Angel K. Markov

Hemodynamic, electrocardiographic, and metabolic effects of fructose diphosphate on acute myocardial ischemia

The hemodynamic, electrocardiographic, and metabolic responses of dogs with acute myocardial ischemia to intravenous administration of fructose-1,6-diphosphate (FDP) were assessed. Analysis of the results (compared to dextrose control) revealed evidence of major improvement of LVEDP and cardiac output, significant decrease of the ST segment, and large increases of ATP and CP in the ischemic district and to a lesser degree in the normally perfused myocardium. These results indicate that FDP intervenes in the Embden-Meyerhof pathway not only as a high energy substrate but also as a metabolic regulator influencing the activity of phosphofructokinase and that of pyruvate kinase. FDP also stimulates glycolysis in dog erythrocytes and increases their ATP and 2-3 DPG content by a factor of 2. The most significant finding in these studies is that this biochemical intervention appears to restore the depressed activity of glycolysis in ischemic myocardium.

Attenuation of ischemic renal injury with fructose 1,6-diphosphate

Fructose 1,6-diphosphate (FDP) has been shown to attenuate tissue injury associated with ischemia and shock by enhancing the anaerobic carbohydrate utilization and by inhibiting oxygen-free-radical generation by the neutrophils. Previously, we have reported that FDP prevents ischemic renal failure if administered prior to the ischemic insult. The present study was designed to determine whether this agent could prevent renal damage when administered during the postischemic reperfusion period. Rats were subjected to 30 min of bilateral renal artery occlusion and infused with FDP (350 mg/kg body wt) beginning 10 min after release of the renal artery clamps. Control rats received an equal volume of glucose/saline solution. A third group of rats were sham operated. Twenty-four hours after injury, BUN, creatinine, and fractional sodium excretion values were less in FDP-treated rats than in control rats (P less than 0.001, P less than 0.005, and P less than 0.001, respectively) and not different from values observed in sham-operated rats. Inulin clearance was greater (P less than 0.001) in FDP-treated rats than in control rats (665 +/- 38 microliters/min/g kidney wt). Renal histology was also better preserved in the FDP-treated group. These data suggest that FDP infused after the initiation of an acute ischemic insult provides significant, but not complete, functional and histologic protection from renal damage.

Stimulating Effect of Fructose 1-6 Diphosphate on the Phagocytic Function of Rat RES and on Human Leukocyte Carbohydrate Metabolism

The phagocytic behavior of the reticuloendothelial system in the rat was assessed by a quantitative technique following fructose-1,6-diphosphate (FDP) administration. In addition, the effect of FDP on the carbohydrate metabolism of human leukocytes was investigated. The rate of colloidal carbon clearance from the blood was increased significantly in the FDP-treated rats as compared to dextrose and saline controls (p <0.001). FDP also attenuated the hepatic decrease of ATP (p <0.005) and creatine phosphate (p <0.005) that has been observed after intravenous administration of colloidal carbon. Carbohydrate metabolism in human leukocytes was enhanced by FDP, with a concomitant increase in ATP content (p <0.001). Experimental evidence suggests that FDP intervenes in the Embden-Meyerhof pathway both as a metabolic regulator and as a high energy substrate. These properties of FDP in stimulating the carbohydrate metabolism have recently been described in man.

Therapeutic action of fructose-1,6-diphosphate in traumatic shock

Traumatic shock was induced in 130 rats by tumbling them in a Noble-Collip drum for a total of 600 revolutions at 40 rotations/min. The experimental protocol was designed to evaluate the therapeutic effectiveness of fructose 1,6-diphosphate (FDP) in reducing the mortality rate when given both prior to and following the trauma, or only following the trauma. In the first group (n=50) in which the treatment was given prior to and after trauma, the animals were randomly assigned to 3 subgroups as follows: 20 rats received 350 mg/kg of FDP prior to and an additional 350 mg/kg after trauma; 20 other rats received in the same manner equal amounts of glucose; and 10 rats received no treatment. In the group treated only after inflicting the injury (n=80), 35 rats received 350 mg/kg of FDP after trauma; another 35 received glucose; and 10 received no treatment. The rats from the different subgroups were tumbled at the same time.Survival rates in the pretreated subgroups were 85% for those receiving FDP, 30% for glucose-treated animals (p< 0.005), and 20% for the nontreated ones. In the animals that were treated after trauma, there was also a significant increase in survival rate for the FDP-treated ones (66%), while for those receiving glucose it was 31% (p<0.01), and 20% for the nontreated ones.The results of the present study and those obtained in other etiological types of shock indicate that FDP has profound antishock therapeutic activity. This action appears to be metabolically mediated by augmenting the endogenous energy production via glycolysis.RésuméLe choc traumatique a été provoqué chez 130 rats en les plaÇant dans un tambour Noble-Collip soumis à 600 révolutions, à la vitesse de 40 révolutions par minute. Lexpérimentation a eu pour objet dévaluer lefficacité thérapeutique du fructose-1,6-diphosphate (FDP) en étudiant le taux de survie quand lagent était administré à la fois avant et après lexpérimentation, dune part, et seulement après lexpérimentation, dautre part.Dans le premier groupe (n=50), où le traitement fut institué avant et après le traumatisme, les rats furent répartis au hasard en 3 sous-groupes: 1) 20 rats reÇurent 350 mg/kg de FDP avant et après le traumatisme, 2) 20 autres reÇurent de la mÊme faÇon des quantités égales de glucose, 3) 3 ne reÇurent ni FDP ni glucose. Dans le deuxième groupe (n=80), 35 rats reÇurent du FDP après le traumatisme, 35 du glucose et 10 ne furent soumis à aucun traitement.Les résultats sont les suivants: le taux de survie chez les rats traités par le FDP avant et après le traumatisme atteignit 85%, il fut seulement de 30% chez ceux qui reÇurent du glucose et de 20% chez ceux qui ne subirent aucun traitement.Dans le second groupe où les rats furent traités seulement après le traumatisme, le taux de survie fut de 66% pour ceux qui reÇurent du FDP, de 31% pour ceux qui reÇurent du glucose et de 20% chez les rats qui ne furent soumis à aucun traitement.Les résultats de cette étude et ceux obtenus en présence dautres types de choc indiquent que le FDP possède une action thérapeutique anti-choc indiscutable, cette action étant de type métabolique et relevant de la production dénergie endogénique grâce à la glycolyse.AbstractoEl shock traumático fue inducido en 130 ratas volteándolas en un tambor de Noble-Collip por un total de 600 revoluciones a 40 rotaciones/minuto. El protocolo original fue diseñado para evaluar la efectividad terapéutica de la fructosa-1,6-difosfato (FDP) en la reducción de la tasa de mortalidad cuando se administra antes y después del trauma, o solamente después del trauma.En el primer grupo (n=50), en el cual el tratamiento fue administrado antes y después del trauma, los animales fueron asignados a 3 subgrupos en la forma siguiente: 20 ratas recibieron 350 mg/kg de FDP antes del trauma y 350 mg/kg adicionales postrauma; otras 20 ratas recibieron iguales cantidades de glucosa de la misma manera, y 10 ratas no recibieron tratamiento. En el grupo tratado solo después de producida la lesión (n= 80), 35 ratas recibieron 350 mg/kg de FDP después del trauma; otras 35 recibieron glucosa; 10 no recibieron tratamiento. Las ratas de los diferentes subgrupos fueron volteadas al mismo tiempo. Las tasas de supervivencia en los subgrupos fue de 85% para aquellas que recibieron FDP, de 30% para las tratadas con glucosa (p<0.005) y de 20% para las no tratadas. En los animales que fueron tratados después del trauma, también hubo un aumento significativo de la tasa de supervivencia para los tratados con FDP (66%), en tanto que para aquellos que recibieron glucosa un aumento de 31% (p< 0.01) y de 20% para los no tratados.Los resultados del presente estudio y aquellos obtenidos en otros tipos etiológicos de shock, indican que el FDP posee una profunda actividad terapéutica antishock y que esta acción parece ser metabólicamente inducida mediante el aumento de la production de energía endógena por vía de la glicolisis.

Prevention of Galactosamine-Induced Hepatotoxicity in Rats with Fructose-1,6-Diphosphate

Galactosamine (GalN) administration produces hepatitis-like liver injury in animals. The hepatotoxicity of GalN is attenuated by several interventions, including activation of the reticuloendothelial system (RES). Fructose-1,6-diphosphate (FDP) administration significantly increases the phagocytic activity of the RES in animals. Thus, investigations were designed to determine whether FDP affords protection against GalN toxicity. Rats were injected with GalN (375 mg/kg) and treated with 0.9% NaCl (n = 8) or FDP (n = 9). Eight rats were sham-operated. Serum glutamic oxaloacetic transaminase was 40 times higher in the saline group as compared to the FDP-treated rats (p less than 0.0001). Glutamic pyruvic transaminase, gamma-glutamyltranspeptidase and bilirubin were similarly elevated (saline vs. FDP, p less than 0.005, p less than 0.01 and p less than 0.05, respectively). These values were not different between FDP-treated and sham-operated rats. Extensive hepatic necrosis was observed in all saline-treated rats, whereas in the FDP group only isolated foci of hepatocellular necrosis were noted. The hepatoprotective effect of FDP in this model is attributed to its ability to enhance the phagocytic activity of RES and to suppress release of oxyradicals by the leukocytes during the inflammatory phase.

Fructose-1,6-Diphosphate, when Given Five Minutes after Injury, Does Not Ameliorate Hypoxic Ischemic Injury to the Central Nervous System in the Newborn Pig

Hypoxic ischemic injury to the brain was induced in 12 0- to 3-day-old piglets. At time 0, the carotid arteries were ligated, and the blood pressure was reduced by one third by hemorrhage. At 15 min, inspired FIO2 was reduced from 50 to 6%. After 10 min of flat EEG, the FIO2 was changes to 100%, the carotid ligations were released, and the withdrawn blood was reinfused. Five minutes after reoxygenation, the piglets were randomly assigned to either receive 350 mg of fructose-1,6-diphosphate over 5 min, followed by 6 mg/kg/min for the ensuing 50 min, or an equivalent volume of normal saline. 3 days after the experiment, the animals received a neurologic examination by a blinded observer, were then sacrificed, and the brains examined by a blinded observer. There were no significant differences in the degree of damage between the two groups.

Retrograde Radioisotope Myocardial Perfusion Patterns in Dogs

A retrograde coronary vein injection technique for concentrating radioisotope in ischemic myocardial regions was evaluated in dogs. Potassium-43 in saline solution was injected into the coronary veins during complete closure of the coronary sinus. In the presence of coronary inflow obstruction, the venous potassium-43 was distributed mainly to the low pressure vessels in ischemic heart regions; i.e., the ratio of potassium-43 in the occluded-to-unoccluded areas ranged from 2:1 to 3:1 thirty seconds after retrograde injections. Krypton-85 in saline solution was injected under pressure into the coronary veins during partial closure of the coronary sinus. In the presence of inflow obstruction, the ratio of krypton-85 in the occluded- to-unoccluded areas ranged from 4:1 to 6:1 sixty seconds after retrograde injections; larger ratios may be expected after rapid washout of gas from the normally perfused region is nearly complete. Myocardial potassium-43 imaging techniques were applied to locate and measure the size of the ischemic heart region as a radioisotopic hot spot. Detection of hypoperfused areas of extremely small size may be accomplished by this technique.

Prevention of α-naphthylthiourea-induced pulmonary edema with fructose-1,6-diphosphate

Neutrophil-derived oxygen free radicals have been implicated in the pathogenesis of noncardiogenic pulmonary edema. Fructose-1,6-diphosphate (FDP) has been shown to inhibit oxygen free radicals production by activated neutrophils. Thus, we investigated whether FDP would attenuate formation of pulmonary edema in anesthetized dogs injected with α -naphthylthiourea (ANTU). Hemodynamic studies involved measurements of left ventricular systolic and end-diasystolic pressures (LVSP and LVEDP), pulmonary artery pressure (PaP), heart rate (HR), and cardiac output (CO). Mean wet weight to dry weight ratios of lung tissue samples were calculated. Following baseline measurements, dogs were injected intravenously (IV) with ANTU 5 mg / kg (n = 16) and 10 mg / kg (n = 8) and half of the dogs were randomly selected to receive 75 mg / kg FDP (10%) and subsequent infusion of 7 mg / kg / min. The rest were given 0.9% NaCl in the same manner. Four hours after ANTU administration, the animals were euthanatized. Except for decline in the CO (nonsignificant), no significant changes in systemic hemodynamics within and between the groups were noted. In the FDP group, PaP and pulmonary arteriolar resistance (PaR) remained unchanged. In the saline group, PaP increased from 12.5 ± 2.44 to 21.8 ± 3.14 mm Hg (P <. 001) and PaR from 166 ± 29 to 468 ± 74 dynes · cm / sec 5 (P <. 005). During the study LVDEP, PaO 2, PaCO 2, and hematocrit did not change significantly within and between the groups. The lungs mean wet weight to dry weight ratios for the sham-operated dogs were 4.20 ± 0.41, for the FDP group 4.32 ± 0.59 and 6.22 ± 1.37 for the saline group (P <. 0005). These data indicate that FDP protected the lung from ANTU-induced injury.

Protective Effects of Misoprostol on Carbon Tetrachloride-Induced Liver Damage in the Rat

Effects of misoprostol on histologic and biochemical alterations caused by CCl4 were investigated in the rat. Misoprostol protected against CCl4-induced liver injury. A close correlation occurred between biochemical data and morphological changes. This hepatoprotective effect was observed only when misoprostol was given 30 min before CCl4.

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.