Interaction between the actions of taurine and angiotensin II

Summary. The amino acid, taurine, is an important nutrient found in very high concentration in excitable tissue. Cellular depletion of taurine has been linked to developmental defects, retinal damage, immundeficiency, impaired cellular growth and the development of a cardiomyopathy. These findings have encouraged the use of taurine in infant formula, nutritional supplements and energy promoting drinks. Nonetheless, the use of taurine as a drug to treat specific diseases has been limited. One disease that responds favorably to taurine therapy is congestive heart failure. In this review, we discuss three mechanisms that might underlie the beneficial effect of taurine in heart failure. First, taurine promotes natriuresis and diuresis, presumably through its osmoregulatory activity in the kidney, its modulation of atrial natriuretic factor secretion and its putative regulation of vasopressin release. However, it remains to be determined whether taurine treatment promotes salt and water excretion in humans with heart failure. Second, taurine mediates a modest positive inotropic effect by regulating [Na⁺]_i and Na⁺/Ca²⁺ exchanger flux. Although this effect of taurine has not been examined in human tissue, it is significant that it bypasses the major calcium transport defects found in the failing human heart. Third, taurine attenuates the actions of angiotensin II on Ca²⁺ transport, protein synthesis and angiotensin II signaling. Through this mechanism taurine would be expected to minimize many of the adverse actions of angiotensin II, including the induction of cardiac hypertrophy, volume overload and myocardial remodeling. Since the ACE inhibitors are the mainstay in the treatment of congestive heart failure, this action of taurine is probably very important. Received November 10, 1998, Accepted May 19, 1999     

Effects of chronic taurine treatment on reactivity of the rat aorta

Summary. The effects of chronic taurine treatment on the reactivity of the aorta form male Wistar-Kyoto rats were investigated. Contractile responses to norepinephrine (NE) and potassium chloride (KCl) were attenuated in aortic rings from taurine-treated rats as compared to controls both in the absence and presence of endothelium. However, the degree of attenuation was greater in endothelium-intact tissues contracted with NE. Acetylcholine (Ach)-induced relaxation responses were augmented in endothelium-intact vessels from rats supplemented with taurine compared to the responses observed in control preparations. Relaxation responses of the aortae from control and taurine-treated rats to sodium nitroprusside (SNP) were not different from each other. Our results suggest that taurine treatment attenuates vascular contractility nonspecifically and this effect is partly mediated via the endothelium. Received December 20, 1999/Accepted January 9, 2000     

Effects of endogenous glutamate on extracellular concentrations of taurine in striatum and nucleus accumbens of the awake rat: Involvement of NMDA and AMPA/kainate receptors

Summary. Using microdialysis, the effects of endogenous glutamate on extracellular concentrations of taurine in striatum and nucleus accumbens of the awake rat were investigated. The glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) was used to increase the extracellular concentration of glutamate. PDC (1, 2 and 4 mM) produced a dose-related increase of extracellular concentrations of glutamate and taurine in striatum and nucleus accumbens. Increases of extracellular taurine were significantly correlated with increases of extracellular glutamate, but not with PDC doses, which suggests that endogenous glutamate produced the observed increases of extracellular taurine in striatum and nucleus accumbens. The role of ionotropic glutamate receptors on the increases of taurine was also studied. In striatum, perfusion of the antagonists of NMDA and AMPA/kainate glutamate receptors attenuated the increases of extracellular taurine. AMPA/kainate, but not NMDA receptors, also reduced the increases of extracellular taurine in nucleus accumbens. These results suggest that glutamate-taurine interactions exist in striatum and nucleus accumbens of the awake rat. Received March 5, 1999/Accepted September 22, 1999     

Modulation of taurine uptake in the goldfish retina and axonal transport to the tectum¶Effect of crushing the optic nerve or axotomy

Summary. Although there are a great number of studies concerning the uptake of taurine in several tissues, the regulation of taurine transport has not been studied in the retina after lesioning the optic nerve. In the present study, isolated retinal cells of the goldfish retina were used either immediatly after cell suspension or in culture. The high-affinity transport system of [³H]taurine in these cells was sodium-, temperature- and energy-dependent, and was inhibited by hypotaurine and β-alanine, but not by γ-aminobutyric acid. There was a decrease in the maximal velocity (V_max) without modifications in the substrate affinity (K_m) after optic axotomy. These changes were mantained for up to 15 days after the lesion. The results might be the summation of mechanisms for providing extracellular taurine to be taken up by other retinal cells or eye structures, or regulation by the substrate taurine, which increases after lesioning the optic nerve. The in vivo accumulation of [³H]taurine in the retina after intraocular injection of [³H]taurine was affected by crushing the optic nerve or by axotomy. A progressive retinal decrease in taurine transport was observed after crushing the optic nerve, starting at 7 hours after surgery on the nerve. The uptake of [³H]taurine by the tectum was compensated in the animals that were subjected to crushing of the optic nerve, since the concentration of [³H]taurine was only different from the control value 24 hours after the lesion, indicating an efficient transport by the remaining axons. On the contrary, the low levels of [³H]taurine in the tectum after axotomy might be an index of the non-axonal origin of taurine in the tectum. Axonal transport was illustrated by the differential presence of [³H]taurine in the intact or crushed optic nerve. The uptake of [³H]taurine into retinal cells in culture in the absence or in the presence of taurine might indicate the existence of an adaptive regulation of taurine transport in this tissue, however taurine transport probably differentially occurs in specific populations of retinal cells. The use of a purified preparation of cells might be useful for future studies on the modulation of taurine transport by taurine in the retina and its role during regeneration. Received June 11, 1999/Accepted August 31, 1999     

Effects of high salt diets and taurine on the development of hypertension in the stroke-prone spontaneously hypertensive rat

Summary. Taurine is present in high concentrations in mammalian tissues and has been implicated in cardiovascular control mechanisms. The aim of the present study was to evaluate the ability of taurine to attenuate salt-induced elevations in blood pressure and markers of damage to the kidney and cardiovascular system in stroke prone spontaneously hypertensive rats (SPSHR). Male SPSHR (6 weeks old) were placed on high salt diets that contained 1% (w/w) NaCl added to their normal chow for 84 days and then were switched to 3% added NaCl for the remaining 63 days of the study. SPSHR was given 1.5% taurine in the drinking water (n = 8), a taurine free diet (n = 8) or normal chow (n = 8). A final control group (n = 6) was not given high salt diets. High salt diets caused an acceleration in the development of hypertension in all groups. Taurine supplementation reduced ventricular hypertrophy and decreased urinary excretion of protein and creatinine. The taurine free diet did not alter serum or urinary excretion of taurine, but did result in elevated urinary nitrogen excretion, increased serum cholesterol levels, and impaired performance in a spatial learning task. Alterations in dietary taurine intake did not alter urinary or serum electrolytes (Na⁺, K⁺), but taurine supplementation did attenuate a rise in serum calcium seen with the high salt diets. Urinary excretion (μg/24 h) of epinephrine and dopamine was significantly reduced in SPSHR given 1% NaCl in the diet, but this effect was not seen in SPSHR on taurine free or supplemented diets. Taurine supplementation showed cardioprotective and renoprotective effects in SPSHR given high salt diets. Received April 12, 1999/Accepted September 13, 1999     

Decreases in taurine levels induced by β-alanine treatment did not affect the susceptibility of tissues to lipid peroxidation

Summary. We aimed to investigate the effect of decreased taurine levels on endogenous and induced lipid peroxide levels in liver, brain, heart and erythrocytes as well as prooxidant and antioxidant balance in the liver of rats administered β-alanine (3%, w/v) in drinking water for 1 month to decrease taurine levels of tissues. This treatment caused significant decreases in taurine levels of liver (86%), brain (36%) and heart (15%). We found that endogenous and ascorbic acid-, NADPH- and cumene hydroperoxide-induced malondialdehyde (MDA) levels did not change in the liver, brain and heart homogenates following β-alanine treatment. Also, H₂O₂-induced MDA levels remained unchanged in erythrocytes. In addition, we did not observe any changes in levels of MDA, diene conjugates, glutathione, α-tocopherol, ascorbic acid and the activities of superoxide dismutase, glutathione peroxidase and glutathione transferase in the liver. According to this, buffering or sequestering capacity of tissues to exogenous stimuli was not influenced by reduced taurine levels in tissues of rats.     

Lysophosphatidylcholine Induces Taurine Release from HeLa Cells

The putative role of lysophospholipids in activation and regulation of the volume-sensitive taurine efflux was investigated in HeLa cells using tracer technique. Lysophosphatidylcholine (LPC, 10 μm) with oleic acid increased taurine efflux during hypotonic and isotonic conditions. Substituting palmitic or stearic acid for oleic acid enhanced taurine release during isotonic conditions, whereas ethanolamine, serine or inositol containing lysophospholipids were ineffective. High concentrations of LPC (25 μm) induced Ca²⁺ influx, loss of adenosine nucleotides, taurine and the Ca²⁺-sensitive probe Fura-2, and thus reflected a general breakdown of the membrane permeability barrier. Low concentrations of LPC (5–10 μm) solely induced taurine efflux. The LPC-induced taurine release was unaffected by anion channel blockers (DIDS, MK196) and the 5-lipoxygenase inhibitor ETH 615-139, which all blocked the volume sensitive taurine efflux. Furthermore, LPC-induced taurine release was reduced by antioxidants (NDGA, vitamin E) and the protein tyrosine kinase inhibitor genistein. The swelling-induced taurine efflux was in the absence of LPC unaffected by vitamin E, blocked by genistein, and increased by H₂O₂ and the protein tyrosine phosphatase inhibitor vanadate. It is suggested that low concentrations of LPC permeabilizes the plasma membrane in a Ca²⁺-independent process that involves generation of reactive oxygen species and tyrosine phosphorylation, and that LPC is not a second messenger in activation of the volume sensitive taurine efflux in HeLa cells. Received: 17 December 1999/Revised: 13 April 2000     

Detailed study of the different taurine uptake systems of colon LoVo MDR and non-MDR cell lines

Summary. In human, physiological taurine requirement is partly dependent on nutrition. Study of the human carcinoma LoVo cells shows the presence of a high and a low affinity taurine uptake. Besides them, a diffusion system has been found. A detailed analysis of the properties of the three systems is presented. A comparison of LoVo chemosensitive cells, and LoVo chemoresistant (MDR) cells which overexpress the multidrug transporter P-glycoprotein, shows that the only difference between the two cell types belong to the kinetic properties of the high and low affinity taurine uptake systems. Received May 19, 1999/Accepted August 16, 1999     

Taurine release in mouse brain stem slices under cell-damaging conditions

Summary. Taurine has been thought to be essential for the development and survival of neural cells and to protect them under cell-damaging conditions. In the brain stem taurine regulates many vital functions, including cardiovascular control and arterial blood pressure. We have recently characterized the release of taurine in the adult and developing brain stem under normal conditions. Now we studied the properties of preloaded [³H]taurine release under various cell-damaging conditions (hypoxia, hypoglycemia, ischemia, the presence of metabolic poisons and free radicals) in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. Taurine release was greatly enhanced under these cell-damaging conditions, the only exception being the presence of free radicals in both age groups. The ischemia-induced release was characterized to consist of both Ca²⁺-dependent and -independent components. Moreover, the release was mediated by Na⁺-, Cl⁻-dependent transporters operating outwards, particularly in the immature brain stem. Cl⁻ channel antagonists reduced the release at both ages, indicating that a part of the release occurs through ion channels, and protein kinase C appeared to be involved. The release was also modulated by cyclic GMP second messenger systems, since inhibitors of soluble guanylyl cyclase and phosphodiesterases suppressed ischemic taurine release. The inhibition of phospholipases also reduced taurine release at both ages. This ischemia-induced taurine release could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.     

Relationship of taurine and other amino acids in plasma and in neutrophils of septic trauma patients

Summary. Recently, an interdependency of plasma taurine and other amino acids as well as metabolic and clinical variables implicating therapeutic options was reported. This result may be an indication that plasma taurine levels are directly related to intracellular levels. Therefore, the aim of this study was to analyse the possible relationship between taurine levels in plasma and in neutrophils, the relationship to other amino acids, and variables quantifying metabolic impairment and severity of sepsis in multiple trauma patients developing sepsis. After multiple trauma taurine decreased significantly in plasma in thirty-two patients as well as within the neutrophil and does not recover in sepsis. Lower individual levels in the neutrophil did not follow lower individual levels in plasma and no correlation of taurine in plasma and in the neutrophils could be observed. In sepsis, only plasma showed an interdependency of taurine, aspartate, and glutamate. No association between taurine plasma or intracellular levels and SOFA score as indicator for severity of sepsis or metabolic variables was observed. After multiple trauma and in sepsis, taurine uptake in cells (which is regulated in different ways), and intracellular taurine (which serves e.g. as an osmolyte) can be influenced. Therefore a prediction of the neutrophil taurine pool seems not fully possible from taurine plasma levels. Intracellular taurine has some unique properties explaining the missing interdependency despite some similarities in osmoregulation and metabolic interactions to other amino acids. The association of taurine, aspartate, and glutamate in plasma cannot be simply transferred to the neutrophils intracellular level. The clinical meaning of the plasma correlation remains unclear. A dependency of plasma and neutrophil taurine to severity of sepsis and to metabolic variables seems not possible because of the multifactorial pathophysiology of sepsis.     

Taurine release modified by GABAergic agents in hippocampal slices from adult and developing mice

Summary. In order to characterize the possible regulation of taurine release by GABAergic terminals, the effects of several agonists and antagonists of GABA receptors on the basal and K⁺-stimulated release of [³H]taurine were investigated in hippocampal slices from adult (3-month-old) and developing (7-day-old) mice using a superfusion system. Taurine release was concentration-dependently potentiated by GABA, which effect was reduced by phaclofen, saclofen and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at both ages, suggesting regulation by both GABA_B and GABA_C receptors. The involvement of GABA_A receptors could not be excluded since the antagonist bicuculline was able to affect both basal and K⁺-evoked taurine release. Furthermore, several GABA_B receptor effectors were able to inhibit K⁺-stimulated taurine release in the adults, while the GABA_C receptor agonists trans-4-aminocrotonic acid (TACA) and cis-4-aminocrotonic acid (CACA) potentiated this release. The potentiation of taurine release by agents acting on the three types of GABA receptors in both adult and developing hippocampus further indicates the involvement of transporters operating in an outward direction. This inference is corroborated by the moderate but significant inhibition of taurine uptake by the same compounds. Received June 28, 1999, Accepted August 31, 1999     

Homocysteine, vitamins B6, B12, folate, and risk of coronary artery disease in patients undergoing diagnostic coronary angiography

Summary. Homocysteine and vitamins B were correlated with coronary artery disease in patients undergoing diagnostic coronary angiography. 160 patients having ≧1 stenosis (G1), 55 patients having normal coronary arteries (G2) and 171 healthy volunteers (G3) were prospectively recruited. Homocysteine levels were significantly higher in patients, particulary in those with normal coronary angiograms, than in healthy subjects (13.8 ± 6.3 μmol/L in G1 (p < 0.0001) and 15.2 ± 8.8 μmol/L in G2 (p < 0.0001) versus 10.1 ± 3.1 μmol/L in G3). Homocysteine levels were not related to the extent of coronary artery disease. In patients with normal angiogram, vitamin B12 and folate levels were significantly higher compared with the other groups (p < 0.05 and p < 0.001, respectively) showing that vitamin B deficiency was not involved in the hyperhomocysteinemia. In conclusion, homocysteine and vitamins B levels do not contribute to discriminate for the presence of coronary artery disease in patients undergoing diagnostic coronary angiography. Homocysteine levels, however, were higher in patients referred for coronary angiography than in healthy controls. Received November 7, 1998, Accepted February 20, 1999     

Role of osmoregulation in the actions of taurine

Summary. Taurine regulates an unusual number of biological phenomena, including heart rhythm, contractile function, blood pressure, platelet aggregation, neuronal excitability, body temperature, learning, motor behavior, food consumption, eye sight, sperm motility, cell proliferation and viability, energy metabolism and bile acid synthesis. Many of these actions are associated with alterations in either ion transport or protein phosphorylation. Although the effects on ion transport have been attributed to changes in membrane structure, they could be equally affected by a change in the activity of the affected transporters. Three common ways of altering transporter activity is enhanced expression, changes in the phosphorylation status of the protein and cytoskeletal changes. Interestingly, all three events are altered by osmotic stress. Since taurine is a key organic osmolyte in most cells, the possibility that the effects of taurine on ion transport could be related to its osmoregulatory activity was considered. This was accomplished by comparing the effects of taurine, cell swelling and cell shrinkage on the activities of key ion channels and ion transporters. The review also compares the phosphorylation cascades initiated by osmotic stress with some of the phosphorylation events triggered by taurine depletion or treatment. The data reveal that certain actions of taurine are probably caused by the activation of osmotic-linked signaling pathways. Nonetheless, some of the actions of taurine are unique and appear to be correlated with its membrane modulating and phosphorylation regulating activities. Received January 25, 2000/Accepted January 31, 2000     

Taurine increases mitochondrial buffering of calcium: role in neuroprotection

Summary. We have determined the role of mitochondria in the sequestration of calcium after stimulation of cerebellar granule cells with glutamate. In addition we have evaluated the neuroprotective role of taurine in excitotoxic cell death. Mitochondrial inhibitors were used to determine the calcium buffering capacity of mitochondria, as well as how taurine regulates the ability of mitochondria to buffer intracellular calcium during glutamate depolarization and excitotoxicity. We report here that pre-treatment of cerebellar granule cells with taurine (1 mM, 24 h) significantly counteracted glutamate excitotoxicity. The neuroprotective role of taurine was mediated through regulation of cytoplasmic free calcium ([Ca²⁺] _i ), and intra-mitochondrial calcium homeostasis, as determined by fluo-3 and ⁴⁵Ca²⁺-uptake. Furthermore, the overall mitochondrial function was increased in the presence of taurine, as assessed by rhodamine accumulation into mitochondria and total cellular ATP levels. We specifically tested the hypothesis that taurine reduces glutamate excitotoxicity through both the enhancement of mitochondrial function and the regulation of intracellular (cytoplasmic and intra-mitochondrial) calcium homeostasis. The role of taurine in modulating mitochondrial calcium homeostasis could be of particular importance under pathological conditions that are characterized by excessive calcium overloads. Taurine may serve as an endogenous neuroprotective molecule against brain insults. Authors’ address: Abdeslem El Idrissi, Biology Department and Center for Developmental Neuroscience, College of Staten Island/CUNY, 6S-134 Staten Island, NY 10314, U.S.A.     

Effect of β-alanine administration on carbon tetrachloride-induced acute hepatotoxicity

Summary. Mice were supplemented with β-alanine (3%) in drinking water for one week. β-Alanine intake reduced hepatic taurine levels, but elevated cysteine levels significantly. Hepatotoxicity of CCl₄ in mice fed with β-alanine was decreased as determined by changes in serum enzyme activities. Hepatic glutathione and taurine concentrations after CCl₄ challenge were increased markedly by β-alanine intake. The enhanced availability of cysteine for synthesis of glutathione and/or taurine appears to account for the hepatoprotective effects of β-alanine against CCl₄-induced liver injury.     

Diuretic potential of energy drinks

Summary. Recent literature suggests that both caffeine and taurine can induce diuresis and natriuresis in rat and man. Although they act via different cellular mechanisms, their diuretic actions might be additive. This is of considerable interest, as several commercially available energy drinks contain both substances. In this study we examined the possible diuretic effects of caffeine and taurine in a cross-over-design in which 12 healthy male volunteers received each of 4 different test drinks (750 ml of energy drink containing 240 mg caffeine and 3 g taurine, the three other test drinks either lacked caffeine, taurine or both) after restraining from fluids for 12 h. Mixed model analyses demonstrated that urinary output and natriuresis were significantly increased by caffeine (mean differences 243 ml and 27 mmol; both p < 0.001) and that there were no such effects of taurine (mean differences 59 ml and −4 mmol). Additionally, urinary osmolarity at baseline was significantly related to the urinary output (p < 0.001). Urine osmolarity values at baseline and in the 6 h urine collection did not differ significantly between treatments. Taken together, our study demonstrates that diuretic and natriuretic effects of the tested energy drink were largely mediated by caffeine. Taurine played no significant role in the fluid balance in moderately dehydrated healthy young consumers. Consequently, the diuretic potential of energy drinks will not differ significantly from other caffeine containing beverages.     

Diagnosis and follow-up of cystinuria: Use of proton magnetic resonance spectroscopy

Summary. Proton Nuclear Magnetic Resonance (NMR) Spectroscopy of urine (as well as of other biological fluids) is a very powerful technique enabling multi-component analysis useful in both diagnosis and follow-up of a wide range of inherited metabolic diseases. Among these pathologies, cystinuria is characterised by accumulation in urine of four dibasic amino acids, namely lysine, arginine, ornithine and cystine; the last one, being only slightly water soluble, generates urolithiasis. The mentioned aminoacids can be detected in the urine NMR spectrum of cystinuric patients, the most abundant being the lysine (5 mM and over are often detected), whose typical signals become very high; arginine and ornithine are also usually detectable, although pathologic concentrations are lower (usually below 2 mM). The proposed NMR technique is also suitable in monitoring the therapy with α-mercaptopropionylglycine (MPG), providing quantitation of several metabolites of interest in the follow-up of the pathology, like cystine, creatinine and citrate. Received May 9, 1999; Accepted September 26, 1999     

Observations on the relationship between the extracellular changes of taurine and glutamate during cortical spreading depression, during ischemia, and within the area surrounding a thrombotic infarct

Summary. Taurine and glutamate were monitored by microdialysis technique during various cerebral insults: a. Application of K⁺ triggered a cortical spreading depression (CSD). Taurine and glutamate increased concomitantly but recovery of glutamate was faster than that of taurine. b. Application of NMDA induced also CSD but only taurine increased. c. Induction of an infarct triggered repetitive CSDs. Taurine increased rapidly whereas glutamate rose slowly starting with some delay. d. After induction of ischemia, taurine and glutamate increased after onset of depolarisation. The increase of glutamate occurred late after a small, transient increase in parallel with the depolarisation. These data suggest a close functional relationship between the changes of both amino acids. Therefore, they should be monitored together especially in clinical settings: during excitation, only taurine will increase; during overexcitation, taurine will also increase but to a higher maximum followed by a moderate rise of glutamate; after energy failure, taurine will accumulate to its highest level followed by a continuous rise of glutamate. Received January 25, 2000/Accepted January 31, 2000     

The Melibiose Carrier of Escherichia coli: Cysteine Substitutions for Individual Residues in Helix XI

The melibiose carrier from Escherichia coli is a sugar-cation cotransport system. Previously evidence was obtained that this integral membrane protein consists of 12 transmembrane helices. Starting with the cysteine-less melibiose carrier, cysteine has been substituted individually for amino acids 374–396, which includes all of the residues in the proposed helix XI. The carriers with cysteine substitutions were studied for their transport activity and the effect of the water soluble sulfhydryl reagent p-chloromercuribenzenesulfonic acid (PCMBS). Studies were carried out on both intact cells and inside out vesicles. Cysteine substitution caused loss of transport activity in seven of the mutants (K377C, G379C, A383C, F385C, L391C, G395C and Y396C). PCMBS produced more than 50% inhibition in six of the mutants (S380C, A381C, A384C, F387C, A388C and L391C). Preincubation of the cells with melibiose protected five of these residues from the inhibitory action of PCMBS. It was concluded that the residues whose cysteine derivatives were inhibited by PCMBS probably faced the aqueous channel. Received: 30 September 1999/Revised: 22 November 1999