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J Sehlin

Publications and source records attributed to J Sehlin.

At least 37 records · Page 2Linked to original sources
PubMed1996

Protection against cadmium-metallothionein nephrotoxicity in streptozotocin-induced diabetic rats: role of increased metallothionein synthesis induced by streptozotocin.

Protection against the development of nephrotoxicity following the administration of cadmium-metallothionein (CdMT) at a dose of 0.4 mg Cd per kg body weights was studied in streptozotocin (STZ)-induced diabetic rats. Six groups of Wistar male rats were used (Groups A and B, Groups A1 and C, and Groups A2 and D were injected intraperitoneally with STZ at doses of 0, 50 and 100 mg/kg, respectively, and then 6 days later, Groups B, C and D were injected subcutaneously with CdMT). Proteinuria, albuminuria and transferrinuria were observed after the administration of CdMT, and a dose-related decrease following the increased STZ dose was seen in Groups B, C and D. The concentrations of metallothionein (MT) and zinc (Zn) in liver and kidney were dose-dependently increased in Groups B, C and D. Induction of increased MT synthesis in liver and kidney as the result of the STZ treatment was observed in this study. In particular, a remarkable increase in liver MT concentration was induced by STZ, and transport to the kidney of MT synthesized in liver may perhaps explain the protection against cadmium nephrotoxicity in STZ-induced diabetic rats.

Animals↗
PubMed1996

Thiocyanate induces vasoconstriction in rat-tail artery primed with norepinephrine.

The vasoregulating effects of thiocyanate (SCN-) were studied by means of a new rat tail artery perfusion model that uses constant driving pressure (1000 mm H2O). When a 30 mm long artery was perfused with 20 micromol/L verapamil, the flow rate increased 6%. Norepinephrine (10 to 1000 nmol/L) caused a dose-dependent flow inhibition. SCN- alone (0.05 to 5 mmol/L) had a slight, if any, effect on the arterial flow. However, when the artery was pretreated with norepinephrine (1000 nmol/L) for 10 minutes, followed by a basal-medium washout that left a 13% norepinephrine-induced flow inhibition, 0.05 to 5 mmol/L SCN- caused a marked flow rate reduction of between 20.4% +/- 9.8% and 28.0% +/- 21.8%, as calculated for the entire test perfusion. The decrease in flow rate correlated with the SCN- concentration (p < 0.05) and showed a clear reversibility. A similar SCN(-)-induced (0.05 mmol/L) vasoconstriction (p < 0.05) was seen when the artery was given a basal tone by continuous perfusion with low-dose norepinephrine, 10 nmol/L. Nifedipine (100 nmol/L) abolished the effect of 0.05 mmol/L SCN- but did not affect the norepinephrine priming. We conclude that SCN- amplifies the norepinephrine-induced vascular smooth muscle tone and that this may be caused by an altered calcium channel activity.

Animals↗
PubMed1996

Glucose-stimulated elevation of cytoplasmic calcium is defective in the diabetic Chinese hamster islet B cell.

To characterize insulin release and cytoplasmic free Ca2+ ([Ca2+]i) levels in the diabetic Chinese hamster islet B cell, islets from genetically normal (subline M) and diabetic (subline L) hamsters were collagenase isolated. Insulin release and glucose utilization (conversion of D-[5-(3H)]glucose to 3H2O) were measured in whole islets; [Ca2+]i levels were measured in single islet cells using fura-2. The Ca2+ channel agonist, 12 mmol/l perchlorate, ClO4-, increased the subnormal insulin response during 20 mmol/l glucose perifusion, but did not normalize it. Glucose utilization measured over a 2-h period was normal. Glucose induced an initial decrease and then a rise in [Ca2+]i in 85% of the normal (presumably B) cells. In diabetic cells, the [Ca2+]i response was delayed, subnormal and only observed in 23% of the cells. When perchlorate or another Ca2+ channel agonist, 10 mumol/l CGP 28392, was added with glucose, a larger proportion of the diabetic cells (61-67%) showed increased [Ca2+]i and the mean [Ca2+]i response was not different from normal. However, neither perchlorate nor CGP 28392 could normalize glucose-stimulated insulin release, and K(+)-induced insulin release was decreased in diabetic islets. The K(+)-induced [Ca2+]i rise was essentially normal in all the diabetic islet cells. Therefore, the diabetic hamster islet appears to metabolize glucose normally, but has a diminished insulin response to glucose and K+. The Ca2+ channel agonists markedly improve the subnormal [Ca2+]i response but not the insulin response. Glucose-induced elevation of [Ca2+]i and exocytosis appear defective in the diabetic Chinese hamster B cell.

Animals↗
PubMed1996

Effects of UK-14,304, noradrenaline, and propranolol on insulin release from transplanted mouse islets.

To elucidate the adrenergic responsiveness of transplanted pancreatic islets, normal BALB/c mice received 150 syngeneic islets under the left kidney capsule. After 12-40 weeks, the grafts were removed and compared with untransplanted islets by an in vitro perifusion technique. Noradrenaline (NA), 3 mumol/l, completely inhibited glucose-stimulated insulin release from untransplanted islets but not from grafts, whether or not the beta adrenergic blocker, L-propranolol, was present. UK-14,304, an alpha 2-specific adrenergic agonist, inhibited glucose-induced insulin secretion from untransplanted islets by 80-92% at 0.1 or 1 mumol/l, and by 35-56% at 5-10 nmol/l. Insulin secretion from islet grafts was also markedly inhibited by 0.1 or 1 mumol/l, but not by 5 or 10 nmol/l, UK-14,304. It is suggested that the diminished adrenergic inhibition of insulin release from islet grafts reflects an altered function of the alpha 2 adrenoceptors on the beta-cells.

Adrenergic Agonists↗
PubMed1995

Protective effects of calcium channel blockers on acute bromobenzene toxicity to isolated rat hepatocytes. Inhibition of phenylephrine-induced calcium oscillations.

BACKGROUND AND METHODS: Protective effects of verapamil, nifedipine, diltiazem, and ethylene glycol tetraacetic acid (EGTA) on acute bromobenzene (BB) toxicity to rat hepatocytes were evaluated, and cytosolic [Ca2+]i was monitored in single BB-exposed rat hepatocytes. Additionally, the effect of nifedipine on phenylephrine-stimulated calcium oscillations was investigated. RESULTS: BB at 0.8-2.4 mM increased the lactate dehydrogenase (LDH) leakage rate dose-dependently. Pretreatment with verapamil (25-35 microM), nifedipine (35-45 microM), diltiazem (25 microM), or EGTA (1.5-5 mM) markedly attenuated the BB-induced (1.6 mM) LDH leakage rate during 2 h of incubations. BB did not cause any detectable acute change in [Ca2+]i. BB interfered with phenylephrine-stimulated calcium oscillations, by blocking the oscillations in 58% of the cells and reducing the oscillation frequency in the rest. Nifedipine (100 and 200 microM) blocked the phenylephrine-induced calcium oscillations completely in 55% and 88% of the cells, respectively. CONCLUSIONS: The findings demonstrate that verapamil, nifedipine, diltiazem, and EGTA significantly protect rat hepatocytes against BB toxicity. BB interferes with phenylephrine-stimulated calcium oscillations. Nifedipine inhibits the oscillations at doses higher than those exerting a protective effect.

Animals↗
PubMed1994

The susceptibility of spontaneously diabetic mice to cadmium-metallothionein nephrotoxicity.

Cadmium metallothionein (CdMT) was injected subcutaneously into obese hyperglycaemic Umeå ob/ob mice or their lean litter mates (normal mice) at doses of 0, 0.1 and 0.4 mg Cd/kg. Proteinuria and calciuria were induced in both types of mice, but in the ob/ob mice this condition developed at a lower dose of CdMT (0.1 mg Cd/kg) than in the normal mice (0.4 mg Cd/kg). These results show, therefore, that Umeå ob/ob mice are particularly susceptible to CdMT-induced nephrotoxicity. The mechanism underlying this phenomenon needs to be further investigated. After the administration of CdMT, a dose-related increase in glycosuria was observed in both types of mice, in spite of decreased levels of serum insulin and glucose. It is suggested that such glycosuria induced by CdMT could be one of the signs of cadmium nephrotoxicity. The results of the present study thus indicate that metabolic changes like those in diabetes may increase susceptibility to cadmium-induced renal tubular damage.

Animals↗
PubMed1994

Insulin secretion in pancreatic islets from rats with cirrhosis.

Cirrhosis was induced in rats by subcutaneous injections of CCl4 for 13 or 17 weeks. The morphology of the pancreatic islets from the CCl4-treated rats was found to be normal. The CCl4-treated rats had lower fasting serum glucose levels and higher serum insulin levels than the controls. After an oral glucose load (3 g/kg body weight), glucose levels in CCl4-treated rats stayed within the normal range, whereas the serum insulin levels remained higher with a delayed decline of insulin with time. In vitro perifusion of islets from the CCl4-treated rats showed that the response to 16.7 mmol/l glucose was reduced with both lower total insulin output and stimulated insulin output, whereas the patterns of first and second phase of insulin release did not differ. The insulin content of the perifused islets was not affected by 13 weeks of CCl4 treatment. Islets from rats treated with CCl4 for 17 weeks showed normal secretory response to 20 mmol/l L-arginine. Taken together, the results, showing normal or reduced capacity for insulin secretion, suggest that the hyperinsulinemia accompanying CCl4-induced cirrhosis is not due to increased secretion of the pancreatic islets. It may rather be associated with decreased insulin degradation by the liver with cirrhosis.

Animals↗
PubMed1994

Effect of perchlorate on glucose-stimulated insulin release and 45Ca2+ uptake in pancreatic islets from diabetic Chinese hamsters.

Insulin release and 45Ca2+ uptake were studied in isolated islets from Chinese hamsters of genetically diabetic and normal sublines. The calcium channel agonist, perchlorate (ClO4-, 12 mmol/L), augmented both 45Ca2+ uptake and insulin release from normal islets in the presence of 20 but not 1 mmol/L glucose. The agonist also amplified the glucose-stimulated 45Ca2+ uptake and insulin release from diabetic islets but did not normalize the insulin release despite normal insulin concentration in the diabetic Chinese hamster islets. The dry weight of the diabetic islets was subnormal (54%, p < 0.005) but the insulin concentration (insulin per dry weight of islet tissue) was not different from normal (122%). It appears that there are defective mechanisms in addition to the glucose-stimulated influx of Ca2+ in diabetic islet B cells.

Animals↗
PubMed1993

Evidence for separate Na+, K+, Cl- and K+, Cl- co-transport systems in mouse pancreatic beta-cells.

The effects of H 25 and H 74 on ouabain-resistant 86Rb+ influx were tested in beta-cell-rich mouse pancreatic islets. Both H 25, which is considered to be a specific inhibitor of Na+, K+, Cl- co-transport, and H 74, a specific inhibitor of K+, Cl- co-transport, reduced the ouabain-resistant 86Rb+ influx. The specific inhibitory effects of H 25 and H 74 on 86Rb+ influx did not overlap. The data suggest that mouse pancreatic beta-cells are equipped with separate systems for Na+, K+, Cl- and K+, Cl- co-transport.

Acetonitriles↗
PubMed1993

Interaction between perchlorate and nifedipine on insulin secretion from mouse pancreatic islets.

In order to elucidate the mechanisms responsible for the stimulatory effect of perchlorate (ClO4-) on insulin secretion, we have investigated the interaction between this chaotropic anion and the organic calcium antagonist nifedipine. This drug, known as a blocker of L-type calcium channels, was chosen as a tool to test the idea that ClO4- acts on insulin secretion by stimulating the gating of voltage-controlled Ca2+ channels. ClO4- amplified the stimulatory effect of D-glucose on insulin release from perfused pancreas (first and second phases) as well as from isolated islets incubated in static incubations for 60 min. This indicates that ClO4- amplifies physiologically regulated insulin secretion. Nifedipine reduced D-glucose-induced (20 mM) insulin release in a dose-dependent manner with half-maximum effect at about 0.8 microM and apparent maximum effect at 5 microM nifedipine. In the presence of 20 mM D-glucose, the inhibitory effects of 0.5, 1 or 5 microM nifedipine were only slightly, if at all, counteracted by perchlorate. When 12 mM ClO4- and 20 mM D-glucose were combined, calculation of the specific effect of ClO4- revealed that nifedipine produced almost maximum inhibition already at 0.05 microM. Thus, the perchlorate-induced amplification of D-glucose-stimulated insulin release shows higher sensitivity to nifedipine than the D-glucose-effect as such. This supports the hypothesis that perchlorate primarily affects the voltage-sensitive L-type calcium channel in the beta-cell.

Animals↗
PubMed1991

Volume regulation in mouse pancreatic beta-cells is mediated by a furosemide-sensitive mechanism.

A possible role for loop diuretic-sensitive Cl-/cation cotransport in volume regulation in the pancreatic beta-cells was investigated by measuring 86Rb+ efflux from beta-cell-rich pancreatic islets as well as the size of isolated beta-cells under different osmotic conditions. Lowering the osmolarity to 262 mosM (83% of control) resulted in a rapid cell swelling which was followed by regulatory volume decrease (RVD). RVD was completely inhibited by furosemide (1 mM), an inhibitor of Cl-/cation co-transport. The hypotonic medium (262 mosM) induced a rapid and strong increase in 86Rb+ efflux from beta-cell-rich mouse pancreatic islets and the furosemide-sensitive portion of the efflux was significantly increased. A slightly less hypotonic medium (285 mosM, 90% of control) induced only cell swelling and no RVD. With this medium only a marginal increase in 86Rb+ efflux was observed. Increasing the osmolarity by adding 50 mM NaCl (final osmolarity: 417 mosM, 132% of control) induced a rapid cell shrinkage but no regulatory volume increase (RVI). When the osmolarity was increased from a slightly hypotonic medium (262 mosM) to an isotonic medium (317 mosM) an initial cell shrinkage was followed by RVI. This RVI was inhibited by 1 mM furosemide. The data suggest that RVD as well as RVI in the beta-cells are mediated by loop diuretic-sensitive cotransport of chloride and cations and that these cells show a threshold for hypotonic stimulation of RVD.

Animals↗
PubMed1990

Barium mimics the effect of D-glucose on 86Rb+ fluxes in mouse pancreatic beta-cells.

The interaction between Ba2+, furosemide and D-glucose on 86Rb+ fluxes in ob/ob mouse islets was investigated. Ba2+ (2 mM) significantly reduced the ouabain-resistant 86Rb+ influx, without affecting the ouabain-sensitive influx. D-Glucose (20 mM) reduced the 86Rb+ influx in the absence of Ba2+ (2 mM) but not in the presence of the cation. Furosemide, an inhibitor of Na+, K+, Cl- co-transport, reduced the 86Rb+ influx and the effect was partly additive to the effect of 2 mM Ba2+. When the islets were preincubated with Ba2+ (2 mM) the specific effect of 1 mM furosemide on the 86Rb+ influx was reduced, whereas, in acute experiments, Ba2+ (2 mM) did not affect the specific effect of furosemide on 86Rb+ influx. 86Rb+ efflux from preloaded islets was significantly reduced by 2 mM Ba2+ and during the first 5 min of ion efflux the effect of the combination of 2 mM Ba2+ and 1 mM furosemide was stronger than the effect of Ba2+ alone. The data show that Ba2+ reduces 86Rb+ fluxes in the beta-cells and suggest that this is mainly mediated by inhibition of K+ channels in the beta-cell plasma membrane. Long-term exposure to Ba2+ may also reduce the activity of the Na+, K+, Cl- co-transport system. The effect of Ba2+ on K+ channels may help to explain the stimulatory effect on insulin release in the absence of nutrient secretagogues.

Animals↗
PubMed1990

Na+ participates in loop diuretic-sensitive Cl(-)-cation co-transport in the pancreatic beta-cells.

In order to investigate whether Na+ participates in loop diuretic-sensitive Cl(-)-cation co-transport in the beta-cells, we tested the interaction between the effects of Na+ deficiency, furosemide and D-glucose on 86Rb+ fluxes in beta-cell-rich mouse pancreatic islets. Removal of extracellular Na+ slightly reduced the ouabain-resistant 86Rb+ influx and the specific effect of 1 mM furosemide on this influx was significantly smaller in Na(+)-deficient medium. The capacity of 20 mM D-glucose to reduce the ouabain-resistant 86Rb+ influx was not changed by removal of extracellular Na+. The 86Rb+ efflux from preloaded islets was rapidly and reversibly reduced by Na+ deficiency. Furosemide (1 mM) reduced the 86Rb+ efflux and the effect of the combination of Na+ deficiency and 1 mM furosemide was not stronger than the effect of furosemide alone. 22Na+ efflux was reduced by both ouabain and furosemide and the effects appeared to be additive. The data suggest that Na+ participates in loop diuretic-sensitive Cl(-)-cation co-transport in the pancreatic beta-cells. This adds further support to the idea that beta-cells exhibit a Na+, K+, Cl- co-transport system. Since some of the furosemide effect on 86Rb+ efflux persisted in the Na(+)-deficient medium, it is likely that also loop diuretic-sensitive K+, Cl- co-transport exists in this cell type.

Animals↗
PubMed1990

Insulin, glucagon, somatostatin, and thyrotropin-releasing hormone content and secretion by perifused fetal rat islets during culture.

In the neonatal period of the rat, pancreatic thyrotropin-releasing hormone content decreases and the sensitivity of insulin secretion to glucose increases. In adult rat islets, TRH inhibits glucose-induced insulin release. The aim of this study was to investigate whether a high TRH content and release can be part of the explanation for the functional immaturity of neonatal islets. For that purpose, we have measured the tissue content and the secretion of immunoreactive insulin, glucagon, somatostatin and TRH in islets from 21.5-day-old rat fetuses cultured for up to one week. Insulin, glucagon and somatostatin content increased during one week of culture in the presence of 11.1 mmol/l glucose. The TRH content decreased during culture, but did not equal adult values. Insulin, glucagon and somatostatin responses to glucose were present after one week of culture. Glucose had no effect on TRH release in cultured fetal islets, but inhibited TRH release in adult islets. We conclude that glucose can stimulate insulin secretion without inhibiting TRH release, but that a decrease in islet TRH content and a sensitization of TRH secretion to glucose may be important in the full maturation of fetal pancreatic islets.

Animals↗
PubMed1989

Basic mechanisms for transmembrane ion fluxes. A review.

The principles for transport of ions across cell membranes are briefly reviewed and some cell physiological applications of ion flux are discussed, including the regulation of electrical activity, intracellular pH and cell volume.

Animals↗
PubMed1988

Furosemide and Ca2+ affect 86Rb+ efflux from pancreatic beta-cells by different mechanisms.

The interaction between furosemide, calcium and D-glucose on the 86Rb+ efflux from beta-cell-rich mouse pancreatic islets was investigated in a perifusion system with high temporal resolution. Raising the glucose concentration from 4 to 20 mM induced an initial decrease in 86Rb+ efflux, which was followed by a steep increase and then a secondary decrease. Removal of extracellular calcium increased the 86Rb+ efflux at 4 mM D-glucose but reduced it at 20 mM. The initial biphasic changes in 86Rb+ efflux induced by 20 mM D-glucose were inhibited by calcium deficiency. Furosemide (100 microM) reduced the 86Rb+ efflux rate both at 4 and 20 mM D-glucose and the magnitudes appeared to be similar at either glucose concentration. Furosemide (100 microM) reduced the glucose-induced (10 mM) 45Ca+ uptake but did not affect the basal (3 mM D-glucose) 45Ca+ uptake. However, the ability of furosemide (100 microM) to reduce the 86Rb+ efflux at a high glucose concentration (20 mM) was independent of extracellular calcium. The inhibitory effects of furosemide and calcium deficiency on the 86Rb+ efflux rate appeared to be additive. It is concluded that the effect of furosemide on 86Rb+ efflux is not secondary to reduced calcium uptake and that the effects of furosemide and calcium deficiency are mediated by different mechanisms. The effect of furosemide is compatible with inhibition of loop diuretic-sensitive co-transport of Na+, K+ and Cl- and the effect of calcium deficiency with reduced activity of calcium-regulated potassium channels.

Animals↗
PubMed1988

Furosemide-induced glucose intolerance in mice is associated with reduced insulin secretion.

The effect of furosemide on carbohydrate metabolism was studied in ob/ob mice. Intraperitoneal injection of a single dose of furosemide (200 mg/kg body weight) into fasted mice resulted in acute hyperglycaemia and two days after such a single dose, the mice showed fasting hyperglycaemia and glucose intolerance. Pancreatic islets from mice that had been injected with furosemide (200 mg/kg body weight) two days prior to the in vitro experiments showed increased basal (3 mmol/1 D-glucose) and decreased glucose-stimulated (20 mmol/1) insulin release. Islets from furosemide- or saline-injected animals showed no difference in islet insulin content. The results show that furosemide has both acute and long-term effects on carbohydrate metabolism in ob/ob mice. It is suggested that this, at least in part, is due to an effect on the pancreatic beta-cells.

Animals↗