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PubMed1983

Effect of caffeine on intramembrane charge movement and calcium transients in cut skeletal muscle fibres of the frog.

1. The authors have studied the effect of caffeine in subthreshold concentration (0.5 mmol l(-1) at 2-4 degrees C) on the contraction threshold, on intramembrane charge movement and calcium transients in voltage-clamped frog skeletal muscle fibres.2. The single-gap technique (Kovács & Schneider, 1978) was used for the voltage clamping of terminated segments of cut fibres. Ionic conductances were minimized by using caesium glutamate at the open end pool and tetraethylammonium sulphate and tetrodotoxin at the closed end pool.3. Myoplasmic calcium transients evoked by depolarizing pulses were recorded by measuring the changes in absorbance of the fibres at 720 nm after the intracellular application of Antipyrylazo III dye.4. The strength-duration curve for contraction threshold was shifted towards more negative membrane potentials in the presence of caffeine. Shift was more definite at shorter pulse durations than at the rheobase.5. The total amount of charge moving during the depolarizing pulses at different membrane potentials was not changed by caffeine treatment, whereas the threshold amounts of charge moved during the critical periods of the contraction threshold decreased at different voltages (by about 23%).6. In the presence of caffeine, calcium transients accompanying long (100 ms) depolarizing pulses showed increased voltage-dependent peak amplitudes, rising phases and rate coefficients referring to calcium release, but a decreased voltage-dependent re-uptake rate either during or after the pulse.7. Calcium transients evoked by depolarizing pulses along the strength-duration curve for contraction threshold gave the same peak amplitudes (ranging from 0.9 to 2.8 mumol l(-1) free myoplasmic calcium on different fibres), but membrane-potential-dependent latency times and rising phases. The rate coefficients for declining phase did not depend on the preceding pulse voltage.8. On applying caffeine, the calcium transients related to the contraction threshold also had equal but smaller peak amplitudes, shorter latency times and the same magnitude of voltage-independent rate coefficients for the declining phase as in the control solution.9. The twitch potentiating effect of caffeine can be explained by its facilitating calcium release from the sarcoplasmic reticulum, while the re-uptake rate is not modified. The apparent inhibition of re-uptake can be related to the enhanced release of calcium due to caffeine effect. Due to the sensitizing effect of caffeine on the sarcoplasmic reticulum membrane, smaller amounts of charge are needed to reach the contraction threshold than without caffeine.

Animals↗
PubMed1989

Caffeine affects four different ionic currents in the bull-frog sympathetic neurone.

1. Ionic mechanisms related to the caffeine-induced current (Icaffeine) were examined in the single isolated sympathetic neurones of the bull-frog. We used the 'concentration-jump' technique in combination with intracellular perfusion and a rapid external solution change, under single-electrode voltage-clamp conditions. 2. Icaffeine was pharmacologically separated into a tetraethylammonium (TEA)-sensitive transient outward current (ITO), a picrotoxin (PTX)-sensitive transient inward current (ITI) and a TEA- and PTX-insensitive sustained inward current (ISI). At low concentrations of caffeine, a sustained outward current (ISO) was observed instead of ISI. 3. All components of Icaffeine were abolished by intracellular perfusion of 30 mM-EGTA. Pre-treatment with A23187 or ryanodine or the simultaneous application of procaine either reduced or abolished all the components of Icaffeine in a dose-dependent manner. The concentration causing 50% inhibition (IC50) was 10(-8) M for A23187 and 2 mM for procaine. 4. The peak response of ITO increased abruptly at caffeine concentrations between 3 and 6 mM followed by saturation above 30 mM. A notch was observed on the rising phase of ITO. 5. The reversal potential (Ecaffeine) of ITO shifted 58 mV for a tenfold change of the extracellular K+ concentration. External application of TEA blocked ITO with an IC50 of 1 mM. ITO was relatively insensitive to apamin, 4-aminopyridine and muscarine. 6. In external solution containing 2 mM-Ca2+, ITO induced by 10 mM-caffeine recovered completely within 3 min from a previous exposure to caffeine. In the absence of extracellular Ca2+, there was little such recovery. A 5 min treatment in a Ca2+-free solution reduced ITO induced by the first application of caffeine by 5%. With a continuous application of 3 mM-caffeine, the amplitude of ITO induced by 10 mM-caffeine reduced in 1 min, and showed a partial recovery in 3 min. The amplitude of ITO increased by increasing the concentration of intracellular Cl-. 7. ITI was activated around the peak of ITO and was rapidly inactivated. ITI was evoked at caffeine concentrations of about 6-10 mM. When the intracellular Cl- concentration was changed, the amplitude of ITI behaved like a Cl- electrode. The Ecaffeine of ITI was close to the Cl- equilibrium potential (ECl). 8. ISI was a 'plateau' response and persisted for over 3 min. ISI was due to a decrease in K+ conductance. In the presence of muscarine (3 x 10(-5) M), ISI was occluded.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Release of intracellular calcium and modulation of membrane currents by caffeine in bull-frog sympathetic neurones.

1. Calcium release and sequestration were studied in whole-cell voltage-clamped bull-frog sympathetic neurones by image analysis of Fura-2 signals. 2. Application of caffeine (10 mM) to cells voltage clamped at -38 mV caused a rapid increase in intracellular calcium concentration ([Ca2+]i) to a mean value of 352 +/- 33 nM, which activated an outward current. In the continued presence of caffeine the rise in [Ca2+]i slowly declined to a sustained plateau of 196 +/- 20 nM (112 nM above control levels), while the outward current rapidly decayed. Peak calcium release was highest at the edge of the cell. 3. The caffeine-evoked intracellular calcium increase was reduced by two inhibitors of calcium-induced calcium release, ryanodine and procaine. The residual non-suppressible increase in [Ca2+]i may indicate that caffeine can release calcium from two pharmacologically distinct intracellular stores. 4. Inhibition of the caffeine-evoked release of calcium by ryanodine was both concentration and 'use dependent' so that the full inhibitory effect was only observed when caffeine was applied for the second time in the presence of ryanodine. In contrast, the action of procaine did not show any 'use dependence' and unlike ryanodine was fully reversible. 5. The outward current was sensitive to blockers of the large conductance calcium-activated potassium current, Ic. Analysis of variance from this current indicated that it arose at least partly from summation of spontaneous miniature outward currents. 6. The magnitude and duration of calcium release by caffeine was dependent on the resting level of intracellular calcium and the caffeine exposure time. This, together with the pharmacology of the release, suggests that caffeine increases intracellular calcium by sensitizing calcium-induced calcium release. 7. The evoked [Ca2+]i increase was enhanced in amplitude by intracellular application of Ruthenium Red. This effect was mimicked by extracellular application of the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP) but not by internal application of FCCP or other inhibitors of mitochondrial Ca2+ uptake. This suggests that the evoked increase in [Ca2+]i is predominantly buffered by a Ruthenium Red-sensitive sequestration process which is not mitochondrial.

Animals↗
PubMed2005

Direct block of human ether-a-go-go-related gene potassium channels by caffeine.

The human ether-a-go-go-related gene (hERG) potassium channel is expressed in a variety of cell types, including neurons, tumor cells, and cardiac myocytes. In the heart, it is important for repolarization of the cardiac action potential. Attenuation of hERG current can cause long QT syndrome and cardiac arrhythmias such as torsades de pointes. Caffeine is frequently used as a pharmacological tool to study calcium-dependent transduction pathways in cellular preparations. It raises cytosolic calcium by opening ryanodine receptors and may also inhibit phosphodiesterases to increase cytosolic cAMP. In this study, we show 5 mM caffeine rapidly and reversibly attenuates hERG currents expressed in human embryonic kidney 293 cells to 61.1 +/- 2.2% of control. Caffeine-dependent inhibition of hERG current is not altered by raising cAMP with forskolin, buffering cytosolic calcium with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, or inhibition of protein kinase C. Thus, the effects of caffeine are unlikely to be mediated by cAMP or intracellular calcium-dependent mechanisms. Further experiments showed caffeine directly blocks hERG in an open state-dependent manner. Furthermore, caffeine inhibition is greatly reduced by the pore mutants Y562A and F656A hERG, which disrupt block of most previously tested hERG antagonists. Thus, caffeine attenuates hERG currents by binding to a drug receptor located within the inner cavity of the channel. Dietary intake of caffeine is unlikely to cause long QT syndrome because plasma concentrations do not reach sufficiently high levels to significantly inhibit hERG currents. However, the effects of caffeine have implications for its use in examining calcium-dependent pathways in cellular preparations expressing hERG.

Animals↗
PubMed2005

Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells.

Caffeine is an efficient inhibitor of DNA repair and DNA damage-activated checkpoints. We have shown recently that caffeine inhibits retroviral transduction of dividing cells, most likely by blocking postintegration repair. This effect may be mediated at least in part by a cellular target of caffeine, the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. In this study, we present evidence that caffeine also inhibits efficient transduction of nondividing cells. We observed reduced transduction in caffeine-treated growth-arrested cells as well as caffeine-treated terminally differentiated human neurons and macrophages. Furthermore, this deficiency was observed with a human immunodeficiency virus type 1 (HIV-1) vector lacking Vpr, indicating that the effect is independent of the presence of this viral protein in the infecting virion. Finally, we show that HIV-1 transduction of nocodazole-arrested cells is reduced in cells that express an ATR dominant-negative protein (kinase-dead ATR [ATRkd]) and that the residual transduction of ATRkd-expressing cells is relatively resistant to caffeine. Taken together, these data suggest that the effect(s) of caffeine on HIV-1 transduction is mediated at least partly by the inhibition of the ATR pathway but is not dependent on the caffeine-mediated inhibition of cell cycle checkpoints.

Caffeine↗
PubMed1997

A caffeine-sensitive Ca2+ store modulates K+-evoked secretion in chromaffin cells.

Catecholamine release from bovine adrenal medulla chromaffin cells superfused with a Krebs-N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid solution was monitored on-line with an electrochemical detector. Caffeine (10 mM) progressively depressed the magnitude of secretory responses to depolarizing pulses of 70 mM K+ and 2 mM Ca2+ (70 K+/2 Ca2+) in cells superfused with a Krebs-N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid solution containing 0 mM Ca2+ + 0.5 mM EGTA; blockade reached 80% at the third 70 K+/2 Ca2+ challenge given in the presence of caffeine. A similar effect was obtained when, instead of continuous superfusion, prepulses of caffeine were applied (10 mM for 60 s). The blocking effects of caffeine on K+-induced secretion depended on the time of exposure to the drug: the longer the exposure time the greater the blockade. The recovery of the K+ secretory responses previously impaired by caffeine was always gradual and followed a staircase mode. This contrasts with the effects of caffeine on various parameters measuring Ca2+ entry through Ca2+ channels, which did not parallel its effects on K+-evoked secretion. The secretion data, however, are compatible with the disappearance and recovery of an intracellular Ca2+ concentration signal triggered by K+ in single chromaffin cells loaded with fura 2 and treated with 10 mM caffeine. Thus, contrary to previous views, the depression of secretion by caffeine does not seem to be associated with inhibition of extracellular Ca2+ entry through Ca2+ channels. These functional data are, rather, compatible with the view that the degree of filling of a caffeine-sensitive intracellular Ca2+ store might regulate the extent of exocytosis. When emptied, such a store might act as a sink for the external Ca2+ entering through Ca2+ channels during cell depolarization, thus decreasing the intracellular Ca2+ concentration available for exocytosis.

Animals↗
PubMed1983

Abolition of digitalis tachyarrhythmias by caffeine.

Digitalis-induced ventricular tachyarrhythmias (VTAs) are believed to be due to oscillatory afterpotentials (OAPs) generated by an oscillatory release of calcium from the sarcoplasmic reticulum (SR). Caffeine blocks the calcium uptake into the SR and then may influence VTAs by depleting the SR stores of calcium. We studied the action of digitalis and caffeine, singly and in combination, in the isolated guinea pig heart perfused by means of a modified Langendorff apparatus. Digitalis (beta-methyldigoxin 1.27 X 10(-6) M) caused VTAs and ventricular fibrillation (VF) in all the hearts. Caffeine alone decreased heart rate but never caused VTAs. With the administration of digitalis and caffeine (1 mM), VTAs rarely developed and VF never occurs. With digitalis and higher concentration of caffeine (10 mM), neither VTAs nor VF were observed. In hearts with complete atrioventricular block, digitalis increased the ventricular rate from 143 +/- 10 to 270 +/- 13 beats/min (n = 8) in 12 +/- 1.9 min and provoked the appearance of multiple ventricular pacemakers. The addition of 10 mM caffeine to the digitalis-containing solution reduced the ventricular rate to 171 +/- 12 beats/min (P less than 0.001 vs. digitalis alone, not significant vs. control, n = 8) and abolished the digitalis-induced multiple pacemakers. Ventricular asystole was occasionally observed during the perfusion with digitalis + 10 mM caffeine. Caffeine alone did not modify the diastolic pressure, whereas caffeine and digitalis rapidly increase it. These results represent indirect evidence to support that SR plays an important role in the origin of the digitalis-induced VTAs.

Animals↗
PubMed1995

Endothelium-dependent and -independent vasodilation of isolated rat aorta induced by caffeine.

Caffeine (10(-4)-10(-3) M) induced concentration-dependent relaxations of phenylephrine-precontracted rat aortic rings with endothelium. Endothelial denudation significantly, but only partially, attenuated caffeine-induced relaxation. Pretreatment with NG-nitro-L-arginine, oxyhemoglobin, and methylene blue attenuated the relaxations to an extent similar to endothelial denudation. Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) contents of aortic strips with endothelium increased significantly after exposure to caffeine (10(-3) M). Endothelial denudation attenuated caffeine-induced cGMP increase. Pretreatment with ryanodine (2 x 10(-5) M), which has been shown to combine with receptors on endoplasmic reticulum (ER) of endothelium, attenuated caffeine-induced relaxation and cGMP content increase of rings with endothelium. Pretreatment with caffeine potentiated sodium nitroprusside-induced relaxations and cGMP increase of rings without endothelium. These results demonstrated that caffeine-induced relaxation comprises two components. In the endothelium-dependent mechanism, caffeine promotes nitric oxide synthesis in endothelium by release of Ca2+ from ER through a ryanodine-sensitive Ca2+ channel, and the suppression of cGMP degradation also contributes to the relaxation. In the endothelium-independent mechanism, caffeine acts as a 3',5'-cyclic-nucleotide phosphodiesterase inhibitor.

Animals↗
PubMed1986

Abolition of ventilatory response to caffeine in chemodenervated lambs.

In this study we have evaluated the role of the peripheral chemoreceptors in the ventilatory response to caffeine at a dose currently used in human infants for treatment of central apneas (10 mg/kg). Twelve lambs were studied; six had carotid body denervation (CBD) and six had a sham denervation (intact). The denervation was done the 2nd wk of life, and the study of the response to caffeine infusion was carried out at a mean age of 82 days. The awake and nonsedated animals received 10 mg/kg of caffeine, and caffeine blood levels were, respectively, 8.8 and 9.0 mg/l in the intact and in the CBD lambs. The intact lambs responded to caffeine by a significant immediate increase in minute ventilation (VE) of 46% from 274 to 400 ml X min-1 X kg-1 (P less than 0.001), 1 min after caffeine infusion. This response rapidly faded, but VE was still increased at 2 h, 314 ml X min-1 X kg-1. The increase in ventilation was brought about by a change in mean inspiratory flow (VT/TI), which increased from 9.9 to 14.0 ml X s-1 X kg-1 within 1 min (P less than 0.01); VT/TI was still increased at 11.2 ml X s-1 X kg-1 2 h later. In contrast, for the CBD lambs there was no response to caffeine infusion as measured by VE or VT/TI. We conclude that bolus caffeine infusion produces a rapid response in VE followed by a fall in VE that remained above base line until at least 2 h postinfusion, and the intact chemoreceptor function appears as an essential mediator for these increases in ventilation, since the peripheral chemodenervation has completely abolished the VE response to this particular dose of caffeine.

Animals↗
PubMed1994

Effects of acute caffeine withdrawal on habituated male runners.

This study investigated the effects of caffeine withdrawal on six trained caffeine-habituated male runners: age 29.8 +/- 5.8 (SD) yr, height 180.4 +/- 5.4 cm, weight 77.3 +/- 6.7 kg, maximal O2 uptake 63.0 +/- 5.4 ml.kg-1.min-1, and daily caffeine intake 674 +/- 128 mg. The subjects received a loading dose (5 mg/kg body wt) of caffeine 48 h before each testing session. They were then given (using a repeated-measures double-blind design) additional doses of caffeine (5 mg/kg body wt) or a placebo 36, 24, 12, and 2 h before testing. They ran at a velocity corresponding to their lactate threshold for 60 min in a caffeine withdrawal or caffeinated condition. Caffeine withdrawal resulted in no significant differences in absolute O2 uptake, O2 uptake relative to maximal O2 uptake, respiratory exchange ratios, or free fatty acid concentrations. Glycerol concentrations were significantly attenuated in the withdrawal condition. No significant differences were revealed in calculated substrate utilization. It was concluded that caffeine withdrawal significantly affects lipolysis but not substrate utilization during prolonged running.

Adult↗
PubMed1998

Effects of caffeine on blood pressure, heart rate, and forearm blood flow during dynamic leg exercise.

This study examined the acute effects of caffeine on the cardiovascular system during dynamic leg exercise. Ten trained, caffeine-naive cyclists (7 women and 3 men) were studied at rest and during bicycle ergometry before and after the ingestion of 6 mg/kg caffeine or 6 mg/kg fructose (placebo) with 250 ml of water. After consumption of caffeine or placebo, subjects either rested for 100 min (rest protocol) or rested for 45 min followed by 55 min of cycle ergometry at 65% of maximal oxygen consumption (exercise protocol). Measurement of mean arterial pressure (MAP), forearm blood flow (FBF), heart rate, skin temperature, and rectal temperature and calculation of forearm vascular conductance (FVC) were made at baseline and at 20-min intervals. Plasma ANG II was measured at baseline and at 60 min postingestion in the two exercise protocols. Before exercise, caffeine increased both systolic blood pressure (17%) and MAP (11%) without affecting FBF or FVC. During dynamic exercise, caffeine attenuated the increase in FBF (53%) and FVC (50%) and accentuated exercise-induced increases in ANG II (44%). Systolic blood pressure and MAP were also higher during exercise plus caffeine; however, these increases were secondary to the effects of caffeine on resting blood pressure. No significant differences were observed in heart rate, skin temperature, or rectal temperature. These findings indicate that caffeine can alter the cardiovascular response to dynamic exercise in a manner that may modify regional blood flow and conductance.

Adult↗
PubMed2001

Caffeine increases endurance and attenuates force sensation during submaximal isometric contractions.

Caffeine has known ergogenic effects, some of which have been observed during submaximal isometric contractions. We used 15 subjects in a randomized, double-blind, repeated-measures experiment to determine caffeine's ergogenic effects on neuromuscular variables that would contribute to increased endurance capacity. Subjects performed repeated submaximal (50% maximal voluntary contraction) isometric contractions of the right quadriceps to the limit of endurance (T(lim)) 1 h after oral caffeine administration (6 mg/kg). Time to reach T(lim) increased by 17 +/- 5.25% (P < 0.02) after caffeine administration compared with the placebo trial. The changes in contractile properties, motor unit activation, and M-wave amplitude that occurred as the quadriceps reached T(lim) could not account for the prolonged performance after caffeine ingestion. In a separate experiment with the same subjects, we used a constant-sensation technique to determine whether caffeine influenced force sensation during 100 s of an isometric contraction of the quadriceps. The results of this experiment showed that caffeine reduced force sensation during the first 10-20 s of the contraction. The rapidity of this effect suggests that caffeine exerts its effects neurally. Based on these data, the caffeine-induced increase in T(lim) may have been caused by a willingness to maintain near-maximal activation longer because of alterations in muscle sensory processes.

Adult↗
PubMed2002

Chronic caffeine treatment causes changes in cardiac adenosine receptor function in rats.

Caffeine exerts a number of cardiovascular effects via antagonism of adenosine A1 and A2a receptors, and chronic caffeine intake has been suggested to be a preventable risk factor for cardiovascular disease. We attempted, therefore, to determine the effects of chronic caffeine treatment on adenosine receptor function and the heart rate and blood pressure of anaesthetized rats. Rats were given two weeks of drinking water containing either caffeine (0.2%) or tap water alone. Rats were then anaesthetized and blood pressure and heart rate was assessed, as well as cardiovascular responses to adenosine receptor agonists and antagonists. Following 2 weeks caffeine treatment, both the resting blood pressure and heart rate of the treated rats were significantly increased compared to the non-caffeine treated (147 +/- 5 compared to 161 +/- 3 mm Hg). Negative chronotropic responses to A1 receptor agonist N6 cyclopentyladenosine occurred at lower concentrations in caffeine-treated rats than control (2.5-fold decrease in the ED50 of bradycardic responses to N6 cyclopentyladenosine), whilst vasodilator and reflex tachycardic responses to A2a receptor agonist CGS 21680 were unchanged. A shorter duration of caffeine- treatment resulted in moderate increases in heart rate and bradycardic responses to N6 cyclopentyladenosine. In summary, we found changes in resting heart rate and blood pressure in caffeine-treated rats which were concurrent with changes in adenosine receptor function.

Adenosine↗
PubMed1992

Interactive ventilatory effects of two respiratory stimulants, caffeine and doxapram, in newborn lambs.

Caffeine and doxapram are two respiratory stimulants used in the treatment of apnea in newborns. When used concurrently, these drugs may produce interactive effects on the control of breathing in the newborn. The ventilatory effects of these drugs, given alone or together, were measured during 150 min of drug infusion in two groups of awake lambs 2-5 days old. The first group (n = 5) received a caffeine loading dose of 10 mg/kg followed by a maintenance dose of 0.1 mg/kg/h and incremental doses of doxapram: 0.25, 0.5, 1.25 and 2.5 mg/kg/30 min. The second group (n = 5) received a doxapram loading dose of 5.5 mg/kg followed by a maintenance dose of 1 mg/kg/h and incremental doses of caffeine: 2.5, 5.0, 7.5 and 10.0 mg/kg/30 min. In the first group, ventilation increased after the caffeine loading dose from 566 +/- 55 to 680 +/- 74 ml/kg/min (plasma caffeine = 14.7 +/- 1.6 mg/l) and progressively increased with the addition of incremental doses of doxapram up to 1,000 +/- 108 ml/kg/min at 2.5 mg/kg of doxapram (p less than 0.001 compared to baseline and caffeine loading dose). In contrast, in the second group, the doxapram loading dose markedly increased ventilation from 582 +/- 50 to 936 +/- 75 (p less than 0.002 and p less than 0.04 compared to caffeine loading dose) at plasma doxapram of 5.3 +/- 0.8 mg/l, but incremental doses of caffeine had no effects. We conclude that doxapram exerts a brisk and powerful respiratory stimulant effect and produces an additional dose-dependent ventilatory response when added to caffeine.

Animals↗
PubMed1986

Theophylline and caffeine disposition in the neonatal piglet.

A pharmacokinetic study to evaluate the piglet as a model for caffeine and theophylline disposition was undertaken in 28 animals who received a 10.0-mg/kg intravenous dose of either methylxanthine, followed by multiple blood sampling over a 24-hour period. Theophylline and caffeine concentrations were quantitated from serum using a microanalytical HPLC technique (coefficient of variability less than 7% at 0.1-100 mg/l). The influence of postnatal development on drug disposition was examined by dividing the experimental animals into three age groups (newborn, 2 days; perinatal, 4-5 days; infants or young, 15-22 days). Pharmacokinetic parameters were calculated from nonlinear curve fitting of serum concentration vs time data. On the basis of the terminal elimination rate constant (lambda z) and total clearance (CL) for both theophylline and caffeine, differences were found among the age groups. The apparent volume of distribution (Vz) for both methylxanthines was not found to be different when compared between age groups. Covariance determinations between age and pharmacokinetic parameters revealed linear correlations for Vz of caffeine and CL for both theophylline and caffeine. In all piglets receiving theophylline, no caffeine was detected in serum during a 24 hr period. Theophylline, however, was detected (0.4 +/- 0.2 mg/l at 11.5 hr) in the four oldest piglets who received caffeine. Similarities between pharmacokinetic parameters for caffeine and theophylline reported for human neonates were found only for newborn piglets. Furthermore, the biotransformation of theophylline to caffeine reported for human neonates was not observed in neonatal piglets.

Animals↗
PubMed2000

Hypertension risk status and effect of caffeine on blood pressure.

We compared the acute effects of caffeine on arterial blood pressure (BP) in 5 hypertension risk groups composed of a total of 182 men. We identified 73 men with optimal BP, 28 with normal BP, 36 with high-normal BP, and 27 with stage 1 hypertension on the basis of resting BP; in addition, we included 18 men with diagnosed hypertension from a hypertension clinic. During caffeine testing, BP was measured after 20 minutes of rest and again at 45 to 60 minutes after the oral administration of caffeine (3.3 mg/kg or a fixed dose of 250 mg for an average dose of 260 mg). Caffeine raised both systolic and diastolic BP (SBP and DBP, respectively; P<0.0001 for both) in all groups. However, an ANCOVA revealed that the strongest response to caffeine was observed among diagnosed men, followed by the stage 1 and high-normal groups and then by the normal and optimal groups (SBP F(4),(175)=5.06, P<0.0001; DBP F(4,175)=3.02, P<0.02). Indeed, diagnosed hypertensive men had a pre-to-postdrug change in BP that was >1.5 times greater than the optimal group. The potential clinical relevance of caffeine-induced BP changes is seen in the BPs that reached the hypertensive range (SBP >/=140 mm Hg or DBP >/=90 mm Hg) after caffeine. During the predrug baseline, 78% of diagnosed hypertensive men and 4% of stage 1 men were hypertensive, whereas no others were hypertensive. After caffeine ingestion, 19% of the high-normal, 15% of the stage 1, and 89% of the diagnosed hypertensive groups fell into the hypertensive range. All subjects from the optimal and normal groups remained normotensive. We conclude that hypertension risk status should take priority in future research regarding pressor effects of dietary intake of caffeine.

Adult↗
PubMed1992

Effect of caffeine on expression of cardiac myosin heavy chain gene in adult hypothyroid and fetal rats.

Changes in cardiac myosin heavy chain (MHC) gene expression and isozyme transitions have been shown to be caused by developmental changes, hemodynamic overload, or the activity of various hormones. In this study, to examine whether caffeine, which has teratogenic effects on the fetal cardiovascular system, causes the distribution of cardiac MHC phenotype and, if so, to evaluate the mechanisms of the distribution of cardiac MHC phenotype by caffeine, we examined the effects of caffeine, theophylline, and cAMP on the cardiac MHC isoform transitions at the gene and protein levels using hypothyroid adult rats. Furthermore, we examined the expression of alpha- and beta-MHC gene in cardiac muscles of fetuses whose dams had received caffeine. The results showed that caffeine, theophylline, and cAMP caused accumulations of alpha-MHC mRNA and MHC isozyme V1. Furthermore, in the fetal hearts, it was recognized that caffeine induced an accumulation of alpha-MHC gene expression, as was also seen in the dams. However, this effect of caffeine on the heart was stronger in the fetus than in the dam. Intracellular cAMP concentration was increased by the administration of caffeine, theophylline, or cAMP, and the levels showed a positive correlation with those of alpha-MHC mRNA. These results suggest that the induction of alpha-MHC mRNA expression by the administration of caffeine may be induced by an increase in intracellular cAMP concentration.

Aging↗
PubMed1986

Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension.

Animals↗