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Biomedical subjects

R Larsson

Publications and source records attributed to R Larsson.

At least 199 records · Page 11Linked to original sources
PubMed1987

Dimethyl sulfoxide increases cytoplasmic Ca2+ concentration and inhibits parathyroid hormone release in normal bovine and pathological human parathyroid cells.

The acute effects of dimethyl sulfoxide (DMSO) on parathyroid hormone (PTH) release and the cytoplasmic Ca2+ concentration (Ca2+i) were studied in dispersed bovine cells and cells isolated from human parathyroid adenomas. At extracellular Ca2+ concentrations in the 0.5-3.0 mM range, but not at less than 25 nM, addition of 2% DMSO caused a rapid rise of Ca2+i. This effect corresponded to an inhibition of PTH release and there was a strong negative correlation between Ca2+i and secretion. The actions of DMSO on Ca2+i and PTH release were less pronounced in the pathological human cells. The data are consistent with a DMSO effect on the Ca2+-sensor function of the parathyroid cell, possibly mediated by an altered plasma membrane fluidity.

Adenoma↗
PubMed1987

Monoclonal anti-parathyroid antibodies interfering with a Ca2+-sensor of human parathyroid cells.

Previous findings indicate that binding of Ca2+ to an external receptor is part of the mechanism by which extracellular Ca2+ regulates cytoplasmic Ca2+ and hormone release of parathyroid cells. We now present evidence that two newly generated monoclonal anti-parathyroid antibodies react with structures involved in this sensing and/or gating of Ca2+. Microfluorimetric studies of fura 2-loaded human parathyroid cells thus revealed that the antibodies competed with Ca2+ and antagonized the rise in cytoplasmic Ca2+ normally obtained when parathyroid cells are exposed to increasing concentrations of extracellular Ca2+.

Antibodies, Monoclonal↗
PubMed1987

Bimodal regulation of secretion by cytoplasmic Ca2+ as demonstrated by the parathyroid.

Bovine parathyroid cells were used to study parathyroid hormone (PTH) release and the cytoplasmic Ca2+ concentration (Cai2+). When the extracellular Ca2+ concentration was decreased from 3.0 to 0.5 mM, perifused cells reacted with rapid stimulation of PTH release. However, a further reduction of extracellular Ca2+ to less than 10 nM resulted in prompt inhibition. Both effects were readily reversible. Using the intracellular Ca2+ indicator quin-2 also as a buffer for calcium it was possible to control Cai2+ within the 20-600 nM range. PTH release was found to increase with Cai2+ up to 200 nM but was gradually suppressed above this concentration.

Aminoquinolines↗
PubMed1987

Cytoplasmic Ca2+ concentration of single normal human and bovine parathyroid cells measured by dual wavelength microfluorometry.

Dual wavelength microfluorometry was utilized to measure the cytoplasmic calcium concentration (Cai2+) of single parathyroid cells loaded with the indicator fura-2. The method enabled the first registrations of Cai2+ of normal human parathyroid cells, available only in minute numbers. At 0.5 mM extracellular Ca2+, the Cai2+ levels were similar in normal human and bovine cells. Both cell types responded with an initial Cai2+ transient followed by a sustained increase when raising extracellular Ca2+ to 3.0 mM. The sustained effect exhibited a sigmoidal relation to extracellular Ca2+ in the 0.5-3.0 mM range. Although the increase was somewhat greater in the human cells, the half maximal responses were obtained at almost identical extracellular Ca2+ concentrations. Whereas K+ depolarization decreased Cai2+, the Ca2+ channel blocker D-600 had dual actions, raising Cai2+ at 0.5 mM Ca2+ and decreasing it at 3.0 mM Ca2+, and the effects were similar in the bovine and human cells. The present experimental approach verified the validity of utilizing bovine cells as controls in studies of human parathyroid tissue and it appears suitable for analysis of the role of different subpopulations of parathyroid cells in the abnormal parathyroid tissue of patients with hyperparathyroidism.

Animals↗
PubMed1987

TPA induces cytoplasmic alkalinization in human monoblastic U-937 cells without activation of Na+/H+ exchange.

The effect of the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) on cytoplasmic pH (pHi) and H+ extrusion was studied in the human monoblastic cell line U-937. About 2 min after addition of TPA, pHi started to increase and reached a steady state 10-15 min later. The resulting alkalinization corresponded to 0.03 and 0.09 pH units at 10(-10) and 10(-7) M TPA, respectively. The TPA-induced increase in pHi was independent of the presence of extracellular Na+. Moreover, TPA did not affect the H+ extrusion from the U-937 cells. Together these observations indicate the presence of a novel mechanism for TPA-induced cytoplasmic alkalinization. This mechanism is independent of Na+/H+ exchange across the plasma membrane, but may involve organelle sequestration of H+.

Carrier Proteins↗
PubMed1987

Long-term stability in vivo of a thromboresistant heparinized surface.

A surface with covalently bonded heparin was tested in an in vivo model. Heparinized and non-heparinized tubings were inserted in the pig aorta. They were left in place for up to 16 wk. After removal they were analysed for their capacity to take up and inhibit thrombin. A comparison was also made with tubings that had not been inserted in animals. The heparin surface showed some specific alterations after implantation but its capacity to inhibit thrombin was not impaired. The heparinized tubings caused less intimal hyperplasia and thrombi than non-heparinized tubings.

Animals↗
PubMed1987

Development of abnormal parathyroid cell function during monolayer culture and its relation to cellular hypertrophy and proliferation.

Primary cultures of adult bovine parathyroid cells grown for up to 8 days were used to study the relationship between regulation of parathyroid hormone (PTH) release, cytoplasmic Ca2+ (Ca2+i) and cell growth. Cell counting indicated that proliferation was inversely proportional to the seeding density. The culture was associated with cell enlargement without apparent relation to the proliferation rate. Moreover, flow cytometric analysis of the DNA distribution excluded that the hypertrophy was due to a high proportion of the cells being in the S and G2 stages of the cell cycle. With progressive time in culture there was a gradual deterioration of the ability of increasing concentrations of extracellular Ca2+ to suppress PTH secretion and raise Ca2+i. This functional dedifferentiation developed to the same extent despite considerable differences in proliferation rates. The data show that parathyroid cells in monolayer culture develop functional and some of the morphological characteristics of parathyroid cells from patients with hyperparathyroidism and that the functional abnormality seems to be related to hypertrophy but not to proliferation of the cells.

Animals↗
PubMed1987

Biocompatible surfaces prepared by immobilized heparin or hyaluronate.

Artificial surfaces modified with immobilized heparin or hyaluronate were evaluated as possible approaches to improve biocompatibility. The heparin surface was highly thromboresistant in contact with blood, as manifested by minimal cell adhesion and a pronounced capacity to inactivate coagulation enzymes such as thrombin and factor Xa. The hyaluronate coating also reduced cell adhesion, but this coating seemed to be less effective than the heparin surface. Outgrowth of human macrophages was not affected by the hyaluronate coating, nor did it display any capacity to inactivate coagulation enzymes. It is concluded that the heparin surface exhibits a high degree of biocompatibility in contact with blood and cell culture, which should make it an interesting candidate for use in the ear compartment.

Biocompatible Materials↗
PubMed1986

Dual effects of a new hypocalcemic agent, WR-2721, on cytoplasmic Ca2+ and parathyroid hormone release of dispersed parathyroid cells from patients with hyperparathyroidism.

The effects of the new hypocalcemic agent, WR-2721, on calcium-regulated parathyroid hormone (PTH) release, cytoplasmic Ca2+ (Ca2+i) and membrane potential were measured in dispersed parathyroid cells from patients with hyperparathyrodisim (HPT). The drug had no effects in the absence of extracellular Ca2+ but acted synergistically with Ca2+ in the 0.5-1.5 mM range by depolarizing the cells, increasing Ca2+i and inhibiting PTH release. Although the depolarizing effect of 3.0 mM Ca2+ was unaffected by WR-2721 the drug antagonized the effect of Ca2+ by decreasing Ca2+i and stimulating PTH release. Whereas the inhibitory actions of WR-2721 on PTH release may result from the activation of the mechanism for Ca2+ gating in the parathyroid cell plasma membrane, the stimulatory effect probably reflects increased intracellular Ca2+ sequestration. The drug is considered potentially important for the treatment of HPT.

Amifostine↗
PubMed1986

Calcium-activated calcium permeability in parathyroid cells.

The Ca2+ receptor mechanism of the parathyroid cell was studied using La3+ as a probe. La3+ was found to bind to the cell surface without further penetration. Measurements of 45Ca fluxes and the cytoplasmic Ca2+ concentration (Ca2+i) revealed a stimulatory component in the action of La3+ on Ca2+ permeability resulting in a rise in Ca2+i. These effects mimicked those obtained when raising the extracellular Ca2+ concentration from 0.5 to 3.0 mM, but the actions of La3+ and Ca2+ were not additive. The results suggest the existence of a novel Ca2+ permeability physiologically activated by binding of Ca2+ to an external receptor.

Animals↗
PubMed1986

Thrombin uptake and inhibition on heparinized polytetrafluoroethylene (PTFE) grafts and native sheep vessels.

Non-heparinized and covalently-heparinized PTFE grafts, sheep aorta, carotid artery and jugular vein were evaluated according to their ability to adsorb and inactivate thrombin. All surfaces, except non-heparinized PTFE caused considerable losses of enzymatically active thrombin from the solution. Covalently-heparinized PTFE and jugular veins adsorbed thrombin, which was inactivated on subsequent contact with antithrombin III. Despite the same loss from the solution as was encountered with veins arteries adsorbed significantly smaller amounts of thrombin. Protamine treatment of covalently-heparinized PTFE almost totally abolished the ability to adsorb thrombin. It is concluded that 1) arteries possess a stronger thrombin inhibitory capacity than veins, possible explanations to this being a different glucosaminoglycan or the presence of antithrombin III in the arterial wall and 2) that heparinizing PTFE results in a pronounced ability to inactivate thrombin.

Animals↗
PubMed1986

Thrombin uptake and inhibition on endothelium and surfaces with a stable heparin coating: a comparative in vitro study.

The endothelial lining and two differently heparin-coated surfaces were compared in vitro regarding thrombin uptake and inhibition. One heparin surface was based on stabilized ionic binding of heparin, the other on covalent binding of partially degraded heparin. Both heparin surfaces have previously been shown to have pronounced thromboresistant properties. The two heparinized polyethylene surfaces and the endothelial surface of segments of the porcine aorta were studied. After exposure to the surfaces, thrombin disappeared from the solution and appeared bound to the surfaces. The disappearance rate of thrombin from the solution was the same on exposure to the endothelium and the covalently bonded heparin surface, but less following exposure to the ionically bonded heparin surface. The thrombin activity appearing on the endothelium was lower than on the heparin surfaces, indicating that the endothelium exerted a slow thrombin inhibiting capacity. On exposure of the thrombin-loaded endothelium to plasma, thrombin was rapidly inhibited. Thrombin bound to the covalently bonded heparin surface was inhibited at a slower rate than on the ionically bonded surface, but still faster than the rate at which free thrombin was inhibited in nonheparinized plasma. It is concluded that the endothelium and stabilized heparin coatings bind thrombin and accelerate its inhibition by plasma.

Animals↗
PubMed1986

Effects of probenecid on enprofylline kinetics in man.

Enprofylline 1 mg/kg, a new potent antiasthmatic xanthine derivative, which is mainly eliminated by renal excretion, was given intravenously to 6 normal subjects with and without oral pretreatment with 1 g probenecid. The latter caused a drop in the average total body clearance of enprofylline from 21 to 9.8 l/h, and in the average renal clearance from 17 to 8.0 l/h. The average half-life increased from 1.8 to 3.0 h. The volumes of distribution, Vz and Vss, both fell by about 25%, indicating that probenecid had restricted the distribution of enprofylline in the body. The plasma protein binding of enprofylline was not altered by probenecid. The results confirm the opinion that active tubular secretion accounts for a large proportion of the total elimination of enprofylline.

Adult↗
PubMed1986

Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment.

Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30-63 ml/min) and 7 patients with severe renal impairment had hypertension. The mean urinary recovery of milrinone was 82% in healthy subjects, the renal clearance was 288 ml/min and the plasma half-life (t1/2) was 0.94 h. In CRI the mean plasma t1/2 was prolonged (CRI I 1.78 h, CRI II 3.24 h). There was a significant linear relationship between creatinine clearance and the elimination rate constant, and between creatinine clearance and the renal clearance of milrinone. During the study day there was a tendency to a decrease in supine BP from 1 to 6-8 h after dosing, with the maximal decrease at 2-3 h (healthy subjects 118/71----107/56, CRI 159/95----136/79 mmHg). The same degree of change was seen in standing BP. A slight rise in standing HR was seen from 2-6 h after dosing. Changes in BP and HR are difficult to evaluate since the study was not placebo-controlled. The plasma elimination rate of milrinone was decreased in CRI and dose adjustment may be necessary. Placebo-controlled studies of milrinone in hypertensive patients would be required to validate its possible antihypertensive effect.

Adult↗
PubMed1986

Cellular effects of N(4-ethoxyphenyl)p-benzoquinone imine, a p-phenetidine metabolite formed during peroxidase reactions.

The interaction of N-(4-ethoxyphenyl)p-benzoquinone imine (NEPBQI), a metabolite formed during peroxidase catalyzed metabolism of p-phenetidine, with GSH and its effects in isolated rat hepatocytes were investigated. When reacted with GSH NEPBQI formed both a mono- and a diglutathione conjugate as well as GSSG. Formation of glutathione conjugates and GSSG also occurred when NEPBQI was added to isolated hepatocytes. The formation of GSSG was, however, only detectable if the hepatocytes had been pretreated with the GSSG reductase inhibitor BCNU (1,3-bis-(2-chloroethyl-1-nitrosourea). Similarly, NEPBQI caused a rapid decrease in cellular free protein thiols when added to hepatocytes, however this was expressed at higher concentrations than for effects on GSH. The protein thiol decrease was correlated with protein binding of NEPBQI. NEPBQI was also shown to be toxic to isolated hepatocytes. At a concentration of 400 microM extensive bleb formation was followed by loss of cell membrane integrity and cell death. To assess further the subcellular metabolism of NEPBQI microsomes and cytosol was used. NEPBQI was found to be preferentially reduced by cytochrome P-450 reductase in the microsomes whereas DT-diaphorase catalyzed its reduction in cytosol. NEPBQI did not undergo significant redox cycling since no formation of O2 was observed. Thus, the cytotoxic effect of NEPBQI appears to be due to protein arylation rather than redox cycling.

Animals↗
PubMed1986

Normalizing effect of Ca2+ ionophore on cytoplasmic Ca2+ and parathyroid hormone release of dispersed parathyroid cells from patients with hyperparathyroidism.

The effects of the Ca2+ ionophore A23187 on parathyroid hormone (PTH) secretion and cytoplasmic free Ca2+ concentration (Ca2+i) were measured at different extracellular Ca2+ concentrations using dispersed cells from patients with hyperparathyroidism (HPT). The addition of a low concentration of the Ca2+ ionophore to quin2-loaded cell preparations resulted in the apparent normalization of calcium-regulated Ca2+i. At all extracellular calcium concentrations Ca2+i reached significantly higher values in the presence of the ionophore and the dose-response relationship was shifted to the left. Under similar conditions calcium-regulated PTH release was correspondingly corrected with an increased suppressibility and left-shifted dose-response relationship. The data render strong support for a disturbed regulation of Ca2+i as a major factor in the pathophysiology of HPT.

Aminoquinolines↗