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Biomedical subjects

O Larsson

Publications and source records attributed to O Larsson.

At least 19 recordsLinked to original sources
PubMed1992

Elevated uptake of low density lipoproteins by human lung cancer tissue in vivo.

In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. Previous in vitro and in vivo studies have shown that acute myelogenous leukemia cells have elevated receptor-mediated uptake of low density lipoproteins (LDL), compared to normal WBC. High receptor-mediated uptake of LDL by certain cancer cells in tissue culture and experimental tumors in animals in vivo has also been demonstrated. The present study was undertaken to compare the in vivo assimilation of LDL by human lung cancer tissue with that by surrounding lung tissue. Ten patients with newly diagnosed lung tumors, scheduled for surgery, received an i.v. injection of [14C]sucrose-labeled LDL. Following cellular uptake and degradation of the LDL particle, the radiolabeled sucrose moiety remains trapped in the lysosomal compartment, making this labeling technique useful for in vivo studies of tissue uptake of LDL. Radioactivity was determined in plasma and in tissue biopsies obtained at surgery 1-3 days after injection. The uptake of radioactivity in lung cancer tissue was elevated (1.5-3.0-fold), compared to surrounding tissue, in 7 of 9 patients with primary lung cancer. The most rapid preoperative disappearance of radioactivity from plasma was found in 2 patients with large tumors exhibiting high LDL uptake, relative to normal lung tissue. These findings support the hypothesis that the selectivity of cytotoxic agents can be enhanced also in nonhematological malignancies by administering the drugs incorporated in LDL particles.

Adult↗
PubMed1992

Protein kinase C activity affects glucose-induced oscillations in cytoplasmic free Ca2+ in the pancreatic B-cell.

Acute stimulation of protein kinase C (PKC) inhibited glucose-induced slow oscillations in cytoplasmic free Ca(2+)-concentration, [Ca2+]i, in mouse pancreatic B-cells. In PKC-depleted cells glucose induced rapid transients in [Ca2+]i, lasting for approximately 10 s, superimposed on the slow oscillations in [Ca2+]i. It was demonstrated that the transients did not occur in the absence of extracellular Ca2+. Each transient typically was preceded by a slow increase in [Ca2+]i, representing the rising phase of an ordinary glucose-induced slow oscillation, and the [Ca2+]i, immediately after a transient was lower than just before the spike. These data further emphasize the interplay between voltage-dependent Ca(2+)-channels and the phospholipase C system in the regulation of B-cell [Ca2+]i-oscillations.

Animals↗
PubMed1992

Cytoplasmic calcium transients due to single action potentials and voltage-clamp depolarizations in mouse pancreatic B-cells.

Changes in the cytoplasmic free calcium concentration ([Ca2+]i) in pancreatic B-cells play an important role in the regulation of insulin secretion. We have recorded [Ca2+]i transients evoked by single action potentials and voltage-clamp Ca2+ currents in isolated B-cells by the combination of dual wavelength emission spectrofluorimetry and the patch-clamp technique. A 500-1000 ms depolarization of the B-cell from -70 to -10 mV evoked a transient rise in [Ca2+]i from a resting value of approximately 100 nM to a peak concentration of 550 nM. Similar [Ca2+]i changes were associated with individual action potentials. The depolarization-induced [Ca2+]i transients were abolished by application of nifedipine, a blocker of L-type Ca2+ channels, indicating their dependence on influx of extracellular Ca2+. Following the voltage-clamp step, [Ca2+]i decayed with a time constant of approximately 2.5 s and summation of [Ca2+]i occurred whenever depolarizations were applied with an interval of less than 2 s. The importance of the Na(+)-Ca2+ exchange for B-cell [Ca2+]i maintenance was evidenced by the demonstration that basal [Ca2+]i rose to 200 nM and the magnitude of the depolarization-evoked [Ca2+]i transients was markedly increased after omission of extracellular Na+. However, the rate by which [Ca2+]i returned to basal was not affected, suggesting the existence of additional [Ca2+]i buffering processes.

Animals↗
PubMed1992

Effects of acute and long-term atropine treatment on levels, release and response to VIP and PHI in the submandibular gland of cat and rat.

We have studied the effects of acute and long-term treatment of cats and rats with atropine on the levels, release and effects of two peptides, vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI), that probably co-exist with acetylcholine in the parasympathetic nerves supplying the submandibular gland. Atropine treatment (progressively increasing doses from 2 to 15 mg kg-1 injected s.c.) for 14 days did not alter the contents of VIP- or PHI-like immunoreactivity (-IR) in the cat submandibular gland or in three other tissues (nasal mucosa, trachea and tongue). Acute as well as long-term atropine treatment decreased the vasodilation following low-, but not high-, frequency parasympathetic nerve stimulation. During prolonged stimulation (60 min) there was a decreased vasodilatation response following both acute and long-term atropine treatment. The overflow of VIP-IR and PHI-IR following parasympathetic nerve stimulation was markedly increased by acute, but not by long-term atropine treatment. The VIP- or PHI-induced stimulation of cyclic AMP (cAMP) accumulation in the cat submandibular gland was not altered after long-term atropine treatment. Similarly, treatment of male Sprague-Dawley rats with atropine (20 mg kg-1) or imipramine (20 mg kg-1) for 14 days did not alter the sensitivity to VIP or to PHI of cAMP accumulation in the submandibular gland, nor was there any change in VIP-IR or PHI-IR content. In conclusion, although atropine treatment causes an acute increase in the overflow of VIP and PHI evoked by parasympathetic nerve stimulation, there is no depletion of peptide stores upon long-term treatment, nor is there any change in the effect of exogenous VIP and PHI on cAMP-accumulation.

Adenylyl Cyclases↗
PubMed1992

Dolichol delays G1-arrest for one cell cycle in human fibroblasts subjected to depletion of serum or mevalonate.

It is well-established that some product(s) or metabolite(s) of mevalonate is (are) critical for growth of mammalian cells. In the search for this (these) compound(s) it seems meaningful to distinguish between compounds needed for cell cycle progression in proliferating cells and compounds needed for growth activation of arrested cells. By using time-lapse video recording we have studied the possible regulatory role of cholesterol, dolichol and mevalonate in the cell cycle of human diploid fibroblasts (HDF). HDF, which are serum-dependent, were rapidly growth-arrested in the first part of G1 upon removal of serum factors. They also responded to mevinolin (an HMG CoA reductase inhibitor) by a similar G1-block, indicating that a mevalonate-derived product is involved in the G1-located cell cycle control of HDF. Interestingly, dolichol counteracted the G1-block caused by both types of treatment. Hence, the early G1-cells could traverse the remainder of the cell cycle and divide despite depletion of serum or mevalonate. We also demonstrated that addition of dolichol resulted in a significant decrease in the rate of protein degradation. This protein stabilizing effect may constitute the mechanism by which dolichol delays the G1-arrest of HDF.

Cell Cycle↗
PubMed1991

Characteristics of endothelin A and B binding sites and their vascular effects in pig peripheral tissues.

The characteristics of endothelin-1 (ET-1) and endothelin-3 (ET-3) binding, and their relationship to second messenger formation in vitro and vascular effects in vivo were studied in the pig. Specific high-affinity binding sites for [125I]ET-1 and [125I]-ET-3 with extremely slow dissociation rates were demonstrated in membrane preparations from the spleen, lung, kidney and spinal cord. Displacement studies showed that receptor populations with much higher affinity for ET-1 than for ET-3 (ETA type) were present in the spleen and renal arteries, while in the whole kidney and spinal cord, receptor populations with similar affinity for ET-1 and ET-3 were found (ETB type). In the lung both receptor subtypes may be present. The precursor forms big ET-1 and big ET-3 were poor ligands although big ET-1 was more active on the ETA site than big ET-3 on the ETB site. Scatchard analysis revealed linear plots in all tissues studied. Both ET-1 and ET-3 increased formation of inositol phosphates in the lung, while ET-1 but not ET-3 was effective in the spleen. Neither ET-1 nor ET-3 were observed to influence basal or stimulated cyclic AMP formation in lung or spleen. ET-1 caused a much more potent and long-lasting increase in splenic and renal vascular resistance in vivo than did ET-3. On the other hand, ET-1 and ET-3 decreased vascular resistance with almost equal potency in the bronchial circulation.

Animals↗
PubMed1991

Inositol trisphosphate-dependent periodic activation of a Ca(2+)-activated K+ conductance in glucose-stimulated pancreatic beta-cells.

Glucose-stimulated insulin secretion is associated with the appearance of electrical activity in the pancreatic beta-cell. At intermediate glucose concentrations, beta-cell electrical activity follows a characteristic pattern of slow oscillations in membrane potential on which bursts of action potentials are superimposed. The electrophysiological background of the bursting pattern remains unestablished. Activation of Ca(2+)-activated large-conductance K+ channels (KCa channel) has been implicated in this process but seems unlikely in view of recent evidence demonstrating that the beta-cell electrical activity is unaffected by the specific KCa channel blocker charybdotoxin. Another hypothesis postulates that the bursting arises as a consequence of two components of Ca(2+)-current inactivation. Here we show that activation of a novel Ca(2+)-dependent K+ current in glucose-stimulated beta-cells produces a transient membrane repolarization. This interrupts action potential firing so that action potentials appear in bursts. Spontaneous activity of this current was seen only rarely but could be induced by addition of compounds functionally related to hormones and neurotransmitters present in the intact pancreatic islet. K+ currents of the same type could be evoked by intracellular application of GTP, the effect of which was mediated by mobilization of Ca2+ from inositol 1,4,5-trisphosphate (InsP3)-sensitive intracellular Ca2+ stores. These observations suggest that oscillatory glucose-stimulated electrical activity, which is correlated with pulsatile release of insulin, results from the interaction between the beta-cell and intraislet hormones and neurotransmitters. Our data also provide evidence for a close interplay between ion channels in the plasma membrane and InsP3-induced mobilization of intracellular Ca2+ in an excitable cell.

Animals↗
PubMed1991

Separate processes mediate nucleotide-induced inhibition and stimulation of the ATP-regulated K(+)-channels in mouse pancreatic beta-cells.

The mechanisms by which nucleotides stimulate the activity of the ATP-regulated K(+)-channel (KATP-channel) were investigated using inside-out patches from mouse pancreatic beta-cells. ATP produces a concentration-dependent inhibition of channel activity with a Ki of 18 microns. The inhibitory action of ATP was counteracted by ADP (0.1 mM) and GDP (0.2 mM) but not GTP (1 mM). Stimulation of channel activity was also observed when ADP, GDP and GTP were applied in the absence of ATP. The ability of ADP and GDP to reactivate KATP-channels blocked by ATP declined with time following patch excision and after 30-60 min these nucleotides were without effect. During the same time period the ability of ADP and GTP to stimulate the channel in the absence of ATP was lost. In fact, ADP now blocked channel activity with 50% inhibition being observed at approximately 0.1 mM. By contrast, GDP remained a stimulator in the absence of ATP even when its ability to evoke channel activity in the presence of ATP was lost. These observations show that nucleotide-induced activation of the KATP-channel does not involve competition with ATP for a common inhibitory site but involves other processes. The data are consistent with the idea that nucleotides modulate KATP-channel activity by a number of different mechanisms that may include both regulation of cytosolic constituents and direct interaction with the channel and associated control proteins.

Adenosine Diphosphate↗
PubMed1991

Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic B cells.

Insulin is produced and secreted by the B cells in the endocrine pancreas. In vivo, insulin secretion is under the control of a number of metabolic, neural and hormonal substances. It is now clear that stimulation of insulin release by fuel secretagogues, such as glucose, involves the closure of K+ channels that are sensitive to the intracellular ATP concentration (KATP channels). This leads to membrane depolarization and the generation of Ca2(+)-dependent action potentials. The mechanisms whereby hormones and neurotransmitters such as adrenaline, galanin and somatostatin, which are released by intraislet nerve endings and the pancreatic D cells, produce inhibition of insulin secretion are not clear. Here we show that adrenaline suppresses B-cell electrical activity (and thus insulin secretion) by a G protein-dependent mechanism, which culminates in the activation of a sulphonylurea-insensitive low-conductance K+ channel distinct from the KATP channel.

Animals↗
PubMed1991

Characterization, localization and actions of endothelins in umbilical vessels and placenta of man.

Endothelin-like immunoreactivity was observed in the endothelial lining of umbilical vein and artery as well as in the epithelium of the amniotic membrane. High levels of endothelin-like immunoreactivity (0.4-1.4 pmol g-1) were detected in human amniotic membrane, umbilical vessels and placenta. The concentration of endothelin-like immunoreactivity in the amniotic fluid was much higher (77 pmol l-1) than in umbilical cord plasma (10 pmol l-1). Characterization by reverse phase HPLC revealed that most of the endothelin-like immunoreactivity eluted in the position of synthetic endothelin-1 or oxidized endothelin-1. Specific, high affinity binding sites for endothelin-1 were present in placenta and umbilical artery. Endothelin binding sites were also found in cultured smooth muscle cells from the umbilical artery and vein. In the placenta, endothelin-1 and -3 were almost equipotent as competing ligands for endothelin-1 binding sites, whereas in the umbilical artery endothelin-3 was much less potent than endothelin-1. Scatchard analysis of the binding for placental membranes displayed a straight line (r = -0.994) indicating a single class of endothelin receptors with a Kd-value of 80 pmol l-1 and Bmax of 113 fmol mg-1. Endothelin-1 caused potent contractions of umbilical arteries and veins with threshold effects at 10 pmol l-1 while endothelin-3 had no contractile effect up to 10(-7) mol l-1. It is concluded that endothelin-1 predominates over other endothelins in umbilical vessels, amnion and placenta, and high levels of endothelin-1 was observed in foetal circulation and amniotic fluid. Endothelin-receptors seem to be of different types in placenta (ETB type) and umbilical vessels (ETA type).

Amniotic Fluid↗
PubMed1990

Human fibroblasts show expression of the leukotriene-A4-hydrolase gene, which is increased after simian-virus-40 transformation.

Human fibroblasts in cell culture converted the epoxide intermediate leukotriene A4 into the potent chemotaxin leukotriene B4. The identity of leukotriene B4 was ascertained by its mobility in reverse-phase high performance liquid chromatography, ultraviolet spectroscopy and gas chromatography/mass spectrometry. The presence of the enzyme responsible for the conversion (i.e. leukotriene A4 hydrolase), as well as the corresponding mRNA, were demonstrated by Western and Northern blot analyses. Leukotriene-A4-hydrolase enzyme activity, protein and mRNA were all enhanced (approximately threefold) in human fibroblasts that had been transformed by simian virus 40.

Cell Line↗
PubMed1990

Analgesic efficacy of acetaminophen sustained release.

The analgesic efficacy of acetaminophen sustained release (SR) and acetaminophen immediate plus sustained release (IR + SR) was evaluated in 200 outpatients with pain after oral surgery. Under double-blind conditions SR high dose (2000 mg) or low dose (1000 mg), IR + SR high dose (500 + 1500 mg) or low dose (250 + 750 mg), or acetaminophen standard tablet high dose (1000 mg) or low dose (500 mg) were randomly administered after removal of a lower third molar. The hourly pain intensity was rated on a visual analog scale during 12 hours. The efficacy was based on peak effect (maximum pain intensity difference in percent), pain reduction (mean percentage pain intensity difference), duration of effect (time to remedication) and pain reduction index (pain reduction multiplied by duration of effect). Pain reduction was 37% with the 500-mg tablet and 54% with SR 2000 mg. The peak effect increased from 53% after 1.9 hours for the 500-mg tablet to 67% after 2.6 hours for SR 2000 mg. The SR formulation significantly increased the duration of effect without reduction in peak effect.

Acetaminophen↗
PubMed1990

Calcitonin gene-related peptide stimulates proliferation of human endothelial cells.

The effects of the vasoactive perivascular neuropeptides calcitonin gene-related peptide (CGRP), neurokinin A (NKA), neuropeptide Y (NPY), and vasoactive intestinal polypeptide (VIP) on proliferation of cultured human umbilical vein endothelial cells (HUVECs) were investigated. CGRP was shown to increase both cell number and DNA synthesis, whereas NKA, NPY, and VIP were ineffective. 125I-labeled CGRP was shown to bind to HUVECs and this binding was displaced by addition of unlabeled CGRP, suggesting the existence of specific CGRP receptors. The effect of CGRP on formation of adenosine 3',5'-cyclic monophosphate (cAMP) and inositol phosphates (InsP), two intracellular messengers known to be involved in regulation of cell proliferation, was investigated. CGRP stimulated cAMP formation but was without effect on the formation of InsP. Proliferation, as well as cAMP formation, was also stimulated by cholera toxin. Basic fibroblast growth factor stimulated growth without affecting cAMP or InsP formation, whereas thrombin, which increased InsP formation, did not stimulate proliferation. We thus suggest that CGRP may act as a local factor stimulating proliferation of endothelial cells; that the mechanism of action is associated with cAMP formation; and that this effect of CGRP may be important for formation of new vessels during physiological and pathophysiological events such as ischemia, inflammation, and wound healing.

Calcitonin↗
PubMed1990

VIP and forskolin enhance carbachol-induced K+ efflux from rat salivary gland fragments by a Ca2(+)-sensitive mechanism.

The effect of vasoactive intestinal peptide (VIP) and forskolin on carbachol-induced K+ release from superfused rat submandibular and parotid gland fragments was examined using a K(+)-sensitive electrode. Carbachol (0.1, 1, and 10 microM) superfused over the glandular fragments for 15 min caused a concentration-dependent, transient elevation of K+ efflux, with a peak value after approximately 5 min. The carbachol-induced release of K+ could be divided into two distinct components, one transient peak lasting 5-8 min independent of extracellular Ca2+ and a second component of K+ release dependent on Ca2+ in the perfusion medium. VIP (1 microM) lacked effect on K+ efflux on its own but increased the carbachol (1 microM)-evoked K+ release. The VIP effects on K+ efflux were mimicked by forskolin (10 microM). Omission of Ca2+ from the medium totally abolished the augmenting effect of VIP and forskolin on carbachol-evoked K+ efflux. The Ca2+ ionophore A23187 (1 or 10 microM) induced a prolonged low-rate efflux of K+, which was dependent on Ca2+ in the medium. This effect of A23187 on K+ secretion was potentiated by forskolin (10 microM). The Na(+)-K(+)-ATPase blocker ouabain did not affect K+ release on its own, a lack of effect which remained following pretreatment with forskolin. It is concluded that VIP, by increasing the intracellular levels of cAMP in the glandular cell, potentiates carbachol-evoked Ca2(+)-dependent K+ efflux. These results may help to explain the synergistic effects of the coexisting transmitters VIP and acetylcholine.

Animals↗
PubMed1989

Abolition of mevinolin-induced growth inhibition in human fibroblasts following transformation by simian virus 40.

The basal level of the gene expression and the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase was higher in SV40-transformed human fibroblasts (90-VA VI) than in normal ones (HDF). In both these cell types mevinolin (25 microM) caused an 85-90% depression of HMG CoA reductase activity and of the incorporation of [3H]acetate into sterols. In HDF this was coupled to an efficient block of cell growth, whereas the growth of 90-VA VI was only slightly reduced by mevinolin. In HDF, mevinolin (25 microM) also abolished essentially all dilichol synthesis, as measured by incorporation of [3H]acetate. In contrast, dolichol synthesis remained unaltered, or was increased, in mevinolin-treated 90-VA VI. We suggest that these different responses of dolichol synthesis may depend on different substrate affinities of the rate-limiting enzyme in the dolichol pathway. However, if 90-VA VI was treated with 25-hydroxycholesterol (25-OH), an alternative inhibitor of HMG CoA reductase, the cellular growth as well as dolichol synthesis was significantly decreased. Since the inhibitory effect of 25OH on HMG CoA reductase activity did not exceed that of mevinolin, it seems that 25-OH, besides HMG CoA reductase, inhibits steps distal to HMG CoA reductase. This notion was further supported by the finding that addition of mevalonate did not prevent the 25-OH-induced growth inhibition. However, if dolichol was added along with 25-OH, the block was partially prevented, indicating that a critical level of de novo synthesis of dolichol for cellular growth.

Cell Division↗