Intracellular ATP (ATPi)-sensitive K+ [K+(ATP)] channels are now a recognized site of action of clinically useful hypoglycemic and hyperglycemic sulfonamides. We have further examined the action of these agents on single K+ channels in rat pancreatic B-cells 1) Tolbutamide and glyburide, two hypoglycemic sulfonylureas which decrease K+(ATP) channel activity in the cell-attached patch, affect the kinetics of K+(ATP) channel in a manner similar to glucose. They shorten the duration of the "burst," or cluster of open channel events, while lengthening the intervals between bursts. 2) The hyperglycemic vasodilator diazoxide increases mean K+(ATP) channel activity in the cell-attached patch as well as in the inside-out excised patch exposed to ATPi. It appears to lengthen channel bursts and shorten the intervals between them. Two structurally similar diuretics, hydrochlorothiazide and furosemide, which have mild hyperglycemic effects, do not increase K+(ATP) channel activity even at clinically toxic concentrations. 3) Neither the sulfonylureas nor diazoxide directly affect the activity of single delayed rectifier K+ channels or single calcium and voltage-activated K+ channels in normal B-cells.

In patch-clamped surface cells of human islets, we identified an inwardly rectifying, voltage-independent K+ channel that may be a crucial link between substrate metabolism and depolarization-induced insulin secretion. It is the major channel open at rest. It closes on exposure of the cell to secretagogue concentrations of glucose or other metabolic fuels and oral hypoglycemic sulfonylureas but reopens on addition of either a metabolic inhibitor that prevents substrate utilization or the hyperglycemic sulfonamide diazoxide. Onset of electrical activity coincides with channel closure by the secretagogues. In excised patches, the activity of this channel is inhibited at its cytoplasmic surface by ATP. These results suggest that in humans, as in rodents, 1) rises in cytoplasmic ATP levels during substrate metabolism trigger K+-channel closure and cell depolarization and 2) clinically useful sulfonamides modulate glucose-induced insulin secretion, in part by affecting a readily identifiable resting conductance pathway for K+.

SummaryHemorrhage is one of the most serious complications of chronic liver disease. Deficiency of plasma coagulation factors, thrombocytopenia, and increased vascular fragility have been reported in many patients with Laennec’s cirrhosis. Factors V, VII, IX, X and prothrombin were deficient in a majority of the 25 patients included in this study.Six tests of liver function and seven of plasma coagulation factors were evaluated, using the method of statistical regression analysis. The intercorrelation of tests in each group was evaluated as well as the correlation between liver function tests and plasma coagulation factors. Fibrinogen deficiency was not felt to play a significant role in hemorrhagic diathesis in our cases.

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