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SM-130686, an oxindole derivative, is a novel orally active GH secretagogue (GHS) which is structurally distinct from previously reported GHSs such as MK-677, NN703 and hexarelin. SM-130686 stimulates GH release from cultured rat pituitary cells in a dose-dependent manner. Half-maximum stimulation was observed at a concentration of 6.3+/-3.4 nM. SM-130686-induced GH release was inhibited by a GHS antagonist, but not by a GH-releasing hormone antagonist. SM-130686 dose-dependently inhibited the binding of radiolabeled ligand, (35)S-MK-677, to human GHS receptor 1a (IC(50)=1.2 nM). This indicates that SM-130686 stimulates GH release through the GHS receptor. The effect of a single oral administration of SM-130686 on GH release in pentobarbital-anesthetized rats was studied. After treatment with 10 mg/kg SM-130686, plasma GH concentrations measured by radioimmunoassay significantly increased, reaching a peak at 20-45 min, and remained above baseline during the experimental period (60 min). The anabolic effect of repetitive SM-130686 administration was studied in rats. Rats received 10 mg/kg SM-130686 orally twice a day and were weighed every day for 9 days. At day 9 there was a significant increase in both the body weight and the fat free mass (19.5+/-2.1 and 18.1+/-7.5 g respectively). Serum IGF-I concentration was also significantly elevated 6 h after the last dose of SM-130686. An endogenous GHS ligand for the GHS receptor has recently been identified from stomach extract and designated as ghrelin. The GH-releasing activity in vitro relative to ghrelin (100%) was about 52% for SM-130686. It is likely that SM-130686 is a partial agonist for the GHS receptor. In summary, we describe here an orally active GHS, SM-130686, which acts through the GHS receptor. Repetitive administration of SM-130686 to rats, similar to repetitive administration of GH, significantly increased the fat free mass by an amount almost equal to the gain in body weight.
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An accelerated polyol pathway in diabetes contributes to the development of diabetic complications. To elucidate diabetic nephropathy involving also renal tubular damage, we measured urinary sorbitol concentration concomitantly with urinary N-acetyl-D-glucosaminidase (NAG) excretion in WBN-kob diabetic rats.Twenty-four-hour urinary sorbitol concentrations increased in the diabetic rats in parallel with whole blood sorbitol concentrations. An increase in 24-h urinary NAG excretion coincided with the elevated urinary sorbitol levels in the diabetic rats. The administration of epalrestat, an aldose reductase inhibitor, reduced the increased whole blood and urinary sorbitol concentrations and urinary NAG excretion concomitantly with renal aldose reductase inhibition in the diabetic rats.These results indicate that diabetic nephropathy involves distorted cell function of renal tubules, and that treatment with epalrestat may prevent at least the progress of the nephropathy.
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Free radicals, hydroxyperoxides and H(2)O(2) are all known to damage cell components. This study was designed to compare the concentrations of hydroxyperoxide and free radical scavengers in the cardiac muscles of old rats in the hyper- or hypothyroid condition, to determine whether rates of peroxidation would differ with age, thyroid status, or both. Rats were rendered hyper- or hypothyroid by administration of l-thyroxine or methimazole for 4 weeks. Among the old rats, the lipid peroxide (LPO) concentrations, measured as thiobarbituric acid (TBA) reactants, were significantly greater in the hyperthyroid than in the euthyroid state and the LPO concentrations measured as TBA+Fe(3+) reactants, which may be precursors of LPO, were significantly greater in the hyperthyroid state, whereas in young rats, the LPO concentrations measured by TBA or TBA+Fe(3+) methods did not differ significantly in the hyperthyroid state. In the euthyroid state, the concentration of LPO measured as TBA+Fe(3+) reactants was significantly reduced with age. Xanthine oxidase (XOD) activity also was markedly increased with age, being more pronounced in the hyperthyroid than in the euthyroid state. The Mn and Cu/Zn superoxide dismutase activities were greater in the hyperthyroid than in the euthyroid state. Glutathione peroxidase activity decreased with age in the euthyroid and, particularly, in the hyperthyroid state. Catalase activity was not affected in the old rats. Concentrations of alpha-tocopherol in the old rats were high in the hyperthyroid state and low in the hypothyroid state, whereas the levels of beta- and gamma-tocopherols in these rats were unchanged in both conditions as compared with the euthyroid state findings. Data suggest that the site of free radical generation differs in older rats, with additional shifts in the location of intracellular lipid peroxidation being noted during hyperthyroidism. Thus, as rats age, the reduction of the free radical scavenger system and the increase in LPO and XOD activities might induce myocardial dysfunction.
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The deterioration of glucose metabolism frequently observed in hyperthyroidism may be due in part to increased gluconeogenesis in the liver and glucose efflux through hepatocyte plasma membranes. Glucose transporter 2 (GLUT 2), a facilitative glucose transporter localized to the liver and pancreas, may play a role in this distorted glucose metabolism. We examined changes in the levels of GLUT 2 in livers from rats with l-thyroxine-induced hyperthyroidism or methimazole-induced hypothyroidism by using Western blotting to detect GLUT 2. An oral glucose tolerance test revealed an oxyhyperglycemic curve (impaired glucose tolerance) in hyperthyroid rats (n=7) and a flattened curve in hypothyroid rats (n=7). GLUT 2 levels in hepatocyte plasma membranes were significantly increased in hyperthyroid rats and were not decreased in hypothyroid rats compared with euthyroid rats. The same results were obtained with a densitometric assay. These findings suggest that changes in the liver GLUT 2 concentration may contribute to abnormal glucose metabolism in thyroid disorders.
