6-ketoprostaglandin-f1-alpha and sorbinil

The effect of two structurally unrelated aldose reductase inhibitors, sorbinil and ponalrestat, on glomerular prostaglandin production and urinary albumin excretion was investigated in rats with diabetes induced by streptozotocin. It was found that both aldose reductase inhibitors, when administered from the time of induction of the diabetes, significantly decreased the raised urinary albumin excretion in the diabetic rats, although it remained elevated compared with non-diabetic rats. Glomerular prostaglandin E and 6-keto-prostaglandin F1 alpha production was significantly increased in glomeruli obtained from the diabetic rats. Inhibition of aldose reductase caused a reduction in the raised glomerular prostaglandin production, although this remained above that observed in the non-diabetic rats. Subsequent experiments were performed to determine whether the effects of the aldose reductase inhibitors could be explained by effects on glomerular filtration rate. It was found that ponalrestat, at a dose which markedly reduced urinary albumin excretion, did not significantly affect glomerular filtration rate in non-diabetic rats, rats with untreated streptozotocin-induced diabetes and rats with diabetes partially treated with low dose insulin. Glomerular sorbitol concentrations were significantly elevated in untreated diabetic rats as early as two weeks after the induction of diabetes. It is concluded that the administration of aldose reductase inhibitors from the time of induction of diabetes significantly reduces glomerular prostaglandin production and urinary albumin excretion. The latter effect is not due to an effect on glomerular filtration rate. Increased polyol pathway activity may account in part for the increased glomerular prostaglandin production and urinary albumin excretion in early experimental diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Hypoglycemic Agents; Imidazoles; Imidazolidines; Kidney Glomerulus; Male; Phthalazines; Prostaglandins E; Rats; Rats, Inbred Strains; Reference Values

Increased renal production of prostaglandins (PG) may contribute to the hyperfiltration that accompanies early diabetes. It was postulated that a putative metabolic abnormality of diabetes, ie, increased flux through the polyol pathway, stimulates renal PG production and that this phenomenon can be prevented by aldose-reductase inhibition. To test this hypothesis, the effects of polyol accumulation on urinary excretion rates (UER) of PGE2 and 6-keto-PGF1 alpha were studied, using the galactose-fed rat model. UER of PGE2 and 6-keto-PGF1 alpha were measured in three groups of weanling Wistar male rats. Group 1 was maintained on normal chow (n = 6), group 2 was fed chow supplemented with 30% galactose (n = 6), and group 3 received chow supplemented with 30% galactose and 0.7% sorbinil (n = 6). Ten 24-hour urine samples were obtained from each group between 151 and 240 days on the respective diets. UER of PGE2 (P less than .001) and 6-keto-PGF1 alpha (P less than .01) were higher in group 2 than in group 1. UER of PGE2 (NS) and 6-keto-PGF1 alpha (NS), respectively, were similar in groups 1 and 3. These data indicate that flux through the polyol pathway modulates the UER of PGE2 and 6-keto-PGF1 alpha. This phenomenon may contribute to the glomerular hyperfiltration of early diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aldehyde Reductase; Animals; Dietary Carbohydrates; Dinoprostone; Galactose; Imidazoles; Imidazolidines; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values

Previous studies have suggested a link between hyperfiltration and enhanced polyol pathway activity in the streptozotocin diabetic rat. In the present study we examined the relationship between glomerular sorbitol content, a measure of polyol pathway activity and glomerular filtration rate (GFR), as a function of plasma glucose and time after induction of diabetes. GFR is increased by 1 to 2 weeks in the untreated streptozotocin diabetic rat but falls to values equal to or below control by 2 months. Treatment of diabetic rats with a low dose of insulin to achieve moderate hyperglycemia results in the maintenance of elevated GFR for 2 months. Glomerular sorbitol content in the 1- to 2-week diabetic rats was not significantly different from values in glomeruli from control rats at 1 to 2 weeks but was 11-fold higher than control by 2 months in the untreated diabetic rat. Treatment of diabetic rats with insulin to achieve moderate hyperglycemia resulted in values for glomerular sorbitol content that were not different from control. Thus, elevated GFR was not associated with elevated glomerular sorbitol content in the 1- to 2-week diabetic rat and was dissociated from elevated glomerular sorbitol content in the 2-month diabetic rat. Treatment of 1- to 2-week diabetic rats with sorbinil prevented the rise in GFR observed at this time despite the fact that sorbitol content of glomeruli was not elevated. These results suggested that sorbinil was reducing GFR in the diabetic rat by a mechanism other than aldose-reductase inhibition. The synthesis of vasodilatory prostaglandins by isolated glomeruli and the activity of phospholipase A2 in the particulate cell fraction of glomerular homogenates is higher in 1- to 2-week diabetic rats compared with controls, a finding that may contribute to the elevated GFR in these rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dinoprostone; Female; Fructose; Glomerular Filtration Rate; Imidazoles; Imidazolidines; Kidney; Kidney Glomerulus; Organ Size; Phospholipases A; Phospholipases A2; Rats; Rats, Inbred Strains; Reference Values; Sorbitol; Sugar Alcohol Dehydrogenases