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     

Perinatal taurine exposure affects adult arterial pressure control

Taurine is an abundant, free amino acid found in mammalian cells that contributes to many physiologic functions from that of a simple cell osmolyte to a programmer of adult health and disease. Taurine’s contribution extends from conception throughout life, but its most critical exposure period is during perinatal life. In adults, taurine supplementation prevents or alleviates cardiovascular disease and related complications. In contrast, low taurine consumption coincides with increased risk of cardiovascular disease, obesity and type II diabetes. This review focuses on the effects that altered perinatal taurine exposure has on long-term mechanisms that control adult arterial blood pressure and could thereby contribute to arterial hypertension through its ability to program these cardiovascular regulatory mechanisms very early in life. The modifications of these mechanisms can last a lifetime and transfer to the next generation, suggesting that epigenetic mechanisms underlie the changes. The ability of perinatal taurine exposure to influence arterial pressure control mechanisms and hypertension in adult life appears to involve the regulation of growth and development, the central and autonomic nervous system, the renin–angiotensin system, glucose–insulin interaction and changes to heart, blood vessels and kidney function.     

Interaction between taurine and angiotensin II: Modulation of calcium transport and myocardial contractile function

Summary Angiotensin II modulates several aspects of cardiac function, including myocardial contractility, heart rate and myocyte growth. Most of these actions are intimately associated with alterations in calcium transport. Since taurine also modulates calcium transport, we examined possible interactions between taurine and angiotensin II at the level of the major cellular extruder of calcium, the Na^–-Ca²⁺ exchanger. Over a concentration range of 0.5–25 mM, Turne served as an effective inhibitor of angiotensin II-mediated stimulation of the exchanger. An Arrhenius plot of Na⁺-Ca²⁺ exchange activity revealed that angiotensin II (2 nM) increased transporter activity by reducing the activation energy of the transport process. Taurine (25 mM) inhibited the angiotensin II effect by partially preventing the reduction in activation energy. However, neither agent significantly altered the transition temperature, ruling out a change in membrane fluidity or an alteration in the rate limiting step of the transporter as a cause of the observed effects. Since the Na⁺-Ca²⁺ exchanger plays an important role in the handling of [Ca²⁺]_i by the myocardium, the effect of taurine on angiotensin II's modulation of contractile function was also examined. Hearts perfused with buffer containing angiotensin 11 experienced a slight positive isotropic effect in the absence of taurine but this was converted to a negative inotropic effect in the presence of taurine. The data suggest that Turine inhibits some, but not all of the actions of angiotensin II. The possibility that a phosphorylation event is the site of the angiotensin II-taurine interaction is discussed.     

The potential usefulness of taurine on diabetes mellitus and its complications

Taurine (2-aminoethanesulfonic acid) is a free amino acid found ubiquitously in millimolar concentrations in all mammalian tissues. Taurine exerts a variety of biological actions, including antioxidation, modulation of ion movement, osmoregulation, modulation of neurotransmitters, and conjugation of bile acids, which may maintain physiological homeostasis. Recently, data is accumulating that show the effectiveness of taurine against diabetes mellitus, insulin resistance and its complications, including retinopathy, nephropathy, neuropathy, atherosclerosis and cardiomyopathy, independent of hypoglycemic effect in several animal models. The useful effects appear due to the multiple actions of taurine on cellular functions. This review summarizes the beneficial effects of taurine supplementation on diabetes mellitus and the molecular mechanisms underlying its effectiveness.     

Cardiac and skeletal muscle abnormality in taurine transporter-knockout mice

Taurine, a sulfur-containing β-amino acid, is highly contained in heart and skeletal muscle. Taurine has a variety of biological actions, such as ion movement, calcium handling and cytoprotection in the cardiac and skeletal muscles. Meanwhile, taurine deficiency leads various pathologies, including dilated cardiomyopathy, in cat and fox. However, the essential role of taurine depletion on pathogenesis has not been fully clarified. To address the physiological role of taurine in mammalian tissues, taurine transporter-(TauT-) knockout models were recently generated. TauTKO mice exhibited loss of body weight, abnormal cardiac function and the reduced exercise capacity with tissue taurine depletion. In this chapter, we summarize pathological profile and histological feature of heart and skeletal muscle in TauTKO mice.     

A simple assay of taurine concentrations in food and biological samples using taurine dioxygenase

Taurine demonstrates various physiological functions and pharmacological actions. A successful application of taurine dioxygenase (EC 1.14.11.17) for taurine determination is described. The gene encoding taurine dioxygenase was cloned from Escherichia coli strain K-12, and the enzyme was used to determine taurine in commercially available beverages and some biological samples. The measured values obtained using the current method are close to the declared values with the precolumn derivatization ultra-performance liquid chromatography (UPLC) procedure. Taurine dioxygenase can be used for taurine determination in food control, biological research, and diagnoses based on urinary taurine concentration.     

Separation methods for taurine analysis in biological samples

Taurine plays an important role in a variety of physiological functions, pharmacological actions and pathological conditions. Many methods for taurine analysis, therefore, have been reported to monitor its levels in biological samples. This review discusses the following techniques: sample preparation; separation and determination methods including high-performance liquid chromatography, gas chromatography, ion chromatography, capillary electrophoresis and hyphenation procedures. It covers articles published between 1990 and 2001.     

Regulation of taurine homeostasis by protein kinase CK2 in mouse fibroblasts

Increased expression of the ubiquitous serine/threonine protein kinase CK2 has been associated with increased proliferative capacity and increased resistance towards apoptosis. Taurine is the primary organic osmolyte involved in cell volume control in mammalian cells, and shift in cell volume is a critical step in cell proliferation, differentiation and induction of apoptosis. In the present study, we use mouse NIH3T3 fibroblasts and Ehrlich Lettré ascites tumour cells with different CK2 expression levels. Taurine uptake via the Na⁺ dependent transporter TauT and taurine release are increased and reduced, respectively, following pharmacological CK2 inhibition. The effect of CK2 inhibition on TauT involves modulation of transport kinetics, whereas the effect on the taurine release pathway involves reduction in the open-probability of the efflux pathway. Stimulation of PLA₂ activity, exposure to exogenous reactive oxygen species as well as inhibition of protein tyrosine phosphotases (PTP) potentiate the swelling-induced taurine loss. Inhibition of PI3K and PTEN reduces and potentiates swelling-induced taurine release, respectively. Inhibition of CK2 has no effect on PLA₂ activity and ROS production by NADPH oxidase, whereas it lifts the effect of PTEN and PTP inhibition. It is suggested that CK2 regulates the taurine release downstream to known swelling-induced signal transducers including PLA₂, NADPH oxidase and PI3K.     

Physiological roles of taurine in heart and muscle

Taurine (aminoethane sulfonic acid) is an ubiquitous compound, found in very high concentrations in heart and muscle. Although taurine is classified as an amino acid, it does not participate in peptide bond formation. Nonetheless, the amino group of taurine is involved in a number of important conjugation reactions as well as in the scavenging of hypochlorous acid. Because taurine is a fairly inert compound, it is an ideal modulator of basic processes, such as osmotic pressure, cation homeostasis, enzyme activity, receptor regulation, cell development and cell signalling. The present review discusses several physiological functions of taurine. First, the observation that taurine depletion leads to the development of a cardiomyopathy indicates a role for taurine in the maintenance of normal contractile function. Evidence is provided that this function of taurine is mediated by changes in the activity of key Ca²⁺ transporters and the modulation Ca²⁺ sensitivity of the myofibrils. Second, in some species, taurine is an established osmoregulator, however, in mammalian heart the osmoregulatory function of taurine has recently been questioned. Third, taurine functions as an indirect regulator of oxidative stress. Although this action of taurine has been widely discussed, its mechanism of action is unclear. A potential mechanism for the antioxidant activity of taurine is discussed. Fourth, taurine stabilizes membranes through direct interactions with phospholipids. However, its inhibition of the enzyme, phospholipid N-methyltransferase, alters the phosphatidylcholine and phosphatidylethanolamine content of membranes, which in turn affects the function of key proteins within the membrane. Finally, taurine serves as a modulator of protein kinases and phosphatases within the cardiomyocyte. The mechanism of this action has not been studied. Taurine is a chemically simple compound, but it has profound effects on cells. This has led to the suggestion that taurine is an essential or semi-essential nutrient for many mammals.     

Taurine-diabetes interaction: from involvement to protection

Taurine is a sulfur amino acid (2-amino ethane sulfonic acid) and has been claimed for a number of beneficial actions ranging from anti-epilepsy to anti-hypertension. Taurine in diabetes has an age old story; taurine is involved in the development and protection of insulin apparatus. Taurine and insulin both have mutual stimulating actions with hypoglycemic properties. On the clinical front, taurine supplementation has an acceptable beneficial effect in platelet aggregation and, to name few more, in neuropathy, cardiomyopathy, and nephropathy to retinopathy. Recent studies have provided a role for taurine in fetal development and in blocking the transfer of diabetes from diabetic mother to offspring. A number of mechanisms for the actions of taurine have been advocated, from osmoregulation to anti-oxidation. Though sulfonylurea and recently introduced thiazolidinediones are effective, however they are not free from complications, thus there is a need to design new therapeutics. As taurine is also a sulfonyl derivative, it will be of great interest to develop taurine analogues as an alternative therapy. Considering the great involvement of taurine in diabetes, this review may provide a holistic view of taurine in diabetes and in its prevention in this century.     

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     

Role of taurine in the central nervous system

Taurine demonstrates multiple cellular functions including a central role as a neurotransmitter, as a trophic factor in CNS development, in maintaining the structural integrity of the membrane, in regulating calcium transport and homeostasis, as an osmolyte, as a neuromodulator and as a neuroprotectant. The neurotransmitter properties of taurine are illustrated by its ability to elicit neuronal hyperpolarization, the presence of specific taurine synthesizing enzyme and receptors in the CNS and the presence of a taurine transporter system. Taurine exerts its neuroprotective functions against the glutamate induced excitotoxicity by reducing the glutamate-induced increase of intracellular calcium level, by shifting the ratio of Bcl-2 and Bad ratio in favor of cell survival and by reducing the ER stress. The presence of metabotropic taurine receptors which are negatively coupled to phospholipase C (PLC) signaling pathway through inhibitory G proteins is proposed, and the evidence supporting this notion is also presented.     

Effects of taurine on vascular tone

Taurine is widely distributed at high concentrations in mammalian tissues, and it plays an important role in a wide range of biological effects including modulation of cardiovascular functions. This review summarizes the role of taurine in vascular tone and blood pressure modulation based on experimental and human studies. It is well established that supplementation of taurine prevents development of hypertension in several animal models and p.o. taurine administration reduces blood pressure in hypertensive patients. Both central and peripheral actions of taurine may be involved in its hypotensive effects. In isolated animal arteries, taurine exerts vasodilation through endothelium-dependent and independent mechanisms. Several studies showed that taurine relaxed various animal arteries through opening potassium channels. We have recently shown that taurine relaxes human internal mammary and radial arteries by opening large conductance Ca²⁺-activated K⁺ channels. To date, the molecular mechanism(s) involved in the vascular effects of taurine are largely unknown and require further investigation. Clarifying the mechanisms in which taurine affects the vascular system may facilitate the development of therapeutic and/or diet-based strategies to reduce the burden of vascular diseases.

     

Physiological and experimental regulation of taurine content in the heart

High concentrations of taurine are found in the heart and these are increased still further in congestive heart failure. It appears that taurine is largely derived by influx from the circulation, and this influx is stimulated by cyclic AMP, whereas influx of alpha-amino acids is unaffected. Influx occurs via a saturable transport system that has strict requirements for ligands. Other substances are transported by this system, including beta-alanine, hypotaurine, guanidoethyl sulfonate, and, to a lesser extent, guanidinopropionate; and these are competitive antagonists for taurine transport. Guanidinoethyl sulfonate, in vivo, markedly lowers taurine concentrations over the course of a few days in all tissues examined in the rat and mouse (but not in the guinea pig). The concentrations of other amino acids are unaffected. Guanidinoethyl sulfonate may prove to be a useful substance in the study of the biological role of taurine, in view of its ability to regulate taurine content in a number of species. Despite the numerous pharmacological actions of taurine, its physiological function in the heart remains problematic. One function appears to be the modulation of calcium movements. The inotropic actions of taurine and beta-adrenergic activation may be linked via the cyclic AMP-dependent regulation of taurine influx.     

Characteristics of taurine transport in rat liver lysosomes

Taurine (2-aminoethanesulfonic acid) is a unique sulfur amino acid derivative that has putative nutritional, osmoregulatory, and neuroregulatory roles and is highly concentrated within a variety of cells. The permeability of Percoll density gradient purified rat liver lysosomes to taurine was examined. Intralysosomal amino acid analysis showed trace levels of taurine compared to most other amino acids. Taurine uptake was Na(+)-independent, with an overshoot between 5-10 minutes. Trichloroacetic acid extraction studies and detergent lysis confirmed that free taurine accumulated in the lysosomal space. Kinetic studies revealed heterogeneous uptake with values for Km1 = 31 +/- 1.82 and Km2 greater than 198 +/- 10.2 mM. The uptake had a pH optimal of 6.5 and was stimulated by the potassium specific ionophore valinomycin. The exodus rate was fairly rapid, with a t1/2 of 5 minutes at 37 degrees C. Analog inhibition studies indicated substrate specificity similar to the plasma membrane beta-alanine carrier system, with inhibition by beta-alanine, hypotaurine, and taurine. alpha-Alanine, 2-methylaminoisobutyric acid (MeAIB), and threonine were poor inhibitors. No effects were observed with sucrose and the photoaffinity derivative of taurine NAP-taurine [N-(4-azido-2-nitrophenyl)-2-aminoethanesulfonate]. In summary, rat liver lysosomes possess a high Km system for taurine transport that is sensitive to changes in K+ gradient and perhaps valinomycin induced diffusional membrane potential. These features may enable lysosomes to adapt to changing intracellular concentrations of this osmotic regulatory substance.     

Potential role of taurine in the prevention of diabetes and metabolic syndrome

Metabolic syndrome is characterized by the cluster of a number of metabolic abnormalities in the presence of underlying insulin resistance. The prevalence of metabolic syndrome has steadily increased in all populations worldwide. Taurine (2-aminoethanesulfonic acid) is a sulfur-containing amino acid that is involved in a variety of physiological functions. Clinical and experimental studies show that taurine intake may be beneficial in the prevention of metabolic syndrome including diabetes, obesity, dyslipidemia, and hypertension. This article reviews the effect of taurine on all of the components of metabolic syndrome. In addition, the possible mechanisms by which taurine prevents diabetes and metabolic syndrome are also discussed. Further study is needed to determine the role of taurine in the development of metabolic syndrome in humans, because there is presently limited clinical data available.     

Regulation of taurine transport in Ehrlich ascites tumor cells

Summary Taurine influx is inhibited and taurine efflux accelerated when the cell membrane of Ehrlich ascites tumor cells is depolarized. Taurine influx is inhibited at acid pH partly due to the concomitant depolarization of the cell membrane partly due to a reduced availability of negatively charged free carrier. These results are in agreement with a 2Na, 1Cl, 1taurine cotransport system which is sensitive to the membrane potential due to a negatively charged empty carrier. Taurine efflux from Ehrlich cells is stimulated by addition of LTD4 and by swelling in hypotonic medium. Cell swelling in hypotonic medium is known to result in stimulation of the leukotriene synthesis and depolarization of the cell membrane. The taurine efflux, activated by cell swelling, is dramatically reduced when the phospholipase A₂ is inhibited indirectly by addition of the anti-calmodulin drug pimozide, or directly by addition of RO 31-4639. The inhibition is in both cases lifted by addition of LTD₄. The swelling-induced taurine efflux is also inhibited by addition of the 5-lipoxygenase inhibitors ETH 615-139 and NDGA. It is concluded that the swelling-induced activation of the taurine leak pathway involves a release of arachidonic acid from the membrane phospholipids and an increased oxidation of arachidonic acid into leukotrienes via the 5-lipoxygenase pathway. LTD₄ seems to act as a second messenger for the swelling induced activation of the taurine leak pathway either directly or indirectly via its activation of the Cl^– channels, i.e., via a depolarization of the cell membrane.     

Taurine and liver diseases: a focus on the heterogeneous protective properties of taurine

Taurine (2-aminoethylsulfonic acid) has many physiological and pharmacological functions in most tissues. It is abundantly maintained in the liver by both endogenous biosynthesis and exogenous transport, but is decreased in liver diseases. In the hepatic lobule, there are heterogeneous differences in metabolism between the pericentral (PC) and periportal regions, and the distributions of the biosynthesis capacity and specific taurine transporter expression are predominantly in the PC region. In cases of depletion of hepatic taurine level, serious liver damages were observed in the PC region. Taurine has protective effects against xenobiotics-induced liver damages in the PC region, but not xenobiotics-induced PP region damages. The xenobiotics that injure the PC region are mainly catabolized by NADPH-dependent cytochrome P450 2E1 that is also predominantly expressed in the PC region. Taurine treatment seems to be a useful agent for CYP2E1-related liver diseases with predominant damages in the PC region.     

The effect of taurine on renal ischemia/reperfusion injury

Summary. Ischemia-reperfusion (I/R) injury is one of the most common causes of renal dysfunction. Taurine is an endogenous antioxidant and a membrane-stabilizing, intracellular, free beta-amino acid. It has been demonstrated to have protective effects against I/R injuries to tissues other than kidney. The aim of this study was to determine whether taurine has a beneficial role in renal I/R injury. Forty Wistar-Albino rats were allocated into four groups as follows: sham, taurine, I/R, and I/R + taurine. Taurine 7.5 mg/kg was given intra-peritoneally to rats in the groups taurine and I/R + taurine. Renal I/R was achieved by occluding the renal arteries bilaterally for 40 min, followed by 6 h of reperfusion. Immediately thereafter, blood was drawn and tissue samples were harvested to measure 1) serum levels of BUN and creatinine; 2) serum and/or tissue levels of malondialdehyde (MDA), glutathione (GSH), glucose 6-phosphate dehydrogenase (G-6PD), 6-phosphogluconate dehydrogenase (6-PGD) and glutathione reductase (GSH-red); 3) renal morphology; and 4) immunohistochemical staining for P-selectin. Taurine administration reduced I/R-induced increases in serum BUN and creatinine, and serum and tissue MDA levels (p < 0.05). Additionally, taurine lessened the reductions in serum and tissue glutathione levels secondary to I/R (p < 0.05). Taurine also attenuated histopathologic evidence of renal injury, and reduced I/R-induced P-selectin immunoreactivity (p < 0.05). Overall, then, taurine administration appears to reduce the injurious effects of I/R on kidney.     

Cellular uptake of taurine by lactating porcine mammary tissue

Milk taurine plays a critical role in neonatal development. Taurine uptake in lactating sow mammary tissue has not been characterized previously. The kinetic properties, ion dependence and substrate specificity of taurine uptake were characterized in mammary tissue collected from lactating sows at slaughter. Tissue explants were incubated in an isosmotic physiologic buffer with [³H]taurine tracer to measure taurine uptake. Taurine uptake was dependent upon the presence of extracellular sodium and chloride ions, which is consistent with the co-transport of sodium and chloride with taurine. Uptake was not dependent upon ion exchange mechanisms or upon furosemide-sensitive ion co-transport. Taurine uptake was saturable and exhibited an apparent K_m of 20 μM and a V_max of 386 μmol/kg cell water/30 min. Substrate specificity studies indicated a strong interaction of β-amino acids with the taurine transport system. Taurine transport in lactating sow mammary tissue is therefore a high affinity, sodium-dependent mechanism specific for β-amino acids, and is analogous to sodium-dependent taurine uptake in other tissues. The high affinity and high specificity of the taurine uptake system allows for concentration of taurine within the mammary cell and is ultimately responsible for provision of taurine required for neonatal development.