Protective effects of fructose-1,6-bisphosphate postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing valve replacement: a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: Pharmacological postconditioning can protect against myocardial ischaemia-reperfusion injury during cardiac surgery with extracorporeal circulation. The aim of this study was to observe the protective effects of fructose-1,6-bisphosphate (FDP) postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing cardiac valve replacement with extracorporeal circulation. METHODS: Patients undergoing elective mitral valve replacement and/or aortic valve replacement were divided into normal saline postconditioning group (NS group) and FDP postconditioning group (FDP group). The primary outcome was the plasma concentration of creatine kinase-MB (CK-MB). The secondary outcomes were the plasma concentrations of lactate dehydrogenase, CK, high-sensitivity C-reactive protein, alpha-hydroxybutyrate dehydrogenase and cardiac troponin I, the spontaneous cardiac rhythm recovery profile, the extracorporeal circulation time and duration of surgery, intensive care unit and postoperative hospitalization. RESULTS: Forty patients were randomly assigned to receive intervention and included in the analysis. The serum concentrations of CK-MB, lactate dehydrogenase, CK, cardiac troponin I, alpha-hydroxybutyrate dehydrogenase and high-sensitivity C-reactive protein at T1∼4 were lower in the FDP group than in the NS group (P < 0.001). Compared with the NS group, the dosage of dopamine administered 1-90 min after cardiac resuscitation, the spontaneous cardiac rhythm recovery time and the incidence of ventricular fibrillation were lower in the FDP group (P < 0.001, P < 0.001 and P = 0.040, respectively). The values of ST- changes were increased more significantly in the NS group than in the FDP group (median [standard deviation] 1.3 [0.3] mm vs 0.7 [0.2] mm; P < 0.001). Compared with the NS group, the time of recovery of ST-segment deviations was shorter in the FDP group (50.3 [12.3] min vs 34.6 [6.9] min; P < 0.001). CONCLUSIONS: The FDP postconditioning could improve both myocardial ischaemia-reperfusion injury and the spontaneous cardiac rhythm recovery during cardiac valve surgery with extracorporeal circulation.

Fructose-1,6-Bisphosphate Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice and Inhibits the Proliferation of Lung Fibroblasts.

Pulmonary fibrosis is a specific form of interstitial pneumonia. In addition to the idiopathic cause, it may be caused by drugs such as bleomycin (BLM)-used in the treatment of tumors. Fructose-1,6-bisphosphate (FBP) is a high-energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory, and immunomodulatory effects. The aim of this study was to investigate the effects of FBP on both BLM-induced pulmonary fibrosis in mice and in a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 mice were divided into four groups: control, FBP, BLM, and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally, and survival, body weight, Ashcroft score, and histological analysis were evaluated. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg-intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased the survival rate and reduced body weight loss (BLM vs. BLM plus FBP-p < 0.05). FBP also prevented BLM-induced loss of pulmonary function and decreased BALF inflammatory cells, level of fibrosis, and superficial collagen density (p < 0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer.

Metabonomic profiling in studying anti-osteoporosis effects of strontium fructose 1,6-diphosphate on estrogen deficiency-induced osteoporosis in rats by GC/TOF-MS.

A novel strontium salt compound strontium fructose 1, 6-diphosphate (FDP-Sr) has been proved to have highly effective for bone loss via dual effects of stimulating bone formation and suppressing bone absorption. In the present study, metabolomic approach was used to identify and study potential biomarkers associated with the effect and safety of FDP-Sr. The metabolomic profiles of bone loss induced by estrogen deficiency in a rat model was described to attain a system-level map of the shift on the metabolic response in plasma using GC/TOF-MS, after FDP-Sr was orally administered at the dose of 110 mg/kg/day for the prevention and 220 mg/kg/day for the treatment. Meanwhile, bone turnover biomarkers and bone mineral density were investigated to identify the specific changes of potential anti-osteoporosis effects of FDP-Sr. The differences in metabolic profiles between osteoporosis rats and FDP-Sr treated rats were well observed by the partial least squares-discriminant analysis (PLS-DA) to the MS spectra. Some metabolites including homocysteine, arachidonic acid, alanine, and hydroxyproline, which significantly changed during osteoporosis progression could be effectively reversed after FDP-Sr therapy. Of course some metabolites such as uric acid, glyceric acid, octadecadienoic acid, docosahexaenoic acid, oleic acid, and hexadecanoic acid were not found to reverse significantly after FDP-Sr administration. These results delineated the FDP-Sr effects-related metabolic alterations in the bone loss rats, suggesting that metabonomic analysis could provide helpful information on the new potential biomarkers relating to the mechanism of anti-osteoporosis action and side effects of FDP-Sr against estrogen deficiency induced bone loss.

Strontium fructose 1,6-diphosphate prevents bone loss in a rat model of postmenopausal osteoporosis via the OPG/RANKL/RANK pathway.

AIM: To evaluate the protective effects of strontium fructose 1,6-diphosphate (FDP-Sr), a novel strontium salt that combined fructose 1,6-diphosphate (FDP) with strontium, on bone in an ovariectomy-induced model of bone loss. METHODS: Eighty female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated. Three months later, the rats were assigned to six groups (10 for each): sham-operated, OVX control, OVX+FDP-Sr (110, 220, or 440 mg/kg), or OVX+strontium ranelate (SR, 180 mg/kg). Drugs were administered orally for 3 months. When the treatment was terminated, the following parameters were assessed: bone mineral density (BMD), the biomechanical properties of the femur and lumbar vertebrae, trabecular histomorphology, serum phosphorus, calcium, bone-specific alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase 5b (TRACP5b), N-telopeptide of type I collagen (NTx) and a series of markers for oxidative stress. Receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) levels in serum were measured using ELISA and their gene expression levels in the bone were measured using R-T PCR. RESULTS: Treatment with FDP-Sr (220 or 440 mg/kg) or SR (180 mg/kg) significantly increased the BMD and improved the bone microarchitecture and bone strength in OVX rats. The treatments also decreased in the levels of H(2)O(2) and MDA, restored the CAT level in serum and bone marrow, increased the serum B-ALP and decreased NTx and TRACP 5b in OVX rats. Treatment with FDP-Sr decreased the RANKL level, and increased the OPG level in serum in a dose-dependent manner. It also significantly down-regulated the RANKL expression and up-regulated OPG expression in bone marrow. CONCLUSION: FDP-Sr may be an effectve treatment for postmenopausal osteoporosis that acts, in part, via a decrease in osteoclastogenesis through the OPG\RANKL\RANK pathway.

Fructose-1,6-bisphosphate reduces the mortality in Candida albicans bloodstream infection and prevents the septic-induced platelet decrease.

Due to the fact that an increased number of patients have experienced bloodstream infections caused by Candida species and the high mortality of this infection, there is a need for a strategy to reduce this scenery. One possible strategy is the use of new drugs, such as fructose-1,6-bisphosphate (FBP), which is a high-energy glycolytic metabolite and has shown to have therapeutic effects in several pathological conditions such as ischemia, shock, toxic injuries, and bacterial sepsis. The aim of this manuscript was to determine the role of FBP in experimental Candida albicans bloodstream infection. We used mice that were divided into three experimental groups: sham (not induced), bloodstream infection (induced with intratracheal instillation of C. albicans) and FBP (bloodstream infection plus FBP 500 mg/kg i.p.). Blood was taken for assessment of complete hematological profile and cytokine assay (IL-6 and MCP-1). Results of the study demonstrated that mortality decreased significantly in groups that received FBP. All cytokine and hematological indexes of FBP group were similar to bloodstream infection group with exception of platelets count. FBP significantly prevented the decrease in platelets. Taken together, our results demonstrate that FBP prevented the mortality in C. albicans bloodstream infection.

Fructose-1,6-bisphosphate protects against Zymosan-induced acute lung injury in mice.

It has been previously showed that fructose-1,6-bisphosphate (FBP) has anti-inflammatory and immunomodulatory effects on several experimental inflammation models. However, the effects and mechanism of FBP on Zymosan-induced acute lung injury (ALI) in mice had not been tested. In this study, our aim was to assess the anti-inflammatory activities of FBP on Zymosan-induced ALI. We found that in vivo treatment with FBP (500 mg/kg i.p.) markedly decreased the nitric oxide (NO) levels in the lungs and significantly reduced bronchoalveolar lavage fluid total cell and neutrophil counts and protein exudation after Zymosan challenge. Furthermore, FBP inhibited inducible nitric oxide synthase (iNOS) activities in RAW macrophages. Meanwhile, FBP did not inhibit the cyclooxigenase 2, interleukin-6, and nuclear factor kappa B transcription. Taken together, these results suggest that FBP shows anti-inflammatory effects through inhibiting lung edema, NO, and iNOS activities.

[Effect of fructose-1,6-diphosphete on myocardial preservation during pulmonary operations].

OBJECTIVE: To investigate the effect of fructose-1,6-diphosphete(FDP) on myocardial preservation in pulmonary operations. METHODS: One hundred and six patients undergoing selective pulmonary lobectomy or segmentectomy were randomly divided into 2 groups with 53 patients each. FDP 200 mg/kg was infused intravenously before anesthesia in the FDP group, while 5% glucose with the same volume was given instead of FDP in the control group. ECGs were monitored from before the anesthesia to 72 h after the operation;the time and type of arrhythmia were recorded. Blood samples were taken before the operation (T0), immediately after the operation(T1), at 24 h(T2),48 h(T3)and 72 h(T(4)) after the operation to determine plasma creatine kinase isoenzyme MB(CK-MB) and cardiac troponin I(cTnI) concentrations. RESULTS: The incidence of arrhythmia in FDP group (35 times) was significantly lower than that in the control group(67 times). The incidence of all types of arrhythmia in the FDP group was also significantly lower than that in the control group. The concentrations of CK-MB and cTnI in the FDP group were significantly lower than those in the control group at T1, T2, T3, and T4. CONCLUSION: FDP is effective for myocardial preservation in pulmonary operations.

Fructose-1,6-diphosphate attenuates acute lung injury induced by lipopolysaccharide in mice.

Fructose-1,6-diphosphate (FDP), a high-energy glycolytic pathway intermediate, is reported to have a salutary effect in endotoxic shock and sepsis, but its underlying mechanism of action in inflammation is incompletely understood. In this study, our aim was to examine the function of FDP on acute lung injury (ALI) induced by lipopolysaccharide (LPS). We found that in vitro pretreatment with FDP remarkably repressed the production of TNF-alpha and IL-6 in murine alveolar macrophages MH-S exposed to LPS. In the mouse model of LPS-induced inflammatory lung injury, intravenous precondition of a single 400 mg/kg dose of FDP resulted in a significant reduction in LPS-mediated extravasation of Evans blue dye albumin, bronchoalveolar lavage leucocyte content, and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Furthermore, histopathologic examination indicated that alveolitis with inflammatory cells infiltration and alveolar hemorrhage in the alveolar space was less severe in the FDP-treated mice than in the mice treated by LPS alone at 24 h. Additionally, pretreatment with FDP markedly decreased the transcription of TNF-alpha, IL-6 and inducible NO synthase (iNOS), and suppressed the nuclear translocation of NF-kappaB in lung tissues in response to LPS challenge. These results thus suggested that FDP plays an anti-inflammatory role in LPS-mediated acute lung injury, possibly through abrogation of NF-kappaB activation.

Fructose-1,6 diphosphate as a protective agent for experimental ischemic acute renal failure.

Cold ischemia time is a risk factor for the development of acute renal failure in the immediate post-transplant period. In this study, we aimed to determine if intravenous fructose-1,6-diphosphate (FDP), given before nephrectomy, attenuates renal cell injury in a cold ischemia model. Male adult Wistar rats were subjected to infusion of either FDP 350 mg/kg (group F, n=6), an equal volume of 0.9% NaCl (group S, n=6), an equal volume/osmolality of mannitol (group M, n=6) or no infusion (group C, n=7). Kidneys were then perfused in situ with Collins solution and nephrectomy was performed. Other kidney slices were stored in Collins solution at 4 degrees C. Adenosine triphosphate (ATP) levels and lactate dehydrogenase (LDH) release were examined at 0, 24, 48 and 72 h. Other slices, obtained after 50 min immersion in Collins solution at 37 degrees C, were frozen for characterization of cytoskeletal preservation using phalloidin-FITC staining. Apical fluorescence intensity of proximal tubule cells, indicative of the F-actin concentration, was measured in a fluorescence microscope interfaced with computer image analysis system. Adenosine triphosphate levels, after up to 72 h of tissue incubation, were higher (P<0.05) in the FDP group when compared to other groups. In addition, LDH release was smaller (P<0.0001) in the FDP group. The F-actin concentration of proximal tubule cells cells was greater in the FDP group (P<0.0001). Results indicate that FDP is a useful tool to increase tissue viability in a rat kidney subjected to cold ischemia, by maintaining ATP cell content, decreasing LDH release and preventing microfilament disruption of proximal tubule cells.

Myocardial protection using fructose-1,6-diphosphate during coronary artery bypass graft surgery: a randomized, placebo-controlled clinical trial.

UNLABELLED: In vitro and in vivo studies suggest that fructose-1,6-diphosphate (FDP), an intermediary glycolytic pathway metabolite, ameliorates ischemic tissue injury through increased high-energy phosphate levels and may therefore have cardioprotective properties in patients undergoing coronary artery bypass graft (CABG) surgery. We designed a randomized, placebo-controlled, double-blinded, sequential-cohort, dose-ranging safety study to test 5 FDP dosage regimens in patients (n = 120; 60 FDP, 60 control) undergoing CABG surgery. Of these dosage regimens, 3 produced no benefit, 1 produced improved cardiac function, and 1 required adjustment as a result of metabolic acidosis. This suggests that we achieved the intended effect of a dose-ranging study. The expected response was observed in patients treated with 250 mg/kg FDP IV before surgery and 2.5 mM FDP as a cardioplegic additive (n = 15). These patients had lower serum creatine kinase-MB levels 2, 4, and 6 h after reperfusion (P < 0.05), fewer perioperative myocardial infarctions (P < 0.05), and improved postoperative cardiac function, as evidenced by higher left ventricular stroke work index (LVSWI) 6, 12, and 16 h (P < 0.01) and cardiac index (CI) at 12 and 16 h (P < 0.05) after reperfusion. Overall efficacy of FDP was tested across all regimens that included IV FDP (n = 88; 44 FDP, 44 control) using 2 (FDP versus placebo) x 3 (dose size) factorial analyses. Area-under-curve (AUC) analysis demonstrated a significant increase in CI (AUC-16h, P = 0.013) and LVSWI (AUC-16h, P = 0.003) and reduction in CK-MB levels (AUC-16h, P < 0.05) in FDP-treated patients. The internal consistency of this dataset suggests that FDP may provide myocardial protection in CABG surgery and supports previous laboratory and clinical studies of FDP in ischemic heart disease. IMPLICATIONS: Fructose-1,6-diphosphate (FDP) may increase high-energy phosphate levels under anaerobic conditions and therefore ameliorate ischemic injury. A dose-ranging safety study for FDP was conducted in patients undergoing coronary artery surgery. Preischemic provision of FDP significantly improved cardiac function and reduced perioperative ischemic injury. These myocardial protective effects may improve patient outcome after cardiac surgery.

Fructose-1,6-bisphosphate for improved outcome after hypothermic circulatory arrest in pigs.

OBJECTIVE: Fructose-1,6-bisphosphate is a high-energy intermediate in the anaerobic metabolism. It enhances glycolysis, preserves cellular adenosine triphosphate, and prevents the increase of intracellular calcium during ischemia. The potential neuroprotective effect of fructose-1,6-bisphosphate during hypothermic circulatory arrest was evaluated in a surviving porcine model. METHODS: Twenty-four pigs were randomly assigned to receive two intravenous infusions of either fructose-1,6-bisphosphate (500 mg/kg) or saline solution. The first infusion was given immediately before a 75-minute period of hypothermic circulatory arrest and the second was given immediately after hypothermic circulatory arrest. RESULTS: The 7-day survivals were 83.3% in the fructose-1,6-bisphosphate group and 41.7% in the control group (P =.09). The treated animals had significantly better postoperative behavioral scores. The administration of fructose-1,6-bisphosphate was associated with higher venous phosphate and sodium levels, lower venous ionized calcium levels, higher blood osmolarity, and a better fluid balance. Intracranial pressure and venous creatine kinase isoenzyme MB were significantly lower in the fructose-1,6-bisphosphate group during rewarming (P =.01 and P =.001, respectively). Among the treated animals, brain glucose, pyruvate and lactate levels tended to be higher, brain glycerol levels tended to be lower, and the histopathologic score of the brain was significantly lower (P =.04). CONCLUSIONS: Intravenous administration of fructose-1,6-bisphosphate at 500 mg/kg before and after hypothermic circulatory arrest in a surviving porcine model was associated with better survival, behavioral outcome, and histopathologic score. The observed lower blood creatine kinase isoenzyme MB and brain glycerol levels and the higher brain glucose, pyruvate, and lactate levels in the fructose-1,6-bisphosphate group suggest that this drug has supportive effects on myocardial and brain metabolisms.

Fructose-1,6-diphosphate attenuates acute lung injury induced by ischemia-reperfusion in rats.

OBJECTIVE: To determine whether fructose-1,6-diphosphate (FDP) pretreatment can attenuate acute lung injury induced by ischemia-reperfusion in our isolated lung model in rats. DESIGN: Randomized, controlled study. SETTING: Animal care facility procedure room. SUBJECTS: Twenty-four adult male Sprague-Dawley rats each weighing 250-350 g. INTERVENTIONS: Typical acute lung injury in rats was induced successfully by 10 mins of hypoxia followed by 75 mins of ischemia and 50 mins of reperfusion. Ischemia-reperfusion significantly increased microvascular permeability as measured by the capillary filtration coefficient, lung weight gain, lung weight to body weight ratio, pulmonary arterial pressure, and protein concentration of bronchoalveolar lav-age fluid. MEASUREMENTS AND MAIN RESULTS: Pretreatment with FDP significantly attenuated the acute lung injury induced by ischemia-reperfusion as shown by a significant decrease in all of the assessed variables (p <.05 p <.001). The protective effect of FDP was nearly undetectable when promazine (an ecto-adenosine 5-triphosphatase inhibitor) was added before FDP pretreatment. CONCLUSIONS: Pretreatment with FDP significantly ameliorates acute lung injury induced by ischemia-reperfusion in rats.

Effect of fructose-1, 6-diphosphate versus diphenhydramine on mortality in compound 48/80-induced shock.

Fructose-1,6-diphosphate (FDP) has a salutary effect on hemorrhagic, traumatic and endotoxic shock. The role of FDP on compound 48/80-induced shock was therefore investigated. Sprague Dawley aged male rats (448+/-7.4 gm body weight) were randomly assigned into three groups and treated intraperitoneally with diphenhydramine (DPHM) 15 mg/kg (n=11), 12.5 ml of 10% FDP (n=10) and 12.5 ml saline (n=10). The rats were injected with compound 48/80 (5 mg/kg) 30 min later, and monitored every 10 min for 60 min. Arterial pressure was higher in FDP rats than in DPHM (P<0.01) or saline (P<0.005) groups. Plasma potassium (K(+)) was lower in the FDP group (P<0.01). Arterial pO2 and pCO2 were within physiological range in all groups. A profound decrease in arterial pH and bicarbonate (HCO3(-)) was also observed in all groups. Mortality at 48 h in the saline group was 100%, in the DPHM group 91%, and in the FDP group 20% (P<0.001 and P<0.005, respectively). FDP improved survival significantly in this study.

Fructose-1,6-diphosphate in the treatment of oleander toxicity in dogs.

Oleander, a flowering plant that grows in the Mediterranean and southern US, contains the cardiac glycosides oleandrin, digitoxigenin and nerium, which inhibit Na(+)-K+ ATPase. Clinical manifestations of oleander toxicity include gastrointestinal irritation, marked hyperkalemia, A-V block, ventricular dysrhythmia, and not uncommonly death. Because fructose-1,6-diphosphate (FDP) has been shown to attenuate digoxin toxicity, we determined whether this agent would be effective in the treatment of the toxicity of these similarly-structured cardiac glycosides. Anesthetized dogs (n = 12) were infused i.v. for 5 min with 40 mg oleander extract/kg and then 6 dogs randomly selected from that group received a 50 mg/kg bolus of 10% FDP followed by a constant infusion. The other control animals received the same dosage of 10% dextrose. Within 5 min after oleander administration, all dogs developed dysrhythmias. The FDP-treated animals reverted to sinus rhythm within 1.58 +/- 0.15 h; none in the control group returned to sinus rhythm. One control dog died at 3 h from ventricular fibrillation. Marked hyperkalemia was observed in the control group; plasma K+ remained unchanged in the FDP group. Throughout the 4 h experimental period the FDP group maintained normal arterial pressures; in the control dextrose group, pressures were profoundly depressed. Cardiac output declined in both groups but remained higher in the FDP group. To determine the mechanism whereby FDP attenuates oleander toxicity, we studied the in vitro effect of FDP on oleander poisoned myocardial sarcolemmal membranes. At concentrations of 1 and 2 mg oleander inhibited Na(+)-K+ ATPase activity and addition of 500 microM FDP restored myocardial sarcolemmal Na(+)-K+ ATPase function. FDP effectively prevented hyperkalemia, reversed dysrhythmias and improved hemodynamics in vivo in this canine model of oleander toxicity and also restored sarcolemmal Na(+)-K+ ATPase activity in vitro.

Fructose-1,6-bisphosphate preserves adenosine triphosphate but not intracellular pH during hypoxia in respiring neonatal rat brain slices.

BACKGROUND: Fructose-1,6-bisphosphate (FBP) sometimes provides substantial cerebral protection during hypoxia or ischemia. 31P/1H nuclear magnetic resonance spectroscopy of cerebrocortical slices was used to study the effects of FBP on hypoxia-induced metabolic changes. In addition, 13C-labeled glucose was administered and 13C nuclear magnetic resonance spectroscopy was used to search for FBP-induced modulations in glycolysis and the pentose-phosphate pathway. METHODS: In each experiment, 80 slices (350 microm) obtained from ten 7-day-old Sprague-Dawley rat litter mates were placed together in a 20-mm nuclear magnetic resonance tube, perfused, and subjected to 30 min of hypoxia (PO2 < 3 mmHg). Nine experiments were performed, with n = 3 in each of three groups: (1) no treatment with FBP; (2) 60 min of prehypoxia treatment with FBP (2 mM); and (3) 60 min of posthypoxia treatment with FBP (2 mM). 31P/1H Interleaved nuclear magnetic resonance spectra at 4.7 T provided average adenosine triphosphate, intracellular pH, and lactate. Cresyl violet stains of random slices taken at predetermined time points were studied histologically. Some experiments had [2-13C]glucose in the perfusate. Slices from these studies were frozen for perchloric acid extraction of intracellular metabolites and studied with high-resolution 13C nuclear magnetic resonance spectroscopy at 11.75 T. RESULTS: With no pretreatment with FBP, hypoxia caused an approximately 50% loss of adenosine triphosphate, an approximately 700% increase in lactate, and a decrease in intracellular pH to approximately 6.4. Pretreatment with FBP resulted in no detectable loss of adenosine triphosphate, no increase in lactate, and minimal morphologic changes but did not alter decreases in intracellular pH. 13C Nuclear magnetic resonance spectra of extracted metabolites showed that pretreatment caused accumulation of [1-13C]fructose-6-phosphate, an early pentose-phosphate pathway metabolite. Posthypoxic treatment with FBP had no effects compared with no treatment. CONCLUSIONS: During severe hypoxia, pretreatment with FBP completely preserves adenosine triphosphate and almost completely preserves cell morphology but does not alter hypoxia-induced decreases in intracellular pH. Pretreatment also substantially augments the flux of glucose into the pentose-phosphate pathway.

[Protective effect of 1,6-diphosphate fructose in ischemic renal failure in elderly rats].

To study the protective effect of 1,6-diphosphate fructose (FDP) on acute ischemia damage in brain, heart and liver, we observed its effect on acute ischemic renal failure (AIRF). AIRF in male Wistar rats was produced by renal arterial clamping for 45 minutes and reperfusion for 90 minutes. The rats were divided into 4 groups according to their age and FDP therapy: G1: young (3-4 months) AIRF rats without FDP; G2: old (26-27 months) AIRF rats without FDP; G3: young AIRF rats with FDP (0.5g/kg) i.v. infusion; G4: old AIRF rats with FDP. Inulin clearance (CIn), PAH clearance (CPAH), urinary sodium (UNA) were examined before ischemia and 30, 60 and 90 minutes after reperfusion. After reperfusion for 90 minutes, renal cortex was taken for the examination of renal mitochondrial ATP synthetic content (miATPs). CIn and CPAH were lower in G2 than in G1 (0.24 +/- 0.12 vs. 1.75 +/- 0.79, P < 0.01; 0.87 +/- 0.42 vs 7.12 +/- 4.04, P < 0.05, at 90 minutes reperfusion). CIn and CPAH in G1 showed an auto-recovery up to 40.1% and 33.7% of the level in contrast to G2. In G3 and G4 original FDP infusion resulted in a significant increase in miATPs and CIn (609 +/- 145 vs 389 +/- 97; 569 +/- 77 vs 338 +/- 61, P < 0.02; 2.47 +/- 0.58 vs 1.75 +/- 0.79, 1.29 +/- 0.42 vs 0.24 +/- 0.12, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of timing of administration in the cardioprotective effect of fructose-1,6-bisphosphate.

We administered fructose-1,6-bisphosphate (FDP), 1 mM, to isolated and perfused rabbit hearts submitted, after 90 minutes of equilibration, to an ischemic period (60 minutes at a coronary flow of 0.17 ml/min/g), followed by a period of reperfusion (30 minutes at a coronary flow of 3.6 ml/min/g). FDP was delivered at different times following the experimental protocol: 60 minutes before ischemia and for the entire experiment; 60 minutes before and during ischemia, but not at reperfusion; at the onset of ischemia and during reperfusion; and only during reperfusion. The FDP cardioprotective effect was evaluated in terms of recovery of left ventricular pressure developed during reperfusion, creatine phosphokinase (CPK) and noradrenaline release, mitochondrial function (expressed as yield, RCI, QO2, ADP/O), ATP and creatine phosphate (CP) tissue contents, calcium homeostasis, and by measuring oxidative stress in terms of reduced and oxidized glutathione release and tissue contents. Our data show that the cytoprotective action of FDP is closely related to the time of administration. Optimal myocardial preservation was achieved when it was present prior to ischemia and during reperfusion. When given at the time of ischemia or only on reperfusion, FDP does not exert cardioprotection. The data suggest that the FDP cardioprotective effect is related to improvement of energy metabolism.

[The antiacidotic and cardioprotective effects of fructose-1,6-diphosphate and dehydroascorbic acid]. / Antiatsidoticheskii i kardioprotektivnyi éffekty fruktozo-1,6-difosfata i degidroaskorbinovoi kisloty.

The antiacidotic and cardioprotective effects of dehydro-L-ascorbic acid and fructose-1,6-diphosphate were compared in experiments of rats. It was found that the both compounds exhibit the antiacidotic effect on the model of metabolic acidosis in the isolated hypoxic heart, decrease the excess-lactate degree, increase ATP level in the myocardium and reduce the size of the necrosis area 4 hours after the modelling of myocardial infarction. The significance of the antiacidotic component in the mechanism of the cardioprotective action of the energy-supplying agents is concluded.

Effect of obstructive jaundice on renal Na-K ATPase activity and ATP contents, their response to E. coli or endotoxin and effect of 1-6 fructose diphosphate.

A two-week bile duct ligation (BDL) in Sprague-Dawley (SD) rats raised the serum billirubin level and decreased the mean arterial blood pressure and renal cortical ATP contents compared with those in sham-operated (SO) rats (3.6 +/- 1.15 mg% vs 0.54 +/- 0.36, P less than 0.001; 69 +/- 24 mmHg vs 86 +/- 21, P less than 0.05; 3.72 +/- 0.86 x 10(-10) mol/mg tissue vs 7.27 +/- 0.18, P less than 0.05). No difference could be found in the medullary ATP contents (8.42 +/- 2.20 vs 8.70 +/- 2.80, P = NS). In SO rats, injection of endotoxin (0.7 mg/kg BW) and E. coli (3.1 x 10(5) bacteria/100 g BW) reduced cortical ATP content to 1.86 +/- 0.97 and 1.30 +/- 0.47 (P less than 0.001), and medullar ATP to 1.33 +/- 0.31 and 2.12 +/- 0.46 (P less than 0.001) respectively. In BDL rats, the same treatment led to further decrease in cortical ATP to 1.25 +/- 0.40 and 0.62 +/- 0.20, medullary ATP to 0.97 +/- 0.41 and 1.64 +/- 0.83 (P less than 0.001). Basal Na-K ATPase activity in BDL is the same compared with that in SO both in the cortex (2.85 +/- 2.2 mumol/mgpr/h vs 2.19 +/- 0.75; P = NS) and medulla (2.79 +/- 1.83 vs 3.05 +/- 1.38; P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effects of fructose-1,6-diphosphate on acute and chronic doxorubicin cardiotoxicity in rats.

The effects of fructose-1,6-diphosphate, an intermediate metabolite of glycolysis, on acute and chronic cardiotoxicity of doxorubicin were investigated in rats. In the acute study, urethane-anaesthetized Wistar female rats treated with 10 mg/kg i.v. doxorubicin developed a widening of the S alpha T segment, an impairment of +dP/dtmax, and tachycardia. Pretreatment with 375 and 750 mg/kg i.p. fructose-1,6-diphosphate prevented the S alpha T segment from widening, whereas only 750 mg/kg i.p. significantly attenuated the heart rate increase. Chronic cardiomyopathy was induced over a 6-week period by weekly doses of 3 mg/kg i.v. doxorubicin, being characterized in vivo by the progressive enlargement of the S alpha T segment and the occurrence of histological alterations and in vitro by a marked impairment of the inotropic response elicited by adrenaline in isolated hearts from treated rats. Concurrent treatment with 150 and 300 mg/kg i.p. fructose-1,6-diphosphate thrice a week for 6 weeks did not lessen the chronic heart damage, whereas 600 mg/kg given i.p. significantly reduced the widening of the S alpha T segment and the severity of histological damage in vivo, as well as significantly improving the contractile responses of hearts in vitro. These findings suggest that the administration of fructose-1,6-diphosphate plays a protective role in the acute and chronic cardiotoxicity of doxorubicin in the rat.