Mechanism of the enhancing effect of sorbitol on ileal Ca uptake in rat enterocytes

The effect of sorbitol on Ca uptake by isolated ileal epithelial cells was investigated. Intestinal cells were isolated from rat ileum by mechanical vibration.⁴⁵Ca uptake was approximately 2 times higher in cells exposed to 200 mM sorbitol ofd-alanine than in control cells. This enhancing effect of sorbitol on percentage Ca uptake decreased with increasing Ca concentrations in the incubation medium suggesting an effect on Ca entry velocity. The addition of 10 M nifedipine or 200 M verapamil to the incubation medium was devoid of any effect on Ca uptake in ileal cells, whereas 100 M trifluoperazine or chlorpromazine abolished the stimulatory effect of sorbitol. Finally, the effect of sorbitol on isolated cells was independent of a measurable change of cellular ATP content. In conclusion, the stimulatory effect of sorbitol on ileal Ca uptake is probably exerted through mechanisms other than an increase in intracellular ATP concentration. Sorbitol may enhance enterocyte Ca transport via a direct interaction with calmodulin and/or the Ca pump. It may also exert its effect through an inhibition of the basolateral Na Ca exchanger.     

Role of red cell sorbitol as determinant of reduced erythrocyte filtrability in insulin-dependent diabetics

Summary Erythrocyte deformability measured as filtration index is clearly diminished in diabetics, thus possibly contributing to diabetes-associated microvascular complications. Moreover, the erythrocyte sorbitol level in IDD is clearly higher than that of non-diabetics, suggesting an alteration in the polyol pathway as possible determinant of diabetes-associated complications. Following this line of research, intracellular sorbitol as well as glucose, inositol, galactitol, mannitol and 2,3-diphosphoglycerate have been studied in 21 diabetics and in 14 controls matched for age and sex. In addition to confirming the high levels of intraerythrocytic glucose and sorbitol in diabetic subjects, statistically significant correlations have been demonstrated between sorbitol and filtration index, between plasma glucose, intracellular glucose level and glycosylated hemoglobin, suggesting a relationship between metabolic control and hemorheologic alterations in diabetes.     

High glucose-induced mesangial cell altered contractility: role of the polyol pathway

Summary Glomerular mesangial cells cultured in high glucose conditions display impaired contractile responsiveness. It was postulated that glucose metabolism through the polyol pathway leads to altered mesangial cell contractility involving protein kinase C. Rat mesangial cells were growth-arrested for 24 h with 0.5 % fetal bovine serum in either normal (5.6 mmol/l) or high (30 mmol/l) glucose concentrations or high glucose plus the aldose reductase inhibitor, ARI-509 (100 μmol/l). The reduction of cell planar surface area (contraction) in response to endothelin-1 (0.1 μmol/l), or to phorbol 12-myristate 13-acetate (50 pmol/l), was studied by videomicroscopy. In response to endothelin-1, mesangial cells in normal glucose contracted to 52 ± 3 % of initial planar area. In high glucose, the significantly (p < 0.05) smaller cell size and no contractile responsiveness to endothelin-1 were normalized with ARI-509. Membrane-associated diacylglycerol, measured by a kinase specific ³²P-phosphorylation assay, in high glucose was unchanged after 3 h, but significantly increased (p < 0.05) after 24 h which was normalized with ARI-509. Protein kinase C activity, measured by in situ ³²P-phosphorylation of the epidermal growth factor receptor substrate was: increased by 32 % at 3 h of high glucose, unchanged by ARI-509; and decreased significantly (p < 0.05) at 24 h compared to cells in normal glucose, normalized by ARI-509. Total cellular protein kinase C-alpha, -delta and -epsilon, analysed by immunoblotting, were unchanged in high glucose at 24 h. Only protein kinase C-epsilon content was reduced by ARI-509 in both normal and high glucose. Therefore, high glucose-induced loss of mesangial cell contractility, diacylglycerol accumulation and altered protein kinase C activity are mediated through activation of the polyol-pathway, although no specific relationship between elevated diacylglycerol and protein kinase C activity was observed. In high glucose, altered protein kinase C function, or another mechanism related to the polyol pathway, contribute to loss of mesangial cell contractile responsiveness. [Diabetologia (1998) 41: 507–515] Received: 18 July 1997 and in final revised form: 17 January 1998     

Isoflavonoids from the rhizomes of Belamcanda chinensis and their effects on aldose reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues

Aldose reductase, the key enzyme of the polyol pathway, is known to play important roles in the diabetic complication. The inhibitors of aldose reductase, therefore, would be potential agents for the prevention of diabetic complications. To evaluate active principles for the inhibition of aldose reductase from the rhizomes of Belamcanda chinensis, twelve phenolic compounds were isolated and tested for their effects on rat lens aldose reductase. As a result, isoflavones such as tectorigenin, irigenin and their glucosides were found to show a strong aldose reductase inhibition. Tectoridin and tectorigenin, exhibited the highest aldose reductase inhibitory potency, their IC50 values, being 1.08 x 10(-6) M and 1.12 x 10(-6) M, respectively, for DL-glyceraldehyde as a substrate. Both compounds, when administered orally at 100 mg/kg for 10 consecutive days to streptozotocin-induced diabetic rats, caused a significant inhibition of sorbitol accumulation in the tissues such as lens, sciatic nerves and red blood cells. Tectorigenin showed a stronger inhibitory activity than tectoridin. From these results, it is suggested that tectorigenin is attributed to be a promising compound for the prevention and/or treatment of diabetic complications.     

A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes

We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis.     

Teat tablet with sodium ibuprofen: the effect of sorbitol on therapeutic agent pharmaceutical availability and on physicochemical parameters of a drug form

Dosing pediatric drugs available on pharmaceutical markets of analgesic, antifebrile and anti-inflammatory activity to children up to 3 years of age is not precise and frequently causes problems. The aim of the study was to work out a pediatric teat form of a drug with sodium ibuprofen and to determine the effect of sorbitol content on pharmaceutical availability of the therapeutic agent. Three variants of tablets containing 50 mg of sodium ibuprofen differing in the percentage content of sorbitol (from 37% - batch I to 79% - batch III) were produced. Quality tests of the produced forms of drugs (PPVI) were performed and the tests of therapeutic agent pharmaceutical availability by spatula method and by a method with a teat. Tablets of all batches had a smooth surface and same shape. The content of the therapeutic agent was within the limit of 95-105% of the declared value. The highest value of Q coefficient in the release test by pharmacopeal method and the shortest disintegration time (12 minutes) were obtained for tablets with 79% content of sorbitol. In conclusion, teat tablets with sodium ibuprofen of the highest sorbitol content (79%) demonstrated the expected physicochemical parameters and high pharmaceutical availability.     

山梨醇对籼稻愈伤组织培养的效应

以6个籼稻品种为供试材料,研究结果肯定了培养基中附加成分山梨醇在愈伤组织继代培养中,具有促进愈伤组织生长及提高其分化潜力的效果;籼稻亚种中的不同品种,愈伤组织的生长及再生植株能力,在继代培养的后期表现出明显的品种特异性;分化培养基中加入不同浓度配比激素,对诱导器官分化的效果有明显差别,激动素(KT)与萘乙酸(NAA)的比例为5:1有利于取得根、芽生长的同步性。     

EFFECT OF ERYTHROCYTES AND PROSTACYCLIN PRODUCTION IN THE EFFECT OF FRUCTOSE AND SORBITOL ON PLATELET ACTIVATION IN HUMAN WHOLE BLOOD IN VITRO

We analyzed the in vitro effects of sorbitol and fructose on platelet function. Sorbitol and fructose increased platelet aggregation induced with adenosine diphosphate (ADP) or collagen in whole blood, but had no effect in platelet-rich plasma. The concentration that increased basal aggregation by 50% with ADP as the inducer was 12.89 ± 1.55 mmol/L for fructose, and 18.99 ± 2.01 mmol/L for sorbitol. When collagen was the inducer, these concentrations were 15.02 ± 0.98 mmol/L for fructose, and 12.94 ± 1.57 mmol/L for sorbitol. Both sugars increased, in a concentration-dependent way, the proaggregatory effect of erythrocytes, and erythrocyte uptake of adenosine. Time to uptake of 50% adenosine was 2.1 ± 0.3 min in control samples, 0.14 ± 0.01 min in the presence of fructose, and 0.23 ± 0.03 min with sorbitol. Both sugars reduced vascular prostacyclin synthesis, with 50% inhibitory concentrations of 26.48 ± 1.97 mmol/L for fructose, and 39.53 ± 2.81 mmol/L for sorbitol. Both sugars also increased arterial lipid peroxidation by 30% (sorbitol) and 23% (fructose). We conclude that these two sugars enhance platelet function and disrupt the thromboxane/prostacyclin ratio. © 1997 Elsevier Science Ltd