oocytes after 24 h of culture, while both Cdc2 kinase and MAP kinase activation were inhibited in the oocytes. These results suggest that caffeine, similarly to other purine derivatives, prolongs the meiotic arrest of porcine oocytes at the GV stage, perhaps by its action of increasing the cAMP level and by the suppression of Cdc2 kinase and MAP kinase activities in the oocytes.

Abattoirs↗
PubMed1986

Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors.

A variety of analogues of caffeine and theophylline in which the 1-,3-, and 7-methyl substituents have been replaced with n-propyl, allyl, propargyl, and isobutyl and, in a few cases, with chloroethyl, hydroxyethyl, or benzyl were assessed for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Caffeine and theophylline are nonselective for these receptors. Nearly all of the 22 analogues of caffeine are more potent than caffeine itself at adenosine receptors. Replacement of the 1-methyl moiety with n-propyl, allyl, or propargyl substituent has little effect on potency at the A1 receptor while enhancing potency about 7- to 10-fold at the A2 receptor. 3,7-Di-methyl-1-propylxanthine is only slightly (1.4-fold) more potent than caffeine at the A1 receptor while being 10-fold more potent at the A2 receptor. 1,3-Di-n-propyl-7-methylxanthine is also selective for the A2 receptor, being 8-fold more potent than caffeine at the A1 receptor and 40-fold more potent at the A2 receptor. A number of other caffeine analogues including 3,7-dimethyl-1-n-propylxanthine, 7-allyl-1,3-dimethylxanthine, and 1,3-dimethyl-7-propargylxanthine are also somewhat selective for the A2 receptor. The most potent caffeine analogue was 1,3-di-n-propyl-7-propargylxanthine, which was about 100-fold more potent than caffeine at both A1 and A2 receptors. The 10 theophylline analogues were relatively nonselective except for the 1-ethyl analogue and the 1,3-diallyl analogue, which were selective for the A2 receptor, and the 1,3-di-n-propyl, 1,3-diisobutyl, and 1,3-dibenzyl analogues, which were somewhat selective for the A1 receptor. 1,3-Di-n-propylxanthine was 20-fold more potent than theophylline at the A1 receptor and 5-fold more potent at the A2 receptor.

Animals↗
PubMed1982

The caffeine CO2 breath test: dose response and route of N-demethylation in smokers and nonsmokers.

The optimal conditions for performing the caffeine CO2 breath test (CBT) were investigated in smokers and nonsmokers. Caffeine labeled with 13C or 14C in all three (1, 3, and 7) methyl groups or specifically in the 1-, 3-, or 7-methyl groups were orally administered to healthy adults and the expiration of labeled CO2 was measured for 8 or 24 hr. The absolute rate of labeled CO2 excretion from trilabeled caffeine was proportional to the dose up to 3 mg/kg in all subjects. In smokers, the rate of labeled CO2 excretion averaged twice that in nonsmokers at all doses. A correlation was observed between the 2-hr cumulative CO2 excretion from trilabeled caffeine and the apparent oral metabolic clearance rate (MCR) of caffeine (R = 0.90). Monolabeled CBTs in smokers and nonsmokers demonstrated that 80% +/- 4% of labeled CO2 expired in the breath during the first 2 hr of a trilabeled CBT was derived from the 3 position; at 6 to 8 hr equal amounts were derived from the 3 and 7 positions. Little N-demethylation was observed from the 1 position at any time during the 8-hr test. The results indicate that the 2-hr cumulative excretion of labeled CO2 could be used to accurately predict the metabolic clearance rate of caffeine is the best CBT parameter for detecting the effect of smoking on caffeine N-demethylation. The data suggest that the primary routes of caffeine metabolism are 3-N-demethylation and ring hydroxylation and confirm that caffeine metabolites are N-demethylated primarily in the 3 and 7 positions.

Adult↗
PubMed1988

Cardiovascular effects of caffeine and nifedipine.

Because caffeine and nifedipine may have opposing effects on intracellular calcium concentration, a possible interaction between these agents on blood pressure and heart rate was examined. With a randomized, double-blind, crossover design, 10 normal, caffeine-abstaining subjects received caffeine, 300 mg, or placebo followed by nifedipine, 10 mg, or placebo. Caffeine increased blood pressure, whereas nifedipine reduced it and caused a reflex increase in heart rate. With caffeine pretreatment, nifedipine decreased blood pressure significantly more than with placebo pretreatment. However, nifedipine reduced blood pressure to the same absolute level on both the caffeine and placebo pretreatment days. The reflex increase in heart rate after nifedipine was not affected by prior caffeine or placebo administration. Caffeine pretreatment does not alter the cardiovascular responses to nifedipine but the pressor effect of caffeine is completely reversed by subsequent nifedipine administration.

Adult↗
PubMed1990

Dose-dependency of caffeine metabolism with repeated dosing.

Some recent epidemiologic studies have reported a nonlinear dose-response in the relationship between coffee consumption and health risks, such that the risks increase disproportionately to the increase in dose. Assuming caffeine contributes to the adverse health effects of coffee, a possible explanation for the nonlinear dose-response relationship is dose-dependent metabolism of caffeine. We examined the hypothesis that under chronic dosing conditions the metabolism of caffeine is dose-dependent. Nine healthy subjects were given, in randomized 5-day treatment blocks, placebo, 4.2 (low) and 12 (high) mg/kg/day caffeine in decaffeinated coffee, in six divided doses spaced throughout the day. On the third day of each dosing period, 25 mg of stable-isotope labeled caffeine (2-13C, 1,3-15N2) was given intravenously. Clearance of labeled caffeine fell from 0.118 (placebo treatment) to 0.069 (low dose; p less than 0.005) and to 0.54 (high dose; p less than 0.001) L/hr/kg. The formation and metabolite clearances of paraxanthine, the major primary metabolite of caffeine, also decreased comparing the low and high doses (p less than 0.05). We conclude that caffeine metabolism is dose-dependent, resulting in nonlinear accumulation of methylxanthines in the body. Dose-dependent metabolism of caffeine may explain in part why people who drink large amounts of coffee are at greater risk for cardiovascular disease.

Adult↗
PubMed1990

Dose-dependent pharmacokinetics of caffeine in humans: relevance as a test of quantitative liver function.

Caffeine clearance was determined in 13 healthy control subjects and in 13 patients with histologically proven cirrhosis. On separate occasions, 70 mg, 200 mg, and 300 mg single doses of anhydrous caffeine were administered orally with decaffeinated coffee to each subject. Subjects were analyzed individually, acting as their own controls, thus reducing interindividual variability. The present study showed that caffeine exhibited dose-dependent pharmacokinetics, particularly in subjects who showed high initial clearance with the low dose (70 mg) of caffeine. There was a significant decrease in caffeine clearance with increasing dose from 70 mg to 300 mg (n = 26, p less than 0.01, Dunnett's test), indicating saturable caffeine metabolism in the dose range tested. These findings imply that if caffeine is to be used as a guide to deteriorating liver function, serial caffeine clearance estimations should be performed in each individual subject, with use of the same dose of caffeine each time.

Administration, Oral↗
PubMed1990

Phenylpropanolamine increases plasma caffeine levels.

The effects of the widely consumed drugs caffeine and phenylpropanolamine are mediated through activation of the central and sympathetic nervous systems. Severe, life-threatening, and occasionally fatal hypertensive reactions have been reported after their combined use. This study examined the possible pharmacokinetic interaction of phenylpropanolamine and caffeine. Sixteen normal subjects received combinations of caffeine, phenylpropanolamine, and placebo. In subjects receiving 400 mg caffeine plus 75 mg phenylpropanolamine, the mean (+/- SEM) peak plasma caffeine concentration of 8.0 +/- 2.2 micrograms/ml was significantly greater than after 400 mg caffeine alone (2.1 +/- 0.3 micrograms/ml; t[24] = 2.4; p less than 0.01). Physical side effects were more frequent after the phenylpropanolamine-caffeine combination than after either drug alone or after placebo. Greater increases in both systolic and diastolic blood pressures occurred after the combination than after either drug alone. Because caffeine levels can be increased greatly when certain other drugs are coconsumed, these data indicate that phenylpropanolamine may enhance absorption or inhibit elimination of caffeine and may explain increased side effects reported after their combined use.

Adult↗
PubMed1994

Caffeine as an analgesic adjuvant in tension headache.

Six randomized, double-blind, two-period crossover studies, conducted under similar protocols, compared the efficacy of two analgesic combinations containing caffeine with an acetaminophen 1000 mg control and with a placebo in outpatients with episodic tension-type headaches. In four studies, comprising 1900 patients, the caffeine-containing analgesic consisted of a combination of 500 mg acetaminophen, 500 mg aspirin, and 130 mg caffeine (APAP/ASA/CAF). In two studies, comprising 911 patients, the caffeine-containing analgesic consisted of a combination of 1000 mg acetaminophen and 130 mg caffeine (APAP/CAF). Patients self-medicated for moderate or severe headache pain, and with a self-rating record they rated their pain and its relief hourly for 4 hours. In all six studies, the caffeine-containing analgesics were significantly superior both to placebo and to 1000 mg acetaminophen, and acetaminophen was significantly superior to placebo. The significant analgesic adjuvant effect of caffeine was independent of patients' usual caffeine use or their caffeine consumption in the 4 hours before medication. For each treatment, the pooled analgesic responses for the four studies of APAP/ASA/CAF were virtually superimposable on the responses in the two APAP/CAF studies. The combinations produced more stomach discomfort, nervousness, and dizziness than acetaminophen or placebo.

Acetaminophen↗
PubMed1991

Bovine adrenal chromaffin cells contain an inositol 1,4,5-trisphosphate-insensitive but caffeine-sensitive Ca2+ store that can be regulated by intraluminal free Ca2+.

We have characterized some properties of the caffeine-sensitive Ca2+ store in bovine chromaffin cells. Addition of 10 mM-caffeine to permeabilized cells that were allowed to sequester Ca2+ in the presence of the precipitating anion pyrophosphate induced a transient rise in free Ca2+ concentration that was blocked by 10 microM-Ruthenium Red. Caffeine was able to release Ca2+ after the InsP3-sensitive Ca2+ pool had been completely emptied, and 10 microM-InsP3 still released Ca2+ in the presence of a high dose (50 mM) of caffeine, indicating that there are selectively sensitive Ca2+ pools in these cells. The progressive hydrolysis of pyrophosphate by a cytosolic pyrophosphatase induced a spontaneous Ca2+ release after a latency. Caffeine prevented this spontaneous Ca2+ release, indicating that the pyrophosphate-sensitive Ca2+ pool was caffeine-sensitive. On varying the free Ca2+ concentration within the caffeine-sensitive pool (by using methylenediphosphonic acid, pyrophosphate or no precipitating anion), we observed that the Ca(2+)-releasing effect of caffeine was dependent on an elevated intraluminal free Ca2+ concentration. In conclusion, the caffeine-sensitive Ca2+ store in bovine chromaffin cells is largely distinct from the InsP3-sensitive Ca2+ store, and its release mechanism shares characteristics with the ryanodine receptor of muscle cells.

Adrenal Medulla↗
PubMed1991

The role of caffeine-sensitive Ca2+ stores in agonist- and inositol 1,4,5-trisphosphate-induced Ca2+ release from bovine adrenal chromaffin cells.

In single bovine adrenal chromaffin cells loaded with fura-2, histamine, angiotensin II (AII) and caffeine elicited large transient increases of intracellular free Ca2+ concentration [( Ca2+]i) in the absence of external Ca2+, with peak amplitudes averaging 726 +/- 138 (n = 14), 710 +/- 102 (n = 21) and 830 +/- 100 nM (n = 30) respectively. A substantial portion of the agonist-induced rise in [Ca2+]i depended on Ca2+ release from caffeine-sensitive stores, as pretreatment with caffeine diminished subsequent agonist responses by 90-95%. Conversely, pretreatment with histamine or AII decreased subsequent caffeine responses by 100% and 90% respectively. The effects of caffeine most likely resulted from activation of a Ca(2+)-induced Ca(2+)-release (CICR) process, whereas histamine and AII initially acted through generation of Ins(1,4,5)P3. The relationship of Ins(1,4,5)P3- and caffeine-sensitive Ca2+ pools was studied by using alpha-toxin-permeabilized chromaffin cells. Evidence was found for three non-mitochondrial, ATP-dependent, Ca2+ pools: one exclusively sensitive to Ins(1,4,5)P3 (pool 1), a second sensitive to both Ins(1,4,5)P3 and caffeine (pool 2), and a third exclusively sensitive to caffeine (pool 3). The existence of pools 1 and 3, and the ability of agonists such as histamine to discharge pool 3 completely, supports a two-pool model in which a caffeine-sensitive CICR mechanism plays a major role in the generation of agonist-induced Ca2+ spikes in bovine chromaffin cells.

Adrenal Glands↗
PubMed1994

Heterogeneity of caffeine- and bradykinin-sensitive Ca2+ stores in vascular endothelial cells.

The filling state of Ca2+ stores in endothelial cells regulates Ca2+ entry. The functional relationship between the major Ca2+ stores [i.e. Ins(1,4,5)P3-sensitive (= bradykinin-sensitive stores, 'BsS') and caffeine-sensitive stores] is unknown. In pig right-coronary-artery endothelial cells, caffeine failed to release Ca2+ in 68% of the cells (quiet-responders), but increased bradykinin (Bk)-induced Ca2+ release 2.5-fold. In Bk-pre-stimulated cells, caffeine increased Ca2+ release upon a second stimulation with Bk 3.2-fold. In quiet-responders caffeine alone did not affect net Ca2+ storage, whereas Bk or caffeine followed by Bk decreased the intracellular Ca2+ pool to 45% and 15%, respectively. Blockade of the endoplasmic-reticulum Ca2+ pump by thapsigargin unmasked the effect of caffeine in quiet-responders, resulting in a transient increase in intracellular free Ca2+ concentration ([Ca2+]i). In 37% of the cells caffeine alone transiently increased [Ca2+]i and depleted BsS. This study suggests a heterogeneity in functional organization of endothelial Ca2+ stores. In quiet-responders, caffeine translocates Ca2+ towards the BsS, whereas in overt-responders caffeine empties the BsS.

Animals↗
PubMed2002

Central and peripheral effects of sustained caffeine use: tolerance is incomplete.

AIMS: It is widely held that tolerance develops to the effects of sustained caffeine consumption. This study was designed to investigate the effects of chronic, staggered caffeine ingestion on the responses of an acute caffeine challenge, during -euglycaemia. METHODS: Twelve healthy volunteers were randomized using a double-blind, cross-over design to take either 200 mg caffeine (C-replete) or placebo (C-naïve) twice daily for 1 week. Following baseline measurements being made, the responses to 200 mg caffeine (blood-pressure, middle cerebral artery velocity, mood and cognitive performance) were examined over the subsequent 120 min. Blood glucose was not allowed to fall below 4.0 mmol l-1. RESULTS: After the caffeine challenge, middle cerebral artery blood velocity decreased in both conditions but was greater in the C-naïve condition (-8.0 [-10.0, -6.1] cm s-1 vs -4.9 [-6.8, -2.9] cm s-1 C-replete, P < 0.02). Systolic blood pressure rise was not significantly different in C-naïve, although this rise was more sustained over time (P < 0.04). Mood was adversely affected by regular caffeine consumption with tense aspect of mood significantly higher at baseline in C-replete 11.6 +/- 0.6 C-naïve vs 16.3 +/- 1.6 C-replete, P < 0.01). Cognitive performance was not affected by previous caffeine exposure. CONCLUSIONS: Overall these results suggest that tolerance is incomplete with respect to both peripheral or central effects of caffeine.

Adult↗
PubMed1997

Combination of bright light and caffeine as a countermeasure for impaired alertness and performance during extended sleep deprivation.

Effects of four conditions (Dim Light-Placebo, Dim Light-Caffeine, Bright Light-Placebo and Bright Light-Caffeine) on alertness, and performance were studied during the night-time hours across 45.5 h of sleep deprivation. Caffeine (200 mg) was administered at 20.00 and 02.00 hours and bright-light exposure (> 2000 lux) was from 20.00 to 08.00 hours each night. The three treatment conditions, compared to the Dim Light-Placebo condition, enhanced night-time performance. Further, the combined treatment of caffeine and all-night bright light (Bright Light-Caffeine) enhanced performance to a larger degree than either the Dim Light-Caffeine or the Bright Light-Placebo condition. Beneficial effects of the treatments on performance were largest during the early morning hours (e.g. after 02.00 hours) when performance in the Dim Light-Placebo group was at its worst. Notably, the Bright Light-Caffeine condition was able to overcome the circadian drop in performance for most tasks measured. Both caffeine conditions improved objective alertness on the Maintenance of Wakefulness Test. Taken together, the above results suggest that the combined treatment of bright light and caffeine provides an effective intervention for enhancing alertness and performance during sleep loss.

Adolescent↗
PubMed2003

The effect of caffeine consumption and nausea on the risk of miscarriage.

Evidence for a harmful effect of caffeine intake on risk of miscarriage (spontaneous abortion) is inconsistent and nausea during pregnancy has been claimed to explain any association seen. The objective of this analysis was to determine whether caffeine consumption both before and during pregnancy influenced the risk of miscarriage in a group of pregnant women in the UK. We examined the association with maternal caffeine intake in a case-control study of 474 nulliparous women. Participants were recruited during the years 1987-89 from the Royal Berkshire Hospital in Reading and from a large group practice situated within the hospital's catchment area. Cases were 160 women with a clinically diagnosed miscarriage and controls were 314 pregnant women attending for antenatal care. Information on coffee/tea/cola consumption and potential confounders was collected by interview and caffeine content was assigned to individual drinks according to published data on caffeine content of beverages. Compared with a maternal caffeine intake of < 151 mg/day, we found evidence that caffeine consumption > 300 mg/day doubled the risk of miscarriage. Adjusted odds ratios were 1.94 [95% CI 1.04, 3.63] for 301-500 mg/day and 2.18 [95% CI 1.08, 4.40] for > 500 mg/day. This effect could not be explained by nausea in pregnancy. Nausea appeared to be strongly independently associated with a reduced risk of miscarriage (test for trend P < 0.0001). There was no evidence that prepregnancy caffeine consumption affected the risk. Our results indicate that high caffeine consumption during pregnancy (>300 mg/day), in particular coffee consumption, is an independent risk factor for increased risk and nausea is an independent protective factor for a lower risk of miscarriage.

Abortion, Spontaneous↗
PubMed2003

Caffeine-induced headache in children and adolescents.

Caffeine is the most widely used behaviourally active substance. Excessive caffeine consumption, mostly in the form of coffee and tea, is a well-recognized cause of headache or migraine, and withdrawal can cause headache. Nevertheless, caffeine abuse headache is not listed as a separate category in the International Headache Society classification, 1988. We report our experience with children and adolescents with daily or near-daily headache and excessive consumption of caffeine in the form of cola drinks. Over a period of 5 years we have encountered, in a tertiary headache clinic in a general hospital, 36 children and adolescents (17 girls and 19 boys) with daily or near-daily headache related to excessive caffeine intake in the form of cola drinks. The mean age of the subjects was 9.2 years (range 6-18) and mean headache duration was 1.8 years (range 0.6-5). All were heavy cola drinks consumers; at least 1.5 L of cola drinks per day (192.88 mg of caffeine daily), and an average of 11 (range 10.5-21) L of cola drinks a week, which amounts to 1414.5 mg of caffeine (range 1350.1-2700.3). Patients were encouraged to achieve gradual withdrawal from cola drinks, which led to complete cessation of all headaches in 33 subjects, whereas one boy and two adolescent girls continued to suffer from migraine without aura not frequent enough to justify prophylactic medication. Children and adolescents with high daily caffeine consumption in the form of cola drinks may suffer from caffeine-induced daily headache. Gradual withdrawal can be achieved without withdrawal headache and with complete disappearance of the induced chronic daily headache.

Adolescent↗
PubMed2004

Effect of the nitrogen source on caffeine degradation by Aspergillus tamarii.

AIMS: To evaluate caffeine degradation and nitrogen requirements during Aspergillus tamarii growth in submerged culture. METHODS AND RESULTS: Aspergillus tamarii spores produced on a coffee infusion agar medium added with sucrose were used. Several caffeine and ammonium sulphate concentrations (0-1 and 0-1.36 g l-1, respectively) were tested simultaneously on fungal biomass production and caffeine degradation. An additional caffeine pulse (4 g l-1) was added for all experiments after 48 h of fermentation. Results revealed that when using 0.90 g l-1 of caffeine and 0.14 g l-1 of ammonium sulphate, biomass production and caffeine degradation were enhanced. Highest biomass production (Xmax = 9.87 g l-1) with a specific growth rate (micro) of 0.073 h-1 and caffeine degradation rate of 0.033 g l-1 h-1, was observed under these conditions. CONCLUSIONS: Caffeine degradation as well as biomass production were characterized. SIGNIFICANCE AND IMPACT OF THE STUDY: These studies set the stage for future characterization studies of intracellular enzymes involved in caffeine degradation. Moreover, results observed may help in the biotreatment of residues from the coffee agroindustry.

Ammonium Sulfate↗
PubMed2002

Long-term caffeine consumption exacerbates renal failure in obese, diabetic, ZSF1 (fa-fa(cp)) rats.

BACKGROUND: Our preliminary studies indicate that chronic caffeine consumption has adverse renal effects in nephropathy associated with high blood pressure and insulin resistance. The purpose of this study was to investigate the effects of early (beginning at 8 weeks of age) and long-term (30 weeks) caffeine treatment (0.1% solution) on renal function and structure in obese, diabetic ZSF1 rats. METHODS: Metabolic and renal function measurements were performed at six-week intervals and in a subset of animals (N = 6 per group) heart rate (HR) and mean arterial blood pressure (MABP) were monitored by a radiotelemetric technique. At the end of the study acute, measurements of renal hemodynamics and excretory function were conducted in anesthetized animals. RESULTS: Caffeine produced a very mild increase (4 to 5%) of MABP and HR, but greatly augmented proteinuria (P < 0.001), reduced creatinine clearance (P < 0.05) and had a mixed effect on metabolic status in obese ZSF1 rats. Caffeine significantly reduced body weight, glycosuria, fasting glucose and insulin levels and improved glucose tolerance, had no effect on elevated plasma triglycerides levels and significantly increased plasma cholesterol level (P < 0.001). Acute measurements of renal function revealed increased renal vascular resistance (95.1 +/- 11 vs. 50.7 +/- 2.4 mm Hg/mL/min/g kidney, P < 0.01) and decreased inulin clearance (0.37 +/- 0.11 vs. 0.97 +/- 0.13 mL/min/g kidney, P < 0.002) in caffeine-treated versus control animals, respectively. Caffeine potentiated the development of more severe tubulointerstitial changes (P < 0.05) and increased focal glomerulosclerosis (14.7 +/- 1.7 vs. 6.5 +/- 0.9%, caffeine vs. control, P < 0.002). CONCLUSION: The present study provides the first evidence that caffeine (despite improving insulin sensitivity) exacerbates renal failure in obese, diabetic ZSF1 rats. Further mechanistic studies of adverse renal effects of caffeine in chronic renal failure associated with metabolic syndrome are warranted.

Animals↗