1. Investigación

Rats chronically treated with two daily doses of tolbutamide, glibenclamide or glipentide were compared with animals treated with placebo. Plasma individual amino acids were determined at 0, 3, 7, 10, 12, 14, 17, 24, 27 and 29 days of treatment 16 hours after the administration of the drug. Rats were fasted for 48 h periods at days 10 to 12 and 27 to 29 of the experiment. Sulfonylurea treated animals show minor changes in the plasma aminogram, although glipentide and glibenclamide produced greater effects than tolbutamide. At the 3rd day after the onset of the treatment, plasma levels of glutamate+ glutamine, arginine and histidine appeared significantly reduced in glipentide and glibenclamide treated animals. When plasma samples were collected 3 h after the drug administration at the 24th day of treatment, the only observed change was a decrease in the levels of arginine in the glipentide treated animals. Fasting produced decreases in plasma levels of alanine, pro line, cysteine, tyrosine, methionine +ornithine and tryptophan, there were no changes in serine, aspartate + asparagine, threonine citruline, arginine and lysine; and glycine, glutamate+ glutamine and leucine + isoleucine show increases. These changes were rapidly compensated with refeeding, appearing a "rebound effect" in certain amino acids. Both fasting and refeeding affect very little the effect of sultonylureas on plasma amino acid levels, although for some individual amino acid they reduce or enhance the effect of the fasting. These small effect of sulfonylureas on plasma amino acid levels could be the result of the juxtaposition of different factors, including the effects of these drugs on circulating insulin levels, on protein biosynthesis and amino acids transamination and hepatic gluconeogenesis.

Female rats were treated with two daily equihypoglycemic doses (as observed in acute treatment) of tolbutamide, glibenclamide or glipentide . by stomach tube, and were compared with control ammals treated with the suspending medium alone. On day 29 the rats were subjected to a 48 h fast and then were injected intraperitoneally with 100 .μMoles of C' -alanine. Blood samples were collected before and 5, 15 and 30 minutes after the alanine injection, at which time the animals were killed. Blood glucose levels increased after the injection of alanine in all groups, but at the different times stll:died, both the glibenclamide and glipentide treated_ anu_n~ls showed hypoglycemia versus controls. The rad10act1:"1ty found in blood glucose and liver glycogen and glycendeglycerol decreased in the glibenclamide treated anima~s compared with controls while in the other groups 1t was similar. The increase in liver glycogen after the injection of alanine was also diminished in the_ glibenclamide treated animals. Alanine produced an mcrease in the plasma levels of gluconeogenic, basic, aromatic and sulphur-containing amino acids in the controls, while in the animals treated with glipentide the alanine effect was less pronounced. The results show an impairment of gluconeogenic function in glibenclamide treated animals. The effects of both tolbutamide and glipentide were less dramatic. Nevertheless, the findings hinted at an effect of both drugs upon glycogen metabolism in liver.