[Treatment of diabetes mellitus with tolazamide].
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Diabetes Mellitus↗
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[Jaundice in diabetics treated with sulfonylureas. On a clinical case of jaundice caused by tolazamide].
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Aged↗
In vitro effects of a sulfonylurea on insulin action in adipocytes. Potentiation of insulin-stimulated hexose transport.
The mechanism(s) by which the oral sulfonylurea, tolazamide, exerts its extrapancreatic hypoglycemic effects was studied using rat epididymal adipose tissue maintained 20-44 h in the presence or absence of the drug. Insulin binding, hexose transport and glucose metabolism were compared in adipocytes isolated from the cultured tissue. In contrast to earlier reports that suggested that sulfonylureas alter the binding of insulin, neither receptor number nor affinity were changed by tolazamide treatment. The uptake of the glucose analogs 2-deoxyglucose and 3-0-methylglucose in the absence of insulin (i.e., basal) was also unchanged. However, exposure to tolazamide resulted in a potentiation of the stimulatory effects of insulin by approximately 30% at each hormone concentration assayed (0.4-40 ng/ml). This potentiation was dependent on the tolazamide concentration (0.003-0.30 mg/ml), with a maximal effect observed at therapeutic levels. A tolazamide analog hypoglycemic activity in vivo was found not to enhance either basal or insulin-stimulated uptake in vitro. Conversion of 0.1-5.0 mM glucose to CO2 and total lipids in the presence of insulin was also potentiated by tolazamide treatment. The inability of the drug to directly stimulate basal glucose uptake was paralleled by its lack of effect on glucose metabolism. At 50 mM glucose, where transport is no longer rate-limiting, tolazamide did not potentiate metabolism in the absence or the presence of insulin. These studies demonstrate that tolazamide in vitro alters postreceptor insulin action without influencing the receptor, and suggests insulin-stimulated hexose transport as the cellular process responsible for the hypoglycemic effect of sulfonyureas in adipose tissue.
Adipose Tissue↗
Potentiation of insulin action by a sulfonylurea in primary cultures of hepatocytes from normal and diabetic rats.
Although sulfonylureas have been used extensively in the treatment of non-insulin-dependent (type II) diabetes, controversy exists as to whether these agents act primarily by increasing insulin secretion or by enhancing insulin action. To determine whether sulfonylureas potentiate insulin action in the liver, we evaluated the ability of the sulfonylurea tolazamide to affect insulin-sensitive lipogenesis utilizing primary cultures of hepatocytes prepared from both normal and nonketotic streptozotocin-diabetic rats. Hepatocytes were cultured for 16 h in serum-free media with no additions, tolazamide alone (0.3 mg/ml), or insulin (10(-10) to 10(-7)M) in the absence and presence of tolazamide. Following culture, lipogenesis and specific insulin binding were assessed. Dose-dependent increases in lipogenesis were found in hepatocytes from both normal and diabetic rats after the chronic exposure to insulin. In hepatocytes from diabetic rats, the basal and the maximal insulin-stimulated rates of lipogenesis were only 27% and 13% of normal, respectively, establishing this as a model of hepatic insulin resistance. In the presence of tolazamide, significant potentiation of insulin action was found in hepatocytes from normal and diabetic rats although hepatocytes from diabetic animals remained relatively resistant to insulin when compared with those from nondiabetic animals. While exposure to tolazamide increased insulin responsiveness in both groups of cells, no changes in insulin sensitivity (ED50) were observed. Tolazamide significantly increased insulin binding (12%) in hepatocytes from normal rats cultured in the absence of insulin, but no alterations in insulin binding were found under incubation conditions in which tolazamide potentiated insulin action. These results give the first direct evidence for an insulin-dependent action of a sulfonylurea on the liver from both normal and diabetic rats and indicate that the enhancement of insulin responsiveness occurs through postbinding mechanisms.
Animals↗
Selective unresponsiveness of pancreatic beta-cells to acute sulfonylurea stimulation during sulfonylurea therapy in NIDDM.
Patients with non-insulin-dependent diabetes mellitus (NIDDM) who have chronic hyperglycemia lose acute incremental insulin responses to glucose but are able to briskly respond to other beta-cell secretagogues. To investigate whether this is a defect specific for glucose or represents a more general phenomenon, we measured the insulin responses to acute intravenous tolbutamide in 10 obese patients with NIDDM both before and during sulfonylurea therapy with tolazamide. Comparable glycemia was achieved with oral dextrose 2 h before intravenous testing. To assess beta-cell responsiveness to a nonsulfonylurea secretagogue, 1 mg glucagon was administered intravenously during tolazamide therapy. In seven patients, the mean peak insulin increment 5 or 10 min after intravenous tolbutamide was 54 +/- 11 microU/ml when not receiving tolazamide (0.14 +/- 1.3 microU/ml) with tolazamide (P less than .001), even though serum insulin responded rapidly to intravenous glucagon. In four patients tested for reversibility of their refractoriness to intravenous tolbutamide during chronic tolazamide therapy, the mean peak insulin increment 1 wk after discontinuing tolazamide was 79 +/- 22 microU/ml. A relatively rapid development of refractoriness was documented in four patients who were tested only 12 h after beginning tolazamide therapy; the mean peak insulin increments 5-10 min after intravenous tolbutamide were undetectable (-0.5 microU/ml), yet responses to intravenous glucagon were evident. In these NIDDM patients, exposure of pancreatic beta-cells to sustained levels of sulfonylureas induces a reversible state of refractoriness to acute stimulation with sufonylureas but not to another secretagogue.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Augmentation of the effects of insulin and insulin-like growth factors I and II on glucose uptake in cultured rat skeletal muscle cells by sulfonylureas.
The effect of sulfonylureas on long-term regulation of glucose uptake by insulin and insulin-like growth factors has been studied in the L6 line of cultured skeletal muscle cells. These cells have previously been shown to possess many characteristics of differentiated skeletal muscle and to bind and respond to physiological concentrations of insulin and insulin-like growth factors I and II. Tolazamide (half-maximal at 0.2 mg/ml) augments the effects of insulin, insulin-like growth factor I, and insulin-like growth factor II on glucose uptake, increasing both sensitivity and maximal efficacy of the hormones. In the absence of added hormone, tolazamide has no effect on glucose uptake. A similar increase in insulin-stimulated glucose uptake with unaltered basal uptake occurs with glyburide (half-maximal at 0.5 microgram/ml). The action of tolazamide requires long-term exposure to the sulfonylurea (22 h) and is inhibited by cycloheximide, suggesting a process that involves new protein synthesis. In contrast to glucose uptake, amino acid uptake in L6 cells is increased by tolazamide in the absence of hormones. Insulin and the insulin-like growth factors also stimulate amino acid uptake, but this effect is not further augmented by tolazamide. Thus, sulfonylureas appear to directly modulate amino acid uptake, but to indirectly augment glucose uptake through an effect on insulin and insulin-like growth factor stimulated pathways. Neither insulin binding nor insulin degradation is altered by tolazamide, indicating a post-binding mechanism of action. The L6 cultured skeletal muscle cell line should be useful in future studies on the mechanism of the extrapancreatic actions of sulfonylureas.
Aminoisobutyric Acids↗
Processing and transport of insulin by vascular endothelial cells. Effects of sulfonylureas on insulin receptors.
Polypeptide hormones such as insulin must cross the vascular barrier to mediate their biologic actions. A substantial vascular barrier may be encountered in muscle and fat tissues, which are supplied by continuous capillaries lined with tightly joined endothelial cells. Endothelial cells have previously been shown to bind and release insulin with minimal degradation. Because 125I-labeled insulin transport was demonstrated to be receptor-mediated, factors regulating insulin-receptor binding may also affect the insulin transport rate across the vascular barrier. Since sulfonylureas may have a glucose-lowering action by altering insulin receptors, the effects of tolazamide and glyburide on vascular endothelial cell insulin receptors were evaluated. Exposure of aortic endothelial cells in culture to insulin at 37 degrees C resulted in a 75 percent loss of receptors. Five to seven days of tolazamide exposure led to a 35 percent time-dependent increase in insulin binding. More strikingly, tolazamide altered the dose-receptor to insulin-induced down-regulation. Cells down-regulated with insulin (10 ng/ml) showed a 100 percent increase in binding in the presence of tolazamide; a dose-dependent effect occurred at the 75 to 200 micrograms/ml dosage level. Scatchard analysis indicated that the increase in 125I-labeled insulin binding was due to an increase in receptor number. When insulin receptors were identified with 125I-labeled insulin, tolazamide-treated cells clearly showed an increase of a band at Mr = 145 K, the alpha subunit of the receptor. Tolazamide may thus help normalize glucose in diabetes by preventing receptor down-regulation in endothelial cells.
Blood Vessels↗
Coordinate regulation of glucose transporter function, number, and gene expression by insulin and sulfonylureas in L6 rat skeletal muscle cells.
The extrapancreatic actions of sulfonylureas on the glucose transport system were studied in the L6 line of cultured rat skeletal muscle cells. Insulin (10(-7) M) increased 2-deoxyglucose uptake in differentiated L6 myotubes by 30-40% after 8 h of incubation. The sulfonylurea tolazamide (0.6 mg/ml, 22 h) had no effect on glucose uptake in the absence of insulin, but increased insulin-stimulated 2-deoxyglucose uptake twofold. The total cellular content of glucose transporters was assessed with a monoclonal anti-transporter antibody by a solid-phase ELISA method. Insulin (8 h) increased the quantity of glucose transporters, with a maximal twofold increase at 10(-7) M and a dose-response curve similar to that for insulin stimulation of glucose uptake. In spite of its lack of effect on glucose uptake, tolazamide alone (0.6 mg/ml) increased the cellular content of transporters by 70%. The effects of insulin and tolazamide on transporter gene expression were studied with probes derived from Hep G2 glucose transporter cDNA. Insulin increased the transporter mRNA level 1.7-fold, tolazamide increased it 1.5-fold, and the combination of insulin and tolazamide increased transporter mRNA 3-fold. It is concluded that sulfonylureas, together with insulin, enhance glucose uptake in L6 skeletal muscle cells by increasing the number of functioning glucose transport molecules. The long-term regulation of the glucose transport system in skeletal muscle by insulin and sulfonylureas in vivo may involve similar changes in transporter function, number, and gene expression.
Animals↗
Effects of oral antihyperglycemic agents on extracellular matrix synthesis by mesangial cells.
BACKGROUND: Increased expression of the glucose transporter GLUT1 in mesangial cells (MCs) markedly stimulates glucose transport and the formation of extracellular matrix (ECM), even when ambient glucose concentrations are low. Certain antihyperglycemic agents cause GLUT1 overexpression and increase glucose transport in various tissues. However, their effects on the kidney are unknown. Because diabetic glomerulosclerosis is characterized by the accumulation of mesangial matrix, was studied the effects of antihyperglycemic agents on matrix metabolism in MCs cultured either in 8 or 20 mM glucose. METHODS: Membrane-associated GLUT1 was measured by immunoblotting. The initial rate of glucose transport was determined according to the 2-deoxy-D[14C(U)]glucose uptake. Collagen metabolism was studied by metabolic radiolabeling with [14C]-proline. Fibronectin in the medium was measured by ELISA. GLUT1 mRNA was estimated by Northern analysis. RESULTS: The sulfonylurea tolazamide increased GLUT1 protein expression by 107 and 69% in 8 and 20 mM glucose-grown cells, respectively. However, GLUT1 mRNA levels remained unchanged. Transporter-dependent deoxyglucose uptake was increased by tolazamide up to 184% in a dose-dependent fashion and was evident at both glucose concentrations after three or five days of exposure to the drug. Tolazamide significantly stimulated transforming growth factor-beta 1 (TGF-beta 1) secretion and the total synthesis of collagen and collagen and fibronectin accumulation in the medium of MCs maintained in high or low glucose concentrations. The biguanide metformin did not alter GLUT1 expression, glucose transport, fibronectin formation, or collagen metabolism, except at high concentrations. CONCLUSION: Tolazamide markedly enhances ECM synthesis and accumulation in MCs probably by stimulating GLUT1 expression, glucose transport and TGF-beta 1 secretion, irrespective of the ambient glucose concentration. This effect was dose-dependent and minimally inducible by metformin.
Administration, Oral↗
Gastric inhibitory polypeptide hypersecretion in diabetes mellitus: effect of sulfonylurea treatment.
We studied gastric inhibitory peptide (GIP) in response to a mixed meal in both adult-onset diabetics and normal controls. The adult-onset diabetic group was also studied for immunoreactive GIP (IR-GIP), insulin, and glucose with a test meal before and after tolazamide therapy. Mean basal and meal-stimulated IR-GIP concentrations were greater (P less than 0.05) in the adult-onset diabetic group than in normal controls. With treatment, mean fasting glucose significantly decreased (P less than 0.05) from 206 +/- 14 to 162 +/- 11 mg/dl, and postprandial glucose concentrations were reduced (P less than 0.05) between 5-180 min. In contrast, after 1 month of treatment with tolazamide, IR-GIP concentrations were not significantly altered. Further, basal and postmeal serum insulin levels were significantly higher (P less than 0.05) after tolazamide therapy. We conclude that the enteroinsular axis in terms of IR-GIP is overactive in adult-onset diabetics; tolazamide therapy does not appear to effect its meal-stimulated response.
Adult↗
Insulin and a sulfonylurea agent in non-insulin-dependent diabetes mellitus.
Using a double-blind crossover design, we studied the effect of tolazamide, an orally administered sulfonylurea, in 11 patients with non-insulin-dependent diabetes mellitus, poorly controlled on 40 units/day or more of insulin; all had previously failed to respond adequately to oral hypoglycemic agents and diet. In addition, six nondiabetic sex-, age-, and weight-matched controls were studied. Tolazamide significantly lowered fasting plasma glucose level from 272 +/- 21 to 222 +/- 31 mg/dL, increased fasting C peptide concentration from 0.09 +/- 0.03 to 0.28 +/- 0.10 pmole/mL (controls, 0.23 +/- 0.2 pmole/mL), and increased integrated C peptide concentration during a test meal (area under the curve) from 42 +/- 18 to 95 +/- 22 pmole/mL X min (controls, 94 +/- 8 pmole/mL X min). These data show that addition of tolazamide markedly increased fasting and meal-stimulated insulin secretion and modestly lowered fasting plasma glucose concentrations. We conclude that some patients who cannot achieve satisfactory control with oral hypoglycemic agents and diet may benefit from combined therapy with oral sulfonylurea agents plus insulin.
Administration, Oral↗
Prolonged sulfonylurea administration decreases insulin resistance and increases insulin secretion in non-insulin-dependent diabetes mellitus: evidence for improved insulin action at a postreceptor site in hepatic as well as extrahepatic tissues.
To determine whether long-term sulfonylurea therapy ameliorates glucose homeostasis in patients with NIDDM predominantly by improving insulin secretion or by improving insulin action, we evaluated changes in fasting plasma glucose concentrations, intravenous glucose tolerance, glucose-stimulated insulin secretion, facilitation of glucose disposal by exogenous insulin, and erythrocyte insulin receptor binding before and after prolonged (congruent to 4 mo) administration of tolazamide to 18 patients with NIDDM. Before tolazamide administration, 15 patients had decreased insulin secretion (50 +/- 31 vs 577 +/- 176 microU/ml X 10 min in nondiabetic subjects, P less than 0.05) and insulin resistance (Km 166 +/- 31 vs 58 +/- 3 microU/ml in nondiabetic subjects, P less than 0.05; Vmax 7.3 +/- 0.6 vs 9.8 +/- 0.2 mg/kg/min in nondiabetic subjects, P less than 0.05), whereas the other three patients had comparably impaired insulin secretion (56 +/- 52 microU/ml X min) but were not insulin resistant (Km 70 +/- 6 microU/ml; Vmax 10.8 +/- 0.6 mg/kg/min). The insulin-resistant patients had fasting hyperinsulinemia (19 +/- 4 vs 11 +/- 1 microU/ml in nondiabetic subjects, P less than 0.05), decreased erythrocyte insulin receptor binding (4.8 +/- 0.4 vs 5.8 +/- 0.3%/1.6 X 10(9) cells in nondiabetic subjects, P less than 0.05), and impairment in both insulin-induced suppression of glucose production (Km 97 +/- 31 vs 21 +/- 7 microU/ml in nondiabetic subjects, P less than 0.05), and insulin-induced stimulation of glucose utilization (Km and Vmax 176 +/- 29 microU/ml and 5.8 +/- 0.7 mg/kg/min vs 50 +/- 2 microU/ml and 9.1 +/- 0.6 mg/kg/min in nondiabetic subjects, both P less than 0.05). The nonresistant patients were not hyperinsulinemic (12 +/- micU/ml), had normal insulin receptor binding (5.9 +/- 0.5%/1.6 X 10(9) cells), and were less hyperglycemic than the insulin-resistant patients (128 +/- 11 vs 181 +/- 12 mg/dl, P less than 0.05). After tolazamide administration, both the early phase of glucose-induced insulin secretion (56 +/- 52 vs 141 +/- 68 microU/ml . 10 min) and insulin binding (5.9 +/- 0.5 vs 7.0 +/- 0.5%/1.6 X 10(9) cells) increased in all three nonresistant patients, but there was no consistent improvement in fasting hyperglycemia (128 +/- 11 vs 130 +/- 24 mg/dl), intravenous glucose tolerance (Kivgtt 0.77 +/- 0.18 vs 0.89 +/- 0.29%/min), or facilitation of glucose disposal by insulin (Km 70 +/- 5 vs 64 +/- 5 microU/ml; Vmax 10.8 +/- 0.6 vs 10.1 +/- 0.2 mg/kg/min).(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Effects of sulfonylureas, alpha-endosulfine counterparts, on glomerulosclerosis in type 1 and type 2 models of diabetes.
BACKGROUND: Previously, we showed the expression of a unique sulfonylurea receptor (SUR) and its putative endogenous ligand, alpha-endosulfine, in mesangial cells and isolated glomeruli. Further, this ligand was up-regulated by high glucose concentration. To investigate the possible role of alpha-endosulfine up-regulation in diabetes, we administered sulfonylureas, the exogenous ligands of SUR, to diabetic animals. METHODS: In streptozotocin-induced, insulin-deficient, diabetic rats, glomerulosclerosis, albuminuria, glomerular expression of fibronectin mRNA, and glomerular filtration rate (GFR) were studied for various periods up to 36 weeks. Several rat groups received either glibenclamide or tolazamide during the entire study period. Also, glomerulosclerosis and albuminuria were determined in insulin-resistant db/db mice, at 26 weeks of treatment with tolazamide. RESULTS: Sulfonylureas did not improve hyperglycemia or reduce glycosylated hemoglobin levels. In insulin-deficient diabetic rats, sulfonylureas significantly decreased the degree of glomerulosclerosis and completely reversed the enhanced albumin excretion. Also, glibenclamide reduced diabetes-induced glomerular overexpression of fibronectin mRNA. Because glibenclamide may improve the afferent arteriolar dilatation of diabetes, thereby reducing glomerular hyperfiltration, its effect on GFR was determined. Glibenclamide did not alter glomerular hyperfiltration or renal hypertrophy, regardless of the intensity of hyperglycemia. Finally, in insulin-resistant mice, tolazamide did not alter the extent of diabetic glomerulosclerosis or increased albuminuria. CONCLUSION: Long-term treatment with sulfonylureas completely prevents glomerular injury in insulin-deficient diabetes in rats. However, this protective effect is not demonstrable in an insulin-resistant model of the disease. We postulate that mesangial alpha-endosulfine up-regulation in the hyperglycemic milieu of insulin-deficient diabetes may retard glomerular extracellular matrix formation and mesangial expansion.
Animals↗
Sulfonylurea-induced inhibition of glucagon secretion from the perfused rat pancreas: evidence for a direct, non-paracrine effect.
The effects of sulfonylurea on glucagon secretion were characterized in the perfused rat pancreas using glibenclamide (1 microgram/ml) or tolazamide (10 micrograms/ml) in the presence of 3.3 mmol/l glucose. Glucagon release, which was unaffected by glibenclamide at 2.75 mmol/l calcium, was suppressed at 1.19 and 0.64 mmol/l but transiently stimulated at 0.25 mmol/l extracellular calcium. The insulinogenic effect of glibenclamide at 0.64 and 0.25 mmol/l calcium was enhanced by 35% and 89%, respectively, compared to the response at 2.75 mmol/l calcium. The stimulatory effect of the compound on somatostatin secretion, however, was lost at the lower calcium levels. The effects of tolazamide at 2.75 and 0.64 mmol/l calcium mimicked those of glibenclamide, thus indicating that our results with the latter compound may be representative for all sulfonylureas. In pancreata from insulin-deficient alloxan-diabetic rats, glibenclamide completely lost its inhibitory effect on glucagon release at 0.64 mmol/l calcium. Inhibition was not restored by adding insulin (25 U/l) to the perfusate. However, when diabetic rats had been treated with insulin for 6-7 days, glibenclamide suppressed glucagon release at low calcium levels in the absence of stimulated insulin and somatostatin release. It is concluded that, at low calcium concentrations, sulfonylureas suppress glucagon secretion by a direct action on the A cell and not through paracrine interactions by insulin and somatostatin. Prolonged insulin deficiency impairs the sulfonylurea action on glucagon secretion.
Animals↗
Effect of sulfonylurea therapy and plasma glucose levels on hemoglobin A1c in type II diabetes mellitus.
It is well known that hemoglobin A1c reflects plasma glucose concentrations in patients with diabetes mellitus. To examine hemoglobin A1c and plasma glucose relationships in sulfonylurea-treated patients, 25 patients with well-controlled type II diabetes (fasting plasma glucose 128 +/- 6 mg/dl, hemoglobin A1c 7.6 +/- 0.5 percent) were evaluated in a double-blind study. This study was divided into two phases (periods I and II). During period I each patient was given a diet plus a placebo and was followed every two weeks until the mean of two consecutive plasma glucose determinations was more than 50 mg/dl above the initial plasma glucose concentration obtained while the patient was taking sulfonylurea. At that point each patient was switched in a double-blind fashion to either diet plus a placebo or diet plus tolazamide. Fasting plasma glucose concentrations increased to 178 +/- 9 mg/dl (p less than 0.005) for all patients by week 2 of period I. The increase in hemoglobin A1c concentration was seen to lag behind the increasing fasting plasma glucose concentration by four to six weeks. Fasting plasma glucose and hemoglobin A1c concentrations returned to values indistinguishable from initial values in patients who were given tolazamide and who responded to it. A positive correlation was noted when the hemoglobin A1c concentration was compared with the fasting plasma glucose concentration measured four to six weeks previously.
Adult↗
Extrapancreatic action of sulfonylureas: hypoglycemic effects are not dependent on altered insulin binding or inhibition of transglutaminase.
It has been proposed by others that sulfonylureas exert their extrapancreatic hypoglycemic effects by increasing insulin binding through inhibition of receptor-mediated hormone internalization. In this study, we examined the possibility that the drugs act by inhibiting transglutaminase, an enzyme thought important in the internalization process. For ten days, male rats were fed pulverized chow containing either no drug, glipizide (5 mg/kg initial body wt/d), or tolazamide (75 mg/kg initial body wt/d). Prior to sacrifice, the six-hour fasting level of serum glucose was significantly reduced from 96 mg/100 ml in the control rats to 81 and 42 mg/100 ml in the glipizide- and tolazamide-treated rats, respectively. In contrast, the serum level of insulin was similar for all groups. The activity of transglutaminase in the postnuclear fraction of liver homogenate also was the same for all experimental groups. The specific binding of labeled insulin to purified liver plasma membranes was examined over a broad range of insulin concentrations; once again, there was no difference between experimental groups. Thus, the hypoglycemia caused by sulfonylurea administration could not be attributed to increases in insulin binding, inhibition of transglutaminase activity, or enhanced insulin levels. These data support our previous suggestion, based on in vitro studies, that sulfonylureas act predominately on processes beyond the binding portion of the insulin receptor.
Acyltransferases↗
Urinary diluting capacity in elderly diabetic subjects.
Urinary concentrating ability declines with normal human aging but diluting capacity has been less well studied as a function of age. We studied free water clearance (CH2O) in a group of Type II diabetic patients, aged 47 to 70 years. Conventional water load testing in sulfonylurea-treated diabetic patients revealed preservation of diluting capacity (ability to achieve Uosm less than 100 mOsm/kg) in subjects greater than 60 years of age. Tolazamide permitted expression of normal CH2O; chlorpropamide administration predictably reduced CH2O relative to tolazamide by 58% in subjects greater than 60 years. Free water clearance (CH2O) and glomerular filtration rate (GFR) were comparable in elderly subjects (greater than 60 years) and those less than or equal to 60 years. Normal CH2O in these diabetic patients was explained by persistently normal GFR in the study group. Osmolar clearance (Cosm) was insignificantly lower in diabetics greater than 60 years. Thus, a fall in CH2O in elderly diabetic patients is not a factor contributing to clinical hypoosmolar states encountered in this population.
Aged↗
Heterogeneity of the inhibitory influence of sulfonylureas on prostanoid-induced smooth muscle contraction.
In addition to their hypoglycemic influence, sulfonylureas have been reported to inhibit prostanoid-induced vasoconstriction. Using isometric tension measurements we investigated whether this inhibitory influence is exerted by different sulfonylureas in various types of blood vessels from different species and in other types of smooth muscle cells. It was found that in addition to glibenclamide and tolbutamide also gliclazide (1 mM) and tolazamide (1 mM) block contractions induced by prostaglandin F2alpha and the thromboxane A2 mimetic U-46619 in rat aorta, but not the contractions elicited by norepinephrine, serotonin or high potassium. Glibenclamide (10 microM) inhibits the prostaglandin F2alpha- and U-46619-induced contractions on rat tail, femoral and renal interlobar arteries and on bovine retinal and ciliary arteries, but not those on aorta and carotid artery from guinea pigs and on human subcutaneous arteries. Glibenclamide (10 microM), tolbutamide (1 mM), tolazamide (1 mM) and gliclazide (1 mM) all block contractions induced by U-46619, but not those induced by carbachol, on rat intrapulmonary bronchioles. However, prostanoid-induced contractions of guinea-pig trachea and main bronchi are not influenced by glibenclamide (10 microM). From these results it is concluded that the ability of sulfonylureas to block prostanoid-induced contractions is shared by all sulfonylureas tested, that this is not limited to vascular smooth muscle cells and that it shows a heterogeneity, that might be linked to interspecies differences.
Animals↗