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PubMed1984

Binding of citrate synthase and malate dehydrogenase to mitochondrial inner membranes: tissue distribution and metabolite effects.

Citrate synthase and malate dehydrogenase bind to mitochondrial membrane preparations obtained from various species of animals and lemon fruit. The amount of enzyme bound per mg mitochondrial protein was comparable in all tissues studied. The effect of various substrates, products, and substrate analogs on citrate synthase binding to rat liver mitochondrial inner membrane was examined. OAA was the most effective inhibitor of binding followed by AcCoA , CoA, citrate, ATP, and MgATP. Neither D- nor L- malate were effective in blocking binding. The wide distribution of binding of citrate synthase and malate dehydrogenase to the inner membrane and specificity of substrate effects on the binding of citrate synthase are discussed in relation to the possible physiologic nature of these phenomena.

Animals↗
PubMed1992

The role of citrate complexes in preventing urolithiasis.

There is considerable clinical evidence that the oral administration of potassium citrate significantly reduces the incidence of calcium oxalate stone formation in the urinary tract. The effectiveness of citrate ions in preventing stone formation could be due to the reduction in the concentrations of calcium and oxalate ions caused by complex ion formation with the citrate ions and/or due to the inhibition of the crystallisation of calcium oxalate. This paper reports an experimental study aimed at elucidating the role of citrate complexes in preventing urolithiasis. An experimental method is described which allows the identification of two hitherto unknown complexes CaOx cit3- and (Ca cit2)4-. The stability constants of these complexes have been determined, respectively, as log K = 4.54 +/- 0.08 and beta 2 cit = 5.15 +/- 0.14 (25 degrees C, I = 0.16). The inclusion of these complexes in ion-equilibrium calculations led to the conclusion that the effectiveness of the citrate ion in preventing calcium oxalate stone formation is due to its inhibition of agglomeration or growth of calcium oxalate crystals rather than any significant reduction in the degree of supersaturation of urine.

Calcium Oxalate↗
PubMed1990

Effect of mitogens on the maximum activities of hexokinase, lactate dehydrogenase, citrate synthase and glutaminase in rat mesenteric lymph node lymphocytes and splenocytes during the early period of culture.

1. The activities of hexokinase, lactate dehydrogenase and citrate synthase were maintained in mesenteric lymph node lymphocytes during 4 hr of culture: the activity of glutaminase increased during this period of time. 2. In splenocytes, the activity of hexokinase decreased markedly during the 4 hr period, whereas those of lactate dehydrogenase and glutaminase remained constant, and that of citrate synthase increased dramatically. 3. In both mesenteric lymphocytes and splenocytes, addition of the T-cell mitogens, phytohaemagglutinin or concanavalin-A, to the culture medium caused decreases in the activities of both hexokinase and citrate synthase. 4. In contrast, these mitogens increased the activity of glutaminase in both cell types. 5. Addition of the B-cell mitogen, bacterial lipopolysaccharide, had little effect on hexokinase, lactate dehydrogenase or citrate synthase but increased markedly that of glutaminase in mesenteric lymph node lymphocytes. 6. In splenocytes this mitogen prevented much of the decrease in hexokinase activity, increased the activities of citrate synthase and glutaminase but had little effect on that of lactate dehydrogenase.

Animals↗
PubMed1992

Crystal structure of Escherichia coli malate dehydrogenase. A complex of the apoenzyme and citrate at 1.87 A resolution.

The crystal structure of malate dehydrogenase from Escherichia coli has been determined with a resulting R-factor of 0.187 for X-ray data from 8.0 to 1.87 A. Molecular replacement, using the partially refined structure of porcine mitochondrial malate dehydrogenase as a probe, provided initial phases. The structure of this prokaryotic enzyme is closely homologous with the mitochondrial enzyme but somewhat less similar to cytosolic malate dehydrogenase from eukaryotes. However, all three enzymes are dimeric and form the subunit-subunit interface through similar surface regions. A citrate ion, found in the active site, helps define the residues involved in substrate binding and catalysis. Two arginine residues, R81 and R153, interacting with the citrate are believed to confer substrate specificity. The hydroxyl of the citrate is hydrogen-bonded to a histidine, H177, and similar interactions could be assigned to a bound malate or oxaloacetate. Histidine 177 is also hydrogen-bonded to an aspartate, D150, to form a classic His.Asp pair. Studies of the active site cavity indicate that the bound citrate would occupy part of the site needed for the coenzyme. In a model building study, the cofactor, NAD, was placed into the coenzyme site which exists when the citrate was converted to malate and crystallographic water molecules removed. This hypothetical model of a ternary complex was energy minimized for comparison with the structure of the binary complex of porcine cytosolic malate dehydrogenase. Many residues involved in cofactor binding in the minimized E. coli malate dehydrogenase structure are homologous to coenzyme binding residues in cytosolic malate dehydrogenase. In the energy minimized structure of the ternary complex, the C-4 atom of NAD is in van der Waals' contact with the C-3 atom of the malate. A catalytic cycle involves hydride transfer between these two atoms.

Amino Acid Sequence↗
PubMed1990

Extracellular-free Ca++ accounts for the sex difference in the aggregation of human platelets in citrated platelet-rich plasma.

It has been shown in Poiseuille flow, that the ADP-induced aggregation of human platelets in citrated plasma from female donors is significantly greater than from male donors over a range of mean tube shear rate, G, from 41.9 s-1 to 1920 s-1 and mean transit time, t, from 0.2 to 86 s. The present work verifies the sex difference at G = 335 s-1 and t = 43 s and deals with the effect of free Ca2+ on it. An inverse correlation between the extent of single platelet aggregation and donor hematocrit, and between hematocrit and the plasma ionized calcium concentration, [Ca2+], as well as a positive correlation between the extent of single platelet aggregation and [Ca2+] was found. This indicated that the sex difference is due to hematocrit-dependent differences in the [Ca2+] that result when a fixed volume of the chelating agent citrate is used to anticoagulate blood. When the initial citrate concentration was adjusted to compensate for the variable volume dilution of citrate in plasma among donors and the [Ca2+] of males raised above that of females, the sex difference was reversed. Again, aggregation correlated with [Ca2+]. At the physiological [Ca2+] in both heparinized PRP and hirudinized PRP, the rate of aggregation and aggregate size were much greater than in citrated plasma but no sex difference was detected.

Anticoagulants↗
PubMed1990

Phospho-oligosaccharide dependent phosphorylation of ATP citrate lyase.

The effect of insulin on ATP citrate lyase phosphorylation has been shown to be mimicked by a phospho-oligosaccharide in intact adipocytes. We demonstrate that the addition of phospho-oligosaccharide to intact adipocytes enhances the phosphorylation of ATP citrate lyase in the same tryptic peptide as insulin does. The addition of phospho-oligosaccharide to an adipocyte extract also results in an increase in ATP citrate lyase phosphorylation but in a different site than that observed in intact cells. The phospho-oligosaccharide-dependent incorporation of phosphate into ATP citrate lyase in intact cells is resistant to isopropanol and acetic acid, but the phosphoenzyme phosphorylated in cell extracts is acid labile. In cell extracts, the addition of phospho-oligosaccharide markedly inhibits ATP hydrolysis, which may explain the effect of this molecule on ATP citrate lyase phosphorylation in broken cells. These results support the hypothesis that this phospho-oligosaccharide mediates some of the effects of insulin on protein phosphorylation. They also indicate that caution should be exercised in interpreting the results obtained by adding phospho-oligosaccharide to broken cell preparations.

ATP Citrate (pro-S)-Lyase↗
PubMedDate not supplied

Citrate binding of Al3+ and Fe3+.

Citrate occurs at about 0.1 mM in blood plasma and is the most likely small molecule plasma binder of both Al3+ and Fe3+. This paper assesses published stability constants for citrate binding to each metal ion. From pH 2 to 5 Al3+ forms a neutral complex with citrate that may be absorbed into the body in the upper regions of the gastrointestinal tract. It is especially dangerous to ingest aluminum-containing antacids with citrus fruit or juices. Ignoring the likely occurrence of a competing 2:1 citrate-Fe3+ complex necessitates adjustments in reported stability constants for Fe3+ binding to transferrin. In the blood, plasma transferrin steals both Fe3+ and Al3+ from citrate.

Aluminum↗
PubMed1995

Testosterone stimulates the biosynthesis of m-aconitase and citrate oxidation in prostate epithelial cells.

Mitochondria (m-)aconitase is a rate-limiting regulatory enzyme in prostate epithelial cells which minimizes citrate oxidation by these cells. This unique metabolite characteristic is responsible for the ability of the prostate to accumulate and secrete extraordinarily high levels of citrate. Testosterone is a major regulator of prostate growth and function, and stimulates citrate oxidation. Therefore, an important action of testosterone might be its stimulation of m-aconitase in prostate epithelial cells. Studies were conducted with rat ventral prostate (VP) epithelial cells to establish the effect of testosterone on the level of m-aconitase and corresponding citrate oxidation. Physiological concentrations (10(-7)-10(-10) M) of testosterone in vitro markedly increased the level of m-aconitase in freshly prepared isolated prostate epithelial cells. This increase was apparent within 3 h of exposure to the hormone. The stimulatory effect of testosterone on m-aconitase was abolished by actinomycin D and by cycloheximide. Both the level of m-aconitase enzyme and the level of m-aconitase activity were similarly increased by testosterone treatment. Correspondingly, testosterone increased the rate of mitochondrial citrate oxidation while having no effect on the rate of isocitrate oxidation, thereby demonstrating that the action of testosterone is specifically targeted at the m-aconitase reaction. In vivo studies revealed that castration markedly decreased and testosterone administration increased the m-aconitase level of prostate epithelial cells. In contrast, neither liver nor kidney m-aconitase level was altered by castration. These studies demonstrate that testosterone regulates the biosynthesis of m-aconitase in prostate epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Aconitate Hydratase↗
PubMedDate not supplied

Assay of citrate in pharmaceutical matrices by indirect photometric liquid chromatography.

The development of a simple HPLC procedure is described for the analysis of citrate in pharmaceutical formulations using the technique of indirect photometric chromatography. A novel mobile phase, using dual eluent species, was developed for rapid elution of citrate. The developed method was found to be linear over the range studied (1-12 micrograms of citrate injected), showed good per cent recoveries (+/- RSD) of 97.5 +/- 3.05% from a generalized matrix solution, and includes very simple sample preparation steps for analysis of commercial products. This method is quite specific for tricarboxylic acids as most other ions are not retained by the column using the developed mobile phase. The resolution of the method is also good as indicated by a baseline resolution (Rs = 1.5) obtained for citrate and tricarballylate, two structurally similar tricarboxylic acids. It is proposed that the developed method be evaluated as an alternative to the tedious procedures employed by the USP for assay of total citrate in some of its monographs.

Chromatography, High Pressure Liquid↗
PubMed2004

Histopathological effects of sildenafil citrate on rat corpus cavernosum.

Sildenafil citrate (Viagra) is widely used for the treatment of erectile dysfunction with various etiologies. The aim of the present study was the investigation of histopathological effects of sildenafil citrate on rat corpus cavernosum using tight and electron microscopical techniques. Twenty male rats were divided into two groups. The first group (n = 10) was used as a control and the second group (n = 10) was treated with sildenafil citrate. Penile tissue was collected, fixed with formalin and embedded in paraffin for light microscopy, or fixed with gluteraldehyde and osmium tetroxide and embedded in Epon for electron microscopy. Light microscopical analysis showed that the corpus cavernosum was elongated and the number of blood vessels was increased. The amount of connective tissue in the penis was increased and dense collagen and smooth muscle fibers were observed in treated rats. Electron microscopical analysis showed that stromal structures of the corpus cavernosum (collagen fibers and number of cellular elements) were increased in treated rats. Fibroblasts showed signs of activation and the number of other stromal cells was increased. Immature newly synthesized collagen fibers were observed and penetrated endothelial basement membranes. In addition, endothelial cells also showed signs of activation such as cytoplasmic granules in treated rats, whereas the surface area of blood vessels was increased and basement membranes were thickened. These histopathological changes due to treatment with sildenafil citrate indicate that prolonged use of sildenafil citrate may increase the risk of fibrosis in the penis.

Animals↗
PubMed2005

Sildenafil citrate treatment for erectile dysfunction after kidney transplantation.

OBJECTIVE: Our goal was to analyze the morbidity of organic erectile dysfunction (ED) in kidney-transplant patients and to evaluate the efficacy and reliability of sildenafil citrate treatment. METHOD: Sixty-five ED patients with normal graft function for 3 to 12 months after kidney transplantation were involved in our study. Erectile dysfunction was diagnosed in all the patients by the International Index of Erectile Dysfunction (IIEF). Among them, 10 patients were in light degree; 32 patients in moderate degree, and 23 patients in severe degree according to IIEF score. All of the patients underwent medical history, physical and chemical examinations. In each patient, the IIEF score, blood urea nitrogen, creatinine, and trough concentrations of cyclosporine were compared before and after taking sildenafil citrate at an initial dose of 50 mg every night. RESULTS: Twenty-six patients without ED before transplantation suffered ED after the operation, and 32 patients with ED before transplantation noticed worsening. Taking sildenafil citrate was effective in 53 patients (81.54%). There were no statistical differences in blood urea nitrogen, creatinine, or trough concentrations of cyclosporine in patients before and after sildenafil treatment. CONCLUSIONS: The morbidity of organic erectile dysfunction increased after transplantation. Sildenafil citrate treatment for ED in kidney-transplant patients was effective and safe. Graft function and trough concentrations of cyclosporine were not affected by sildenafil citrate.

Blood Urea Nitrogen↗
PubMed2006

Effect of sildenafil citrate treatment on serum dehydroepiandrosterone sulfate levels in patients with erectile dysfunction.

OBJECTIVES: To investigate the effect of sildenafil citrate treatment on serum dehydroepiandrosterone sulfate (DHEAS) levels in patients with erectile dysfunction (ED). METHODS: A total of 124 men with a mean age of 45.9 years were included in the study. Group 1 consisted of 78 patients with ED, as determined by the Sexual Health Inventory of Male (SHIM) scale (score less than 21). Group 2 consisted of 46 healthy men with a SHIM score of 21 or greater. The 78 patients with ED took 100 mg sildenafil citrate at least eight times in 1 month. The SHIM scale was administered and serum DHEAS levels measured before and after treatment in the ED group. The serum DHEAS levels were also measured in the control group. The treatment response was defined as positive if the SHIM score was 21 or greater after sildenafil administration. RESULTS: At the end of sildenafil citrate treatment, the serum DHEAS levels and SHIM scores had increased significantly in the ED group (P = 0.013 and P = 0.001, respectively). In groups 1 and 2, the mean pretreatment serum DHEAS level of the men younger than 50 years old was 200.1 +/- 77.9 and 279.4 +/- 125.4 microg/dL, respectively (P = 0.013). The elevation of the serum DHEAS levels and SHIM scores was more significant in the sildenafil responders (P = 0.002 and P = 0.001), respectively. CONCLUSIONS: Serum DHEAS levels were significantly greater in the patients younger than 50 years old than in the older patients in the ED group. The serum DHEAS levels increased significantly after sildenafil citrate treatment in the ED group (especially in the younger men). Also, patient age was an important factor affecting the sildenafil citrate response.

Adult↗
PubMed2006

Sildenafil citrate inhibits agonist induced contractions in isolated rat seminal vesicles.

PURPOSE: Sildenafil is reported to regulate smooth muscle contractility through nitric oxide-cyclic guanosine monophosphate, not only in the corpus cavernosum. Its possible effects on seminal vesicle contractility might be of importance with respect to premature ejaculation. We investigated the effects of sildenafil citrate (Pfizer, New York, New York) on agonist induced isometric contractions of the rat seminal vesicle in vitro. MATERIALS AND METHODS: Seminal vesicles isolated from adult male Wistar rats were suspended in an organ bath and contracted by NE (10 microM), ACh (10 microM) or KCl (60 mM) (Sigma, Deisenhofen, Germany). The effects of sildenafil citrate (100 to 300 microM) were evaluated in terms of mean contraction amplitude, the area under force-time curves and isometric contractility indexes. RESULTS: Sildenafil citrate (300 microM) significantly inhibited the mean amplitude +/- SEM of contractile responses induced by NE (1,061 +/- 153 vs 271 +/- 65 mg, p <0.0001), ACh (475 +/- 51 vs 68 +/- 17 mg, p <0.0001) and KCl (546 +/- 71 vs 59 +/- 18 mg, p <0.0002). It also caused dose dependent concomitant decreases in the area under force-time curves. Additionally, pretreatment with sildenafil citrate markedly prevented the contractile response to NE, ACh and KCl. CONCLUSIONS: Our results indicate that sildenafil citrate inhibits the contractions of isolated rat seminal vesicle that are induced by NE, ACh or KCl. Future studies may support an in vivo effect of sildenafil for delaying or inhibiting seminal vesicle emission, thereby, promoting improvement in patients with premature ejaculation.

Acetylcholine↗
PubMed1991

Effect of meal on the physiological and physicochemical actions of potassium citrate.

The effect of meals on the physiological and physicochemical actions of potassium citrate was examined in 8 patients with nephrolithiasis maintained on a constant metabolic dietary regimen. Potassium citrate (20 mEq. 3 times per day), whether given with food or on an empty stomach, significantly increased urinary pH, citrate and potassium, and decreased urinary calcium and ammonium. Moreover, potassium citrate decreased urinary saturation of calcium oxalate and uric acid, although it slightly increased that of brushite. However, there was no significant difference in these measures when the drug was given with meals from the time when it was given on an empty stomach. Thus, the effect of potassium citrate on urinary risk factors is unaffected by food.

Adult↗
PubMed1991

Calcium metabolism in acidotic patients induced by carbonic anhydrase inhibitors: responses to citrate.

Calcium metabolism and its response to citrate were examined in 51 patients with glaucoma receiving carbonic anhydrase inhibitors (acetazolamide or methazolamide). Metabolic acidosis, hypocitraturia and increased incidence of nephrolithiasis were induced by both drugs. However, the acidosis was milder with methazolamide administration. Normocalciuria was observed in 29 patients and was shown to be a result of low filtered calcium. Renal hypercalciuria in 16 patients was associated with elevated parathyroid hormone but nephrogenic cyclic adenosine monophosphate remained within normal limits. Citrate in the form of potassium citrate (4.3 mmol.) and sodium citrate (4.0 mmol.) did not correct the metabolic acidosis or hypocitraturia but consistently decreased fasting and 24-hour urinary calcium excretion in patients with renal hypercalciuria. This event did not occur in patients with normocalciuria or absorptive hypercalciuria. These results suggest that a small amount of citrate could reverse renal hypercalciuria without correcting the metabolic acidosis.

Acetazolamide↗
PubMed1990

Effect of magnesium citrate and magnesium oxide on the crystallization of calcium salts in urine: changes produced by food-magnesium interaction.

The effect of magnesium citrate and magnesium oxide on urinary biochemistry and on the crystallization of calcium salts was examined in 7 normal subjects and 4 patients with recurrent calcium oxalate nephrolithiasis. When magnesium citrate or magnesium oxide was administered on an empty stomach (10 mEq. 4 times per day or 486 mg. magnesium per day for 2 weeks) urinary magnesium increased by only 77 to 79 mg. per day and urinary citrate increased by 98 to 142 mg. per day. However, urinary calcium increased by 21 to 25 mg. per day. No significant changes were noted in urinary saturation of calcium oxalate or brushite or in the limit of metastability (formation product) of these salts. However, when magnesium salts were provided with meals there were more prominent increases in urinary magnesium (by 92 to 96 mg. per day) and in citrate (by 218 to 226 mg. per day). Moreover, urinary oxalate decreased. Owing to these changes the urinary saturation of calcium oxalate decreased and the formation product increased. If magnesium citrate and magnesium oxide are to be used in the management of recurrent calcium oxalate nephrolithiasis, they should be administered with meals.

Adult↗
PubMed1985

Long-term treatment of calcium nephrolithiasis with potassium citrate.

The long-term effects of potassium citrate therapy (usually 20 mEq. 3 times daily during 1 to 4.33 years) were examined in 89 patients with hypocitraturic calcium nephrolithiasis or uric acid lithiasis, with or without calcium nephrolithiasis. Hypocitraturia caused by renal tubular acidosis or chronic diarrheal syndrome was associated with other metabolic abnormalities, such as hypercalciuria or hyperuricosuria, or occurred alone. Potassium citrate therapy caused a sustained increase in urinary pH and potassium, and restored urinary citrate to normal levels. No substantial or significant changes occurred in urinary uric acid, oxalate, sodium or phosphorus levels, or total volume. Owing to these physiological changes, uric acid solubility increased, urinary saturation of calcium oxalate decreased and the propensity for spontaneous nucleation of calcium oxalate was reduced to normal. Therefore, the physicochemical environment of urine following treatment became less conducive to the crystallization of calcium oxalate or uric acid, since it stimulated that of normal subjects without stones. Commensurate with the aforementioned physiological and physicochemical changes the treatment produced clinical improvement, since individual stone formation decreased in 97.8 per cent of the patients, remission was obtained in 79.8 per cent and the need for surgical treatment of newly formed stones was eliminated. In patients with relapse after other treatment, such as thiazide, the addition of potassium citrate induced clinical improvement. Thus, our study provides physiological, physicochemical and clinical validation for the use of potassium citrate in the treatment of hypocitraturic calcium nephrolithiasis and uric acid lithiasis with or without calcium nephrolithiasis.

Adult↗
PubMed2000

Side-effect profile of sildenafil citrate (Viagra) in clinical practice.

OBJECTIVES: Sildenafil citrate (Viagra) has been shown to be an effective treatment for erectile dysfunction. Initial studies reported a high tolerability and low incidence of certain characteristic adverse reactions. We sought to evaluate the incidence of side effects of sildenafil citrate, independent of industry support and constraints, utilizing a heterogeneous cohort of patients from a university-based practice. METHODS: A prospective, open-label, flexible-dose study of 256 patients treated with sildenafil citrate for erectile dysfunction was performed at a single institution. The patients were questioned explicitly about the occurrence of headache, flushing, dyspepsia, nasal congestion, visual changes, and other side effects. RESULTS: The adverse reactions most commonly observed were flushing (30.8%), headache (25. 4%), nasal congestion (18.7%), and heartburn (10.5%). All events were short lived and mild in nature. In the present study, 31.6% of patients experienced one or more adverse events. However, no one withdrew from the study because of the severity of these events. There was a significant association between higher doses and the occurrence of side effects. CONCLUSIONS: The incidence of adverse events attributable to sildenafil citrate may be higher than initially reported, but an explanation may be the methodology of data collection and the industry-independent nature of this study. The side-effect profile is dose related and mild. Sildenafil citrate remains a safe and well-tolerated treatment for erectile dysfunction.

Adult↗