Regulation of calcium fluxes in rat pancreatic islets. Quinine mimics the dual effect of glucose on calcium movements.

The effects of quinine and 9-aminoacridine, two blockers of potassium conductance in islet cells, on 45Ca efflux and insulin release from perifused islets were investigated in order to elucidate the mechanisms by which glucose initially reduces 45Ca efflux and later stimulates calcium inflow in islet cells. In the absence of glucose, 100 microM quinine stimulated 45Ca net uptake, 45Ca outflow rate and insulin release. Quinine also dramatically enhanced the cationic and the secretory response to intermediate concentrations of glucose, but had little effect on 45Ca net uptake, 45Ca fractional outflow rate and insulin release at a high glucose concentration (16.7 mM). The ability of quinine to stimulate 45Ca efflux depended on the presence of extracellular calcium, suggesting that it reflects a stimulation of calcium entry in the islet cells. In the absence of extracellular calcium, quinine provoked a sustained decrease in 45Ca efflux. Such an inhibitory effect was not additive to that of glucose, and was reduced at low extracellular Na+ concentration. At a low concentration (5 microM), quinine, although reducing 86Rb efflux from the islets to the same extent as a non-insulinotropic glucose concentration (4.4 mM), failed to inhibit 45Ca efflux. In the presence of extracellular calcium, 9-aminoacridine produced an important but transient increase in 45Ca outflow rate and insulin release from islets perifused in the absence of glucose. In the absence of extracellular calcium, 9-aminoacridine, however, failed to reduced 45Ca efflux from perifused islets. It is concluded that quinine, by reducing K+ conductance, reproduces the effect of glucose to activate voltage-sensitive calcium channels and to stimulate the entry of calcium into the B-cell. However, the glucose-induced inhibition of calcium outflow rate, which may also participate in the intracellular accumulation of calcium, does not appear to be mediated by changes in K+ conductance.

Regulation of calcium fluxes in pancreatic islets: the role of membrane depolarization.

The effect of K+-induced depolarization on calcium fluxes and insulin release from isolated islets were investigated in order to elucidate the mechanism by which glucose initially reduces and later increases 45Ca efflux from prelabeled and perifused rat pancreatic islets. Raising the extracellular K+ concentration from 5.0 to 20.0 mM produced a 2- to 3-fold increase in 45Ca net uptake and efflux from isolated islets. The latter effect was dependent on the presence of extracellular Ca2+, suggesting that it resulted from the entry of calcium into the islet cells. In the presence of 20 mM K+, 16.7 mM glucose failed to stimulate 45Ca efflux, while 20 mM K+ further enhanced 45Ca efflux from islets perifused in the presence of the high concentration of glucose. These findings suggest that the effect of glucose to stimulate 45Ca efflux from perifused islets depends mainly on the glucose-induced depolarization of the cell membrane. In the absence of extracellular calcium, 20 mM K+ failed to mimick the effect of glucose to reduce 45Ca efflux. Glucose (16.7 mM) decreased 45Ca efflux from islets perifused in the presence of 20 mM K+ and antagonized the effect of 20 mM K+ to stimulate 45Ca efflux from perifused islets. It is concluded that K+-induced plasma membrane depolarization reproduces the effect of glucose to stimulate but not to inhibit 45Ca efflux from perifused islets.

In vitro metabolism of a new 4-hydroxycoumarin anticoagulant. Structure of an unusual metabolite.

The metabolism of clocoumarol, 3-[1-[P-(2-chlorethyl)phenyl]butyl]-4-hydroxycoumarin, by rat liver microsomes was investigated. The chemical structure of the main metabolite is 6-[1-hydroxy-2-oxo-3-[p-(2-chloro

Parameters for evaluation of lipid metabolism.

The influence of the clinical condition and the intravenous intake on parameters of fat metabolism has been analyzed. Compared to normal subjects, the correlation between plasma concentrations and the turnover rate of glycerol and free fatty acids varies in the opposite direction in nutritionally depleted and severely injured patients. The significance of plasma concentrations as an index of fat mobilization should be interpreted in relation to the clinical condition. Kinetic measurements are particularly interesting in hypermetabolic patients. Plasma triglyceride and cholesterol concentrations are markedly affected by surgical procedures. Any delay (in treatment) following the injury and the type of intravenous regimen used have an important influence on plasma lipid levels and should be taken into account when groups of patients are studied. The infusion of exogenous fat emulsions significantly affects not only plasma triglyceride levels but also phospholipid and cholesterol concentrations and will modify the plasma lipoprotein pattern. Measurements of plasma clearance and oxidation of fat can be used to evaluate individual tolerance and the metabolic utilization of lipids, but these procedures cannot be easily applied in routine clinical practice. Regular monitoring of plasma triglyceride, cholesterol, and phospholipid concentrations during and after cessation of fat infusion is recommended for each patient who is receiving daily fat infusions so that the safe rate of infusion for that individual can be determined.

Regulation of calcium fluxes in rat pancreatic islets: the role of K+ conductance.

The effects of tetraethylammonium (TEA), a specific blocker of K+ conductance, on calcium fluxes and insulin release in isolated islets were investigated in order to explore the possible relevance of changes in K+ conductance to the mechanism by which glucose both decreases Ca fractional outflow rate from and stimulates Ca entry into the beta-cell. TEA reduced 86Rb efflux from prelabeled islets to the same extent as a non-insulinotropic glucose concentration. In the absence of glucose, TEA failed to affect 45Ca fractional outflow rate, 45Ca net uptake and insulin release from isolate islets. The drug lowered the threshold concentration of glucose required to stimulate these parameters and dramatically increased the cationic and secretory responses to intermediate glucose concentrations. The effect of TEA was less marked at a high glucose concentration. In the absence or presence of TEA, the effect of glucose to stimulate 45Ca efflux required the presence of extracellular calcium. It is concluded that TEA by inhibiting K+ conductance mimics to a limited extent the effect of glucose in causing the gating of voltage-sensitive calcium channels in isolated islets. The inhibitory effect of glucose upon Ca outflow rate, however, appears unrelated to changes in K+ conductance.