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  • 1.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Pharmacology.
    Commentary: Artificial neural networks: Useful aid in diagnosing acute appendicitis2008In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 32, no 2, p. 310-311p. 310-311Article in journal (Other academic)
    Abstract [en]

    [No abstract available]

  • 2.
    Andersson, Rolf G
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Bartonek, M
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lindström, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lindström, I M
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Toll, Johan B
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Studies of the mechanism of desensitization of anti-IgE-mediated histamine release from human basophils1989In: Agents and actions, ISSN 0065-4299, Vol. 27, no 1-2, p. 25-28Article in journal (Refereed)
    Abstract [en]

    Human basophils became hyporesponsive to anti-IgE when exposed to this agent in the absence of Ca2+ for more than 10 min. The desensitization process proceeded in parallel to the releasing-process. The mechanism of desensitization seems to involve a very early step in the release-reaction, since the response to phospholipase A2 and diolein, agents involved in the release-reaction, was not affected by the desensitization.

  • 3.
    Andersson, Rolf
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Quirk, Chris
    Royal Perth Hospital, WA Australien.
    Sullivan, John
    Liverpool Hospital, NSW Australien.
    Anderson, Chris
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Cutaneous manifestations of internal disease2008In: Drug Discovery Today : Disease Mechanisms, ISSN 1740-6765, E-ISSN 1740-6765, Vol. 5, no 1, p. e113-e123Article in journal (Refereed)
    Abstract [en]

    The skin mirrors the individual's well being. Visible for both the patient and the attending physician, it can be a source of information for the diagnosis of multi-system diseases and diseases of internal organs. Therapy is usually directed at the primary disease. Pharmaco-therapeutic options for internal diseases are at present not always optimal and specific management of side effects of drugs with vital indication may be necessary. Better understanding of the mechanisms of the cutaneous manifestations may help develop more efficacious, better tolerated therapy and improve the patient's situation.

  • 4.
    Eriksson, Therese
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Svensson, Samuel
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Role of ginsenosides and quercetin in anterograde transport of melanosomesManuscript (preprint) (Other academic)
    Abstract [en]

    Panax ginseng is a traditional herb that has been used in the Orient for several thousands of years as a tonic and restorative. Active components of ginseng include ginsenosides, polysaccharides, flavonoids, polyacetylenes, peptides, vitamins, phenols and enzymes, of which the ginsenosides are considered to be the major bioactive constituents. In spite of extensive use, the exact mechanisms of ginseng and its components are still unknown. In the present study we use melanophores from Xenopus laevis to investigate the effects of Panax ginseng extract G115, ginsenosides and the flavonoid quercetin on pigment organelle transport and signalling. Through coordinated transport of their black pigmented granules (melanosomes), melanophores are capable of fast colour changes. The movement is regulated by changes in cyclic adenosine 3’:5’-monophosphate (cAMP) concentration, where a high or low level induce anterograde (dispersion) or retrograde (aggregation) transport respectively, leaving a dark or light cell. Previously we have shown that Panax ginseng induces dispersion of melanosomes. Here, ginsenoside Rc and Rd and the flavonoid quercetin are shown to stimulate an anterograde transport of pigment organelles. When Rc or Rd and quercetin were combined, a significant synergistic increase in dispersion could be seen. Protein kinase C (PKC) inhibitor Myristoylated EGF-R Fragment (651-658) (M-EGF) decreased the anterograde movement stimulated by ginseng and ginsenoside Rc and Rd. We also demonstrate that ginseng, but not ginsenosides or quercetin, induce a concentration-dependent activation of 44/42-mitogen activated protein kinase (MAPK). PKC-inhibition did not affect the MAPK-activation, suggesting a role for PKC in the ginseng- and ginsenoside-induced anterograde transport but not in the activation of MAPK.

  • 5.
    Eriksson, Therese
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Svensson, Samuel
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Andersson, Tony
    Landstinget i Kronoberg.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Panax ginseng induces anterograde transport of pigment organelles in Xenopus melanophores2008In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 119, no 1, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Melanophores from Xenopus laevis are pigmented cells, capable of quick colour changes through cyclic adenosine 3':5'-monophosphate (cAMP) coordinated transport of their intracellular pigment granules, melanosomes. In this study we use the melanophore cell line to evaluate the effects of Panax ginseng extract G115 on organelle transport. Absorbance readings of melanophore-coated microplates, Correlate-EIA direct cAMP enzyme immunoassay kit, and western blot were used to measure the melanosome movement and changes in intracellular signalling. We show that Panax ginseng induces a fast concentration-dependent anterograde transport of the melanosomes. No significant increase in the cAMP level was seen and pre-incubation of melanophores with the protein kinase C (PKC) inhibitor EGF-R Fragment 651-658 (M-EGF) only partly decreased the ginseng-induced dispersion. We also demonstrate that Panax ginseng, endothelin-3 (ET-3) and alpha-melanocyte stimulating hormone (MSH) stimulate an activation of mitogen activated protein kinase (MAPK). Pre-incubation with M-EGF decreased the MAPK activity induced by ET-3 and MSH, but again only marginally affected the response of Panax ginseng. Thus, in melanophores we suggest that Panax ginseng stimulates an anterograde transport of pigment organelles via a non-cAMP and mainly PKC-independent pathway.

  • 6.
    Fägerstam, JP
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, PA
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: gastromed.
    Andersson, RGG
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Expression of platelet P-selectin and detection of soluble P-selectin, NPY and RANTES in patients with inflammatory bowel disease2000In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 49, no 9, p. 466-472Article in journal (Refereed)
    Abstract [en]

    Objective and Design: P-selectin, a membrane glycoprotein which is expressed on activated platelets and endothelial cells, plays a crucial role in the inflammatory response. The main action is adhesion of leukocytes, facilitation of diapedesis and induction of cytokine production from monocytes (MCP-1 and IL-8), mediated via RANTES released from activated platelets. An abnormal platelet activity has been reported in patients with ulcerative colitis (uc) and Crohn's disease (CD), jointly referred to as inflammatory bowel disease (IBD), which could have an aggravating influence on the inflammatory response. In addition, an up-regulation of platelet IL-8 receptors among patients with IBD has been reported. To reveal a presumptuous platelet dysfunction we analysed the expression of platelet surface P-selectin at resting state and after stimulation with thrombin, collagen, epinephrine and interleukin 8 (IL-8), and plasma levels of soluble P-selectin, neuropeptide Y (NPY) and RANTES in patients with IBD. Subjects: Blood from twelve healthy subjects (control group) and twenty-one patients with IBD who had not taken any anti-platelet drugs or steroids were analysed. Methods: Patients were sub-grouped according to disease entity, disease activity and 5ASA medication. Surface P-selectin expression on isolated human platelets and plasma P-selectin, NPY and RANTES were analysed with ELISA. All values are presented as mean ▒ standard error of the mean (SEM). Mann-Whitney U test and Wilcoxon matched rank test were used for statistical analyses. Results: Patients with IBD in remission (n = 9) had higher basal P-selectin expression, 0.38 ▒ 0.04, compared to the control group (n = 12), 0.22 ▒ 0.03, p < 0.01. UC patients (n = 16) showed down-regulation of P-selectin expression after stimulation with IL-8, 0.26 ▒ 0.03 to 0.22 ▒ 0.02, p < 0.05. No significant differences could be observed concerning soluble P-selectin and NPY in plasma. Patients with 5ASA (n = 12) had lower levels of plasma RANTES, 2.39 ▒ 0.06 ╡g/l, compared to the control group (n = 12), 3.29 ▒ 0.19 ╡g/l, p < 0.01, and patients without 5ASA (n = 9), 2.90 ▒ 0.17 ╡g/l, p < 0.05. Conclusions: Patients with IBD in remission have higher basal platelet surface P-selectin expression. An exaggerated platelet activity with increased expression of platelet P-selectin and release of inflammatory mediators such as RANTES, which is chemotactic and induce chemokine production, could have a reinforcing and aggravating influence on the inflammatory response and increase the susceptibility to IBD. In addition IL-8 has a down-regulating effect on platelet surface P-selectin expression and 5ASA medication seems to lower plasma RANTES. If 5ASA is responsible for lowering the concentration of RANTES this could be one of the beneficial outcomes of 5ASA medication.

  • 7.
    Handley, Dean A.
    et al.
    Sepracor Inc, Marlborough, MA, USA.
    Senanayake, Chris H
    Sepracor Inc, Marlborough, MA, USA.
    Dutczak, William
    Sepracor Inc, Marlborough, MA, USA.
    Benovic, Jeffrey L
    Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA.
    Walle, Thomas
    Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA.
    Penn, Raymond B.
    Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, USA.
    Wilkinson, H. Scott
    Sepracor Inc, Marlborough, MA, USA.
    Tanoury, Gerald J.
    Sepracor Inc, Marlborough, MA, USA.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Johansson, Fredrik
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Morley, John
    Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine and Allergy, Guys, King's and St Thomas' School of Medicine, Denmark Hill, London, UK.
    Biological actions of formoterol isomers2002In: Pulmonary Pharmacology & Therapeutics, ISSN 1094-5539, E-ISSN 1522-9629, Vol. 15, no 2, p. 135-145Article in journal (Refereed)
    Abstract [en]

    Racemic β2 agonists, composed of equal amounts of (R)- and (S)-isomers, can display anomalous actions that compromise their effectiveness as asthma therapies. Loss of efficacy during regular use is characteristic of isoprenaline, albuterol and terbutaline and has in part been attributed to the biological effects of the (S)-isomer. This hypothesis was applied to the (R,R)- and (S,S)-isomers of formoterol. (R,R)-formoterol had 1000-times greater affinity (2.9 nm) to the human β2 adrenoceptor than (S,S)-formoterol (3100 nm), with receptor binding modulating intracellular cAMP levels. The minimum lethal intravenous (IV) dose was determined to be 100 mg/kg for (R,R)- and 50 mg/kg for (S,S)-formoterol, suggesting that the toxicity of (S,S)-formoterol may not be related to the binding of β2 adrenoceptors. In tissues pretreated with (S,S)-formoterol but not with (R,R)- or racemic formoterol contractions to high concentrations of carbachol were exaggerated. In vivo experiments with sensitized guinea pigs demonstrated that (R,R)-formoterol inhibited both histamine and antigen-induced bronchoconstriction with greater potency than (R,R/S,S)-formoterol while (S,S)-formoterol was ineffective. Metabolic radiolabeling experiments of (R,R)-, (S,S)- or (R,R/S,S)-formoterol with crude human liver phenolsulfotransferase (PST) determined the Vmax/Km values to be (0.151), (0.74) and (0.143), respectively. The reciprocal plot illustrates a 2-fold reduction in sulfation rate when (R,R)-formoterol is present as a single isomer. The data presented here suggest that (R,R)-formoterol binds to the β2 adrenoceptor and inhibits the contraction of bronchial tissues by spasmogens. However, (S,S)-formoterol exhibits properties inconsistent as an asthma therapeutic and may antagonize the actions of (R,R)-formoterol.

  • 8.
    Jacobsson, Leif S.
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Aberg, Gunnar
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Karlberg, Bengt E.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Anders G.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Antiatherosclerotic Effects of the Angiotensin-Converting Enzyme Inhibitors Captopril and Fosinopril in Hypercholesterolemic Minipigs1994In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 24, no 4, p. 670-677Article in journal (Refereed)
    Abstract [en]

    We evaluated the two angiotensin-converting enzyme (ACE) inhibitors captopril and fosinopril with regard to possible antiatherosclerotic effects in minipigs. Experimental hypercholesterolemia and atherosclerosis was produced in 33 minipigs of the Gottingen strain by an egg yolk/cholesterol-enriched diet for 1 year. One group (n = 11) was fed the atherogenic diet alone and served as a control. A second group (n = 11) received captopril (80 mg/kg/day) added to the atherogenic diet, and a third group (n = 11) was treated in the same manner but with fosinopril (8 mg/kglday). The drug treatments produced significant reduction in serum ACE activity associated with a reactive increase in plasma renin activity (PRA), but had only minor effects on plasma lipids and lipoproteins. At the end of the treatment period, all animals were killed and examined for degree of atherosclerosis. The percentage of atherosclerotic area in the abdominal aorta was significantly lower in both drug-treated groups as compared with controls. Furthermore, accumulation of cholesterol in the thoracic and abdominal aorta was inhibited by drug treatment. Finally, the percentage of intimal thickening in abdominal aorta was significantly reduced in the drug-treated groups. In conclusion, the ACE inhibitors captopril and fosinopril inhibited development of atherosclerosis in hypercholesterolemic minipigs.

  • 9.
    Johansson, Fredrik
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Albinsson, Sebastian
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Direct and amplifying effects of the ß-adrenoceptor antagonist propranolol on guinea pig airway contractility in vitroManuscript (preprint) (Other academic)
    Abstract [en]

    In the present study we establish that the ß-AA antagonist propranolol can, besides its ß-AR blocking effect, either amplify or direct induce a contraction in guinea pig airway preparations, in vitro.

    Propranolol significantly enhanced the contractile response to ovalbumin (OA). The enhancement was reduced by capsaicin but insensitive to indomethacin pretreatment. These results suggest that propranolol produce airway hyperreactivity to OA by activating a pathway involving tachykinins and that COX-products are of minor significance.

    We also confirm that propranolol can induce a tracheal smooth muscle contraction directly, although pre-treatment with carbachol/formoterol is a prerequisite. Direct contractile responses were completely diminished by indomethacin and reduced by capsaicin and L-659,877 (a NK2-receptor antagonist) pre-treatment. The present study shows that propranolol also enhances NANC (excitatory non-adrenergic noncholinergic) contractions but this enhancement requires pre-treatment with a 13-agonist. When the pre-treatment was excluded propranolol failed to exert either a direct or an amplifying effect on EFS (electrical field stimulation). These results contrast to the recorded enhancement of the OA-induced response, which did not request any pre-treatment.

    In addition, propranolol induced an elevation of [Ca2+], in ASMC (airway smooth muscle cells), this effect was not dependent on any pre-treatment and inhibited by indomethacin treatment.

    The mechanism behind these adverse effects of propranolol is not known, but our results demonstrate that contractile mediators do not originate from the airway epithelium. Since, epithelium removal did not reduce the contractile response. Furthermore, pertussis toxin (PTX) treatment did not effect the propranolol-induced contraction, indicating that a PTX sensitive G-protein coupling pathway not is involved.

    In conclusion our results show that both indomethacin and capsaicin sensitive pathways are involved in the contractile response to propranolol. The relative significance of these systems differs; the direct contractile effect is strongly dependent on an indomethacin sensitive pathway, while the amplifying effect is sensitive to capsaicin and insensitive to indomethacin pre-treatment.

    Further studies are required to elucidate the clinical relevance of these results.

  • 10.
    Johansson, Fredrik
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Svensson, Samuel
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    An indomethacin-sensitive contraction induced by β-antagonists in guinea pig airways2004In: Canadian Journal of Physiology and Pharmacology, ISSN 0008-4212, E-ISSN 1205-7541, Vol. 82, no 6, p. 393-401Article in journal (Refereed)
    Abstract [en]

    β-adrenergic receptor (β-AR) antagonists have been associated with increased airway reactivity in asthmatics and potentiation of contractile stimuli in animal models. In the present study, using an in vitro model of tracheal preparations from guinea pigs, we show that the β-AR antagonists propranolol and pindolol induce a smooth muscle contraction. A prerequisite for this contraction is that the airway preparations have been pre-treated with an β-AR agonist. Our data show that the contractile effect of β-AR antagonists is not a simple consequence of reversing the agonist-induced relaxation. Furthermore, the effect seems to be mediated through interaction with β2-ARs since the response is stereo-selective, and the selective β1-AR receptor antagonist atenolol did not induce any contractile response. SQ 29,546, a thromboxane A2 antagonist; MK 886, a lipoxygenase inhibitor; and indomethacin, a cyclooxygenase inhibitor significantly inhibited the contractions of the tracheal preparations induced with propranolol or pindolol. We put forward the hypothesis that the contractile effect of the β-AR antagonist is a consequence of their inverse agonist activity, which is only evident when the receptor population have a higher basal activity. Our results indicate a novel additional explanation for the known side effect, bronchoconstriction, of β-AR antagonist.Key words: beta antagonist, guinea pig trachea, propranolol, formoterol, pindolol, indomethacin.

  • 11.
    Johansson, Fredrik
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Rydberg, Irene
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Aberg, Gunnar
    Sepracor Inc, Pharmaceutical Divisian, Marlborough, MA.
    Andersson, Rolf G. G.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of albuterol enantiomers on in vitro bronchial reactivity1996In: Clinical reviews in allergy and immunology, ISSN 1080-0549, E-ISSN 1559-0267, Vol. 14, no 1, p. 57-64Article in journal (Refereed)
    Abstract [en]

    No abstract available

  • 12.
    Karlsson, Jan Olof
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Adolfsson, Karin
    County Hospital Ryhov, Sweden .
    Thelin, Bo
    County Hospital Ryhov, Sweden .
    Jynge, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Falkmer, Ursula G
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    First Clinical Experience with the Magnetic Resonance Imaging Contrast Agent and Superoxide Dismutase Mimetic Mangafodipir as an Adjunct in Cancer Chemotherapy-A Translational Study2012In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 5, no 1, p. 32-38Article in journal (Refereed)
    Abstract [en]

    Preclinical research suggests that the clinically approved magnetic resonance imaging contrast agent mangafodipir may protect against adverse events (AEs) caused by chemotherapy, without interfering negatively with the anticancer efficacy. The present translational study tested if pretreatment with mangafodipir lowers AEs during curative (adjuvant) FOLFOX6 chemotherapy in stage III colon cancer (Dukes C). The study was originally scheduled to include 20 patients, but because of the unforeseen withdrawal of mangafodipir from the market, the study had to be closed after 14 patients had been included. The withdrawal of mangafodipir was purely based on commercial considerations from the producer and not on any safety concerns. The patients were treated throughout the first 3 of 12 scheduled cycles. Patients were randomized to a 5-minute infusion of either mangafodipir or placebo (7 in each group). AEs were evaluated according to the National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events and the Sanofi-NCI criteria. The primary end points were neutropenia and neurosensory toxicity. There were four AEs of grade 3 (severe) and one AE of grade 4 (life threatening) in four patients in the placebo group, whereas there were none in the mangafodipir group (P andlt; .05). Of the grade 3 and 4 events, two were neutropenia and one was neurosensory toxicity. Furthermore, white blood cell count was statistically, significantly higher in the mangafodipir group than in the placebo group (P andlt; .01) after treatment with FOLFOX. This small feasibility study seems to confirm what has been demonstrated preclinically, namely, that pretreatment with mangafodipir lowers AEs during adjuvant 5-fluorouracil plus oxaliplatin-based chemotherapy in colon cancer patients.

  • 13.
    Karlsson, Jan Olof G
    et al.
    PledPharma AB, Sweden .
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Flechsig, Susanne
    Expt Pharmacol and Oncology Berlin Buch GmbH, Germany .
    Nasstrom, Jacques
    PledPharma AB, Sweden .
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Superior Therapeutic Index of Calmangafodipir in Comparison to Mangafodipir as a Chemotherapy Adjunct2012In: TRANSLATIONAL ONCOLOGY, ISSN 1944-7124, Vol. 5, no 6, p. 492-502Article in journal (Refereed)
    Abstract [en]

    Mangafodipir is a magnetic resonance imaging contrast agent with manganese superoxide dismutase (MnSOD) mimetic activity. The MnSOD mimetic activity protects healthy cells against oxidative stress-induced detrimental effects, e. g., myelosuppressive effects of chemotherapy drugs. The contrast property depends on in vivo dissociation of Mn2+ from mangafodipir-about 80% dissociates after injection. The SOD mimetic activity, however, depends on the intact Mn complex. Complexed Mn2+ is readily excreted in the urine, whereas dissociated Mn2+ is excreted slowly via the biliary route. Mn is an essential but also a potentially neurotoxic metal. For more frequent therapeutic use, neurotoxicity due to Mn accumulation in the brain may represent a serious problem. Replacement of 4/5 of Mn2+ in mangafodipir with Ca2+ (resulting in calmangafodipir) stabilizes it from releasing Mn2+ after administration, which roughly doubles renal excretion of Mn. A considerable part of Mn2+ release from mangafodipir is governed by the presence of a limited amount of plasma zinc (Zn2+). Zn2+ has roughly 10(3) and 10(9) times higher affinity than Mn2+ and Ca2+, respectively, for fodipir. Replacement of 80% of Mn2+ with Ca2+ is enough for binding a considerable amount of the readily available plasma Zn2+, resulting in considerably less Mn2+ release and retention in the brain and other organs. At equivalent Mn2+ doses, calmangafodipir was significantly more efficacious than mangafodipir to protect BALB/c mice against myelosuppressive effects of the chemotherapy drug oxaliplatin. Calmangafodipir did not interfere negatively with the antitumor activity of oxaliplatin in CT26 tumor-bearing syngenic BALB/c mice, contrary calmangafodipir increased the antitumor activity. Translational Oncology (2012) 5, 492-502

  • 14.
    Karlsson, Jan-Erik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden.
    El-Saadi, Walid
    Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden.
    Ali, Mustafa
    Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden; Department of Radiology, County Council of Jönköping, Jönköping, Sweden.
    Puskar, Werner
    Department of Radiology, County Council of Jönköping, Jönköping, Sweden.
    Skogvard, Patrik
    Department of Internal Medicine, County Council of Jönköping, Ryhov County Hospital, Jönköping, Sweden.
    Engvall, Jan E
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Maret, Eva
    Department of Radiology, County Council of Jönköping, Jönköping, Sweden; Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
    Jynge, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. PledPharma AB, Stockholm, Sweden.
    Mangafodipir as a cardioprotective adjunct to reperfusion therapy: a feasibility study in patients with ST-segment elevation myocardial infarction2015In: European Heart Journal - Cardiovascular Pharmacotherapy, ISSN 2055-6837, Vol. 1, no 1, p. 39-45Article in journal (Refereed)
    Abstract [en]

    Aims The aim of the present study was to examine the feasibility of applying the catalytic antioxidant mangafodipir [MnDPDP, manganese (Mn) dipyridoxyl diphosphate] as a cardioprotective adjunct to primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation (STE) myocardial infarction (STEMI). Both MnDPDP and a metabolite (Mn dipyridoxyl ethyldiamine) possess properties as mitochondrial superoxide dismutase mimetics and iron chelators, and combat oxidative stress in various tissues and conditions.

    Methods and results

    The study tested MnDPDP (n ¼ 10) vs. saline placebo (n ¼ 10), given as a brief intravenous (i.v.) infusion prior to balloon inflation during pPCI in patients with STEMI. Mangafodipir waswell tolerated and did not affect heart rate or blood pressure. Despite longer ischaemic time (205 vs. 144 min, P ¼ 0.019) in theMnDPDPgroup, plasma biomarker releaseswere identical for the two groups. With placebo vs.MnDPDP, mean STE resolutions were 69.8 vs. 81.9% (P ¼ 0.224) at 6 h and 73.1 vs. 84.3% (P ¼ 0.077) at 48 h. Cardiac magnetic resonance revealed mean infarct sizes of 32.5 vs. 26.2% (P ¼ 0.406) andmeanleft ventricular (LV) ejection fractions of 41.8 vs. 47.7% (P ¼ 0.617) with placebovs.MnDPDP.More LVthrombi were detected in placebo hearts (5 of 8) than MnDPDP-treated hearts (1 of 10; P ¼ 0.011).

    Conclusions Mangafodipir is a safe drug for use as an adjunct to reperfusion therapy. A tendency to benefit of MnDPDP needs confirmation in a larger population. The study revealed important information for the design of a Phase II trial.

     

  • 15.
    Kurz, Tino
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grant, Derek
    GE Healthcare, Oslo, Norway.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Robertson, Towart
    Audacter Consulting, Helensburgh, Scotland.
    De Cesare, Michelandrea
    Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milano, Italy.
    Karlsson, Jan Olof G.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of MnDPDP andICRF-187 on Doxorubicin-Induced Cardiotoxicityand Anticancer Activity12012In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 5, no 4, p. 252-259Article in journal (Refereed)
    Abstract [en]

    Oxidative stress participates in doxorubicin (Dx)–induced cardiotoxicity. The metal complex MnDPDP and its metaboliteMnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice wereinjected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, theleft atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility wasmeasured for 60 minutes. In parallel experiments, 10 μM MnDPDP or MnPLED was added directly into the organbath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780)was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP,and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuatedthe negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLEDattenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the antitumoractivity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed anin vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized toMnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotectiontakes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest thatthe previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP.

    Translational Oncology (2012) 5, 252–259

  • 16.
    Laskar, Amit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G G
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Fodipir (Dp-dp) and its dephosphorylated derivative PLED are involved in mangafodipir mediated cyto-protection against 7β-hydroxycholesterol induced cell death2013Manuscript (preprint) (Other academic)
    Abstract [en]

    Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolite of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent, dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7βOH) induced cell death and identify the underlying mechanisms. U937 cells were pre-treated or not with mangafodipir substrate (Ms) (200 μm), MnPLED (100 μM) or Dp-dp (100 μM) for 8 hours and then exposed to 7βOH (28 μM) for 18 hours. Our results revealed that pre-treatment with MnPLED or Dp-dp protected against 7βOH induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dpdp in par with Ms, confer protection against 7βOH induced cytotoxicity by reducing  cellular ROS and stabilization of lysosomal membrane. These results suggest that, fodipir is the active part in mangafodipir, which shows the noted effects and its activity is conserved in MnPLED. These results further confirm the cyto-protective effect of mangafodipir and justify its potential use as a cyto-protective adjuvant.

  • 17.
    Laskar, Amit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fodipir and Its Dephosphorylated Derivative Dipyridoxyl Ethyldiamine Are Involved in Mangafodipir-Mediated Cytoprotection against 7 beta-Hydroxycholesterol-Induced Cell Death2013In: Pharmacology, ISSN 0031-7012, E-ISSN 1423-0313, Vol. 92, no 3-4, p. 182-186Article in journal (Refereed)
    Abstract [en]

    Objective: Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolites of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol-induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7 beta-hydroxycholesterol (7 beta-OH)-induced cell death and identify the underlying mechanisms. Methods: U937 cells were pretreated or not with mangafodipir substrate (Ms; 200 pm), MnPLED (100 mu mol/l) or Dp-dp (100 mu mol/l) for 8 h and then exposed to 7 beta-OH (28 mu mol/l) for 18 h. Results: Our results revealed that pretreatment with MnPLED or Dp-dp protected against 7 beta-OH-induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dp-dp, in par with Ms, confer protection against 7 beta-OH-induced cytotoxicity by reducing cellular ROS and stabilization of the lysosomal membrane. Conclusion: These results suggest that fodipir is the pharmacologically active part in the structure of mangafodipir, which prevents 7 beta-OH-induced cell death by attenuating cellular ROS and by preventing LMP. In addition, MnPLED, which is the dephosphorylated product of fodipir, exerts a similar protective effect against 7 beta-OH-induced cytotoxicity. This result indicates that dephosphorylation of fodipir does not affect its pharmacological actions. Altogether our result confirms the cytoprotective effect of mangafodipir and justifies its potential use as a cytoprotective adjuvant.

  • 18.
    Laskar, Amit
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Miah, Sayem
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G G
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways2010In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, no 640, p. 124-128Article in journal (Refereed)
    Abstract [en]

    Mangafodipir, a MRI contrast agent, has been used as a viability marker in patients with myocardial infarction and showed vascular relaxation effect. It confers myocardial protection against oxidative stress. However mechanisms underlying such protection have not yet been investigated. In this investigation we first studied whether mangafodipir inhibits apoptosis induced by 7beta-hydroxycholesterol (7betaOH), a cytotoxic cholesterol oxidation product found in atherosclerotic lesions in humans and in heart of ethanol-fed rats. We then focused on whether mangafodipir influences the production of reactive oxygen species, lysosomal and mitochondrial membrane permeabilities in the cell model. Our results revealed that pre-treatment with mangafodipir (400microM) protected against cellular reactive oxygen species production, apoptosis, and permeabilization of lysosomal and mitochondrial membranes induced by 7betaOH. In conclusion, a novel effect of mangafodipir on 7betaOH-induced apoptosis is via reduction of cellular reactive oxygen species and stabilization of lysosomal and mitochondrial membranes. This is the first report to show the additional cytoprotective effect of mangafodipir, which may suggest possible use of the drug.

  • 19. Martensson, LGE
    et al.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    A pharmacological interaction between melatonin and the alpha(2)-adrenoceptor in cuckoo wrasse melanophores1999In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 460, p. 221-228Article in journal (Refereed)
  • 20.
    Martensson, L.G.E.
    et al.
    Mårtensson, L.G.E., Department of Zoology, Göteborg University, Box 463, SE-405 30 Göteborg, Sweden.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Is Ca2+ the second messenger in the response to melatonin in cuckoo wrasse melanophores?2000In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 66, no 11, p. 1003-1010Article in journal (Refereed)
    Abstract [en]

    Pigment aggregation in melanophores of Labrus ossifagus is controlled by an a2-adrenoceptor and is somehow modulated by melatonin. The signal transduction mechanisms seem to involve both an attenuation of cAMP and an increase in intracellular Ca2+, inhibiting protein kinase A or activating a phosphatase, respectively. These effects result in dephosphorylation, which in turn induces aggregation. Various a2-adrenoceptor agonists attenuate cAMP levels or increase the concentration of intracellular Ca2+. Noradrenaline, for example, lowers cAMP but does not affect the calcium signal whereas B-HT 920, an a2-adrenoceptor specific agonist, does not induce a cAMP decrease but does appear to induce an increase in intracellular Ca2+. This later inference is drawn from experiments with BAPTA/AM, an intracellular calcium chelator, which counteracts the aggregation induced by B-HT 920. Interestingly, the very potent a2-adrenoceptor agonist medetomidine apparently activates both signal transduction pathways, which could explain its high efficacy in producing aggregation. Melatonin itself does not cause pigment aggregation, but it potentiates noradrenaline-induced aggregation. It has been suggested that melatonin receptors and a2- adrenoceptors follow the same signal transduction pathway, i.e. an attenuation of cAMP. In our experiments, melatonin did not reduce cAMP levels, instead it appears to increase Ca2+ concentration, since melatonin- potentiated aggregation was inhibited by BAPTA/AM. Thus, aggregation amplified by melatonin is probably not mediated by a further decrease in cAMP, but by the same signal transduction mechanism as B-HT 920, i.e. an increase in Ca2+. This further strengthens the suggestion that melatonin and B-HT 920 bind to the same site, but it is unclear if that particular site is on the melatonin receptor or the a2-adrenoceptor.

  • 21.
    Naidu Sjöswärd, Kerstin
    et al.
    Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Schmekel, Birgitta
    Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Metabolism of salbutamol differs between asthmatic patients and healthy volunteers2003In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 92, no 1, p. 27-32Article in journal (Refereed)
    Abstract [en]

    Patients with asthma are a target group for medication with β2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries β2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 μg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.

  • 22.
    Nilsson, Ulrika K.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Ekeroth, Johan
    Linköping University, Department of Physics, Chemistry and Biology.
    Hallin, Elisabeth C.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Lindberg, Jan
    Linköping University, Department of Physics, Chemistry and Biology.
    Svensson, Samuel P.S.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lack of stereospecificity in lysophosphatidic acid enantiomerinduced calcium mobilization in human erythroleukemia cells2003In: Lipids, ISSN 0024-4201, Vol. 38, no 10, p. 1057-1064Article in journal (Refereed)
    Abstract [en]

    Lysophosphatidic acid (LPA) is a lipid mediator that, among several other cellular responses, can stimulate cells to mobilize calcium (Ca2+). LPA is known to activate at least three different subtypes of G protein-coupled receptors. These receptors can then stimulate different kinds of G proteins. In the present study, LPA and LPA analogs were synthesized from (R)- and (S)-glycidol and used to characterize the ability to stimulate Ca2+ mobilization. The cytosolic Ca2+ concentration ([Ca2+]i) was measured in fura-2-acetoxymethylester-loaded human erythroleukemia (HEL) cells. Furthermore, a reverse transcriptase polymerase chain reaction was used to characterize LPA receptor subtypes expressed in HEL cells. The results show that HEL cells mainly express LPA1 and LPA2, although LPA3 might possibly be expressed as well. Moreover, LPA and its analogs concentration-dependently increased [Ca2+]i in HEL cells. The response involved both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores. This is the first time the unnatural (S)-enantiomer of LPA, (S)-3-O-oleoyl-1-O-phosphoryl-glycerol, has been synthesized and studied according to its ability to activate cells. The results indicate that this group of receptors does not discriminate between (R)- and (S)-enantiomers of LPA and its analogs. When comparing ether analogs having different hydrocarbon chain lengths, the tetradecyl analog (14 carbons) was found to be the most effective in increasing [Ca2+]i. Pertussis toxin treatment of the HEL cells resulted in an even more efficient Ca2+ mobilization stimulated by LPA and its analogs. Furthermore, at repeated incubation with the same ligand no further increase in [Ca2+]i was obtained. When combining LPA with the ether analogs no suppression of the new Ca2+ signal occurred. All these findings may be of significance in the process of searching for specific agonists and antagonists of the LPA receptor subtypes.

  • 23.
    Nyhlén, Kristina
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Gautam, Chamilly
    Hospital Pharmacy, University Hospital, Linköping, Sweden.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Modulation of Cytokine-Induced Production of IL-8 in Vitro by Interferons and Glucocorticosteroids2004In: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 28, no 2, p. 77-88Article in journal (Refereed)
    Abstract [en]

    Interleukin-8 (IL-8) has been implicated in the pathogenesis of inflammation and cancer. Intracellular levels of cytokine-induced IL-8 in human umbilical vein endothelial cells (HUVEC) were modulated using interferons and steroids to further elucidate their mechanism. Basal and cytokine-induced production of IL-8 was studied using a novel ELISA application, flow cytometry, and RT-PCR. The intracellular amount of IL-8 increased after 6-h stimulation with TNF- (30%) or IL-1ß (55%) which was doubled when Golgi transport was disrupted using monensin. IFN-γ decreased the intracellular amount of IL-8 by 60% in both unstimulated and TNF--stimulated cells, but only when secretion was blocked using monensin. Dexamethasone inhibited the TNF--induced production by 33%, but had no effect in unstimulated cells. Our study indicated that both, dexamethasone and IFN inhibit TNF--induced upregulation of IL-8 at the mRNA level. It could be speculated that they inhibit IL-8 production by affecting different gene regulatory mechanisms.

  • 24.
    Nyhlén, Kristina
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Linden, Margareta
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Department of Cell & Molecular Biology, Astra Draco AB, Lund, Sweden.
    Uppugunduri, Srinivas
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Corticosteroids and interferons inhibit cytokine-induced production of IL-8 by human endothelial cells2000In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 12, no 4, p. 355-360Article in journal (Refereed)
    Abstract [en]

    IL-8, secreted by endothelial cells at the site of inflammation, participates in recruitment and transmigration of leukocytes. IL-8 may also have pathophysiological consequences in inflammatory and immunological disorders. We have investigated the effect of interferons (IFNs) and glucocorticosteroids (GCs) on cytokine induced secretion and production of IL-8 by human umbilical endothelial cells (HUVEC). There was a low spontaneous secretion of IL-8 by unstimulated HUVEC which increased after 6 or 24 h of stimulation with the pro-inflammatory cytokines TNF-α or IL-1β. IFN-γ as well as the GCs, Dexamethasone and Budesonide, inhibited TNF-α induced IL-8 secretion in a dose-dependent manner. IFNs may have a general modulating effect, since IFN-α also inhibited the TNF-α-induced IL-8 secretion. There was a slight, but significant, increase in the content of intracellular IL-8 in stimulated HUVEC. However, there was no difference between stimulation with IL-1β or TNF-α alone or in combination with IFNs or GCs, whereas inhibition of IL-8 secretion with monensin increased IL-8 content suggesting that IFNs and GCs inhibit synthesis rather than secretion of IL-8. In conclusion, IFNs or GCs may be useful for inhibiting IL-8 production by endothelial cells and could thus be used for therapeutic modulation of the inflammatory response.

  • 25.
    Persson, Ingrid A L
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G G
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective.2011In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 57, no 1, p. 44-50Article in journal (Refereed)
    Abstract [en]

    Evidence suggests that cocoa from the bean of Theobroma cacao L. has beneficial effects on cardiovascular disease. The aim of this study was to investigate if cocoa extract and dark chocolate influence angiotensin-converting enzyme (ACE) and nitric oxide (NO) in human endothelial cells (in vitro) and in healthy volunteers (in vivo). ACE activity was analyzed with a commercial radioenzymatic assay and measured in human endothelial cells from umbilical veins (HUVEC) after 10 minutes of incubation with cocoa extract. NO was measured after 24 hours of incubation. ACE activity and NO were measured at baseline and after 30, 60, and 180 minutes in 16 healthy volunteers after a single intake of 75 g of dark chocolate containing 72% cocoa. Significant inhibition of ACE activity (P < 0.01) and significant increase of NO (P < 0.001) were seen in HUVEC. In the study subjects, a significant inhibition of ACE activity (mean 18%) 3 hours after intake of dark chocolate was seen, but no significant change in NO was seen. According to ACE genotype, significant inhibition of ACE activity was seen after 3 hours in individuals with genotype insertion/insertion and deletion/deletion (mean 21% and 28%, respectively). Data suggest that intake of dark chocolate containing high amount of cocoa inhibits ACE activity in vitro and in vivo.

  • 26.
    Persson, Ingrid A-L
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Andersson, Rolf G G
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of green tea, black tea and Rooibos tea on angiotensin-converting enzyme and nitric oxide in healthy volunteers2010In: Public Health Nutrition, ISSN 1368-9800, E-ISSN 1475-2727, Vol. 13, no 5, p. 730-737Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Tea has been reported to reduce cardiovascular mortality, but the underlying mechanisms are largely unknown. The aim of the current project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos tea (South Africa) on angiotensin-converting enzyme (ACE) and nitric oxide (NO). DESIGN: Seventeen healthy volunteers received a single oral dose of 400 ml green tea, black tea or Rooibos tea in a randomized, three-phase, crossover study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 min) in all phases. ACE activity was analysed by means of a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition, ACE genotype was determined using a PCR method. RESULTS: Oral intake of a single dose of Rooibos tea significantly inhibited ACE activity after 30 min (P < 0.01) and after 60 min (P < 0.05). A significant inhibition of ACE activity was seen with green tea for the ACE II genotype 30 min after intake of the tea (P < 0.05) and for the ACE ID genotype 60 min after intake (P < 0.05). A significant inhibition of ACE activity was also seen with Rooibos tea for the ACE II genotype 60 min after intake (P < 0.05). No significant effect on NO concentration was seen. CONCLUSIONS: These results suggest that green tea and Rooibos tea may have cardiovascular effects through inhibition of ACE activity.

  • 27.
    Persson, Ingrid
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Josefsson, Martin
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Tea flavanols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells2006In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 58, no 8, p. 1139-1144Article in journal (Refereed)
    Abstract [en]

    A diversity of pharmacological effects on the cardiovascular system have been reported for Camellia sinensis: antioxidative, antiproliferative and anti-angiogenic activity, and nitric oxide synthase activation. The purpose of this study was to investigate if the connection between tea and angiotensin-converting enzyme (ACE) and nitric oxide (NO) might be an explanation of the pharmacological effects of tea on the cardiovascular system. Cultured endothelial cells from human umbilical veins (HUVEC) were incubated with extracts of Japanese Sencha (green tea), Indian Assam Broken Orange Pekoe (black tea) and Rooibos tea, respectively. The main flavanols and purine alkaloids in green and black tea were examined for their effects on ACE and NO. After incubation with green tea, black tea and Rooibos tea for 10 min, a significant and dose-dependent inhibition of ACE activity in HUVEC was seen with the green tea and the black tea. No significant effect on ACE was seen with the Rooibos tea. After 10-min incubation with (-)-epicatechin, (-)- epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent inhibition of ACE activity in HUVEC was seen for all four tea catechins. After 24-h incubation, a significantly increased dose-dependent effect on NO production in HUVEC was seen for the green tea, the black tea and the Rooibos tea. After 24-h incubation with (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent increased NO production in HUVEC was seen. In conclusion, tea extracts from C. sinensis may have the potential to prevent and protect against cardiovascular disease. © 2006 The Authors.

  • 28.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effect of Vaccinium myrtillus and Its Polyphenols on Angiotensin-Converting Enzyme Activity in Human Endothelial Cells2009In: Journal of Agricultural and Food Chemistry, ISSN 0021-8561, E-ISSN 1520-5118, Vol. 57, no 11, p. 4626-4629Article in journal (Refereed)
    Abstract [en]

    This study investigates if the connection between Vaccinium myrtillus and angiotensin-converting enzyme (ACE) might be an explanation of the pharmacological effects on circulation. Cultured endothelial cells from human umbilical veins were incubated with bilberry 25E extract. The main anthocyanidins combined in myrtillin chloride and separately in cyanidin, delphinidin, and malvidin, respectively, were examined concerning their effects on ACE. After 10 min of incubation with bilberry 25E, a significant, dose-dependent inhibition of ACE activity was seen, and after incubation with myrtillin chloride a significant inhibition was seen. No effect was seen with the anthocyanidins. The effect seems to be dependent on this specific mixture of anthocyanins in the bilberry. V. myrtillus may thus have the potential to prevent and protect against cardiovascular diseases.

  • 29.
    Persson, Ingrid
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of green tea, black tea and rooibos on angiotensin-converting enzyme activity in healthy volunteers2009In: in Planta Medica(ISSN 0032-0943), 2009, Vol. 75, no 9, p. 1030-1030Conference paper (Refereed)
    Abstract [en]

    Tea has been reported to reduce cardiovascular mortality, but the mechanisms behind are largely unknown. The aim of this project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos on angiotensin-converting enzyme and nitric oxide. Seventeen healthy volunteers received a single oral dose of either 400 ml green tea, black tea or Rooibos tea in a randomized three-phase cross over study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 minutes) in all phases. ACE activity was analysed with a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition ACE genotype was determined using a PCR method. Oral intake of a single dose of Rooibos significantly inhibited ACE activity, p<0.01 after 30 min and p<0.05 after 60 min. A significant inhibition of ACE activity was seen with green tea for the ACE genotype II (p<0.05), 30 minutes after intake of the tea and for the ACE genotype ID (p<0.05), 60 minutes after intake. A significant inhibition of ACE activity was also seen with Rooibos for the ACE genotype II (p<0.05), 60 minutes after intake. No significant effect on NO concentration was seen.

  • 30.
    Persson, Karin
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Biphasic Response to Bradykinin in Isolated Porcine Iliac Arteries is Mediated by Bradykinin B1 and B2 Receptors1998In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 32, no 2, p. 306-313Article in journal (Refereed)
    Abstract [en]

    Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10-10-10-8 M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nω-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10-6 M). Bradykinin (>10-7M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9 [Leu8] bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

  • 31.
    Persson, Karin
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries1999In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 385, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    The influence of the angiotensin-converting enzyme inhibitor captopril on bradykinin-and angiotensin I-induced responses with special regard to nitric oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme activity was studied in isolated porcine iliac arteries. Captopril potentiated bradykinin-induced contraction of preparations with intact endothelium; this potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin B1-receptor antagonist. Captopril did not affect bradykinin-induced relaxation. The captopril-mediated increase of bradykinin-induced contraction was only seen in preparations with intact endothelium, while captopril did not affect arterial strips treated with Nω-nitro-L-arginine. Angiotensin I-induced contractions was less reduced by captopril when the strips were pretreated with Nω-nitro-L-arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine inhibited angiotensin-converting enzyme activity. An additional reduction in angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl-penicillamine was added to captopril-treated preparations. In conclusion, captopril increased bradykinin-induced contraction in a NO-dependent manner. This potentiation is probably mediated by the increased metabolism of bradykinin by kininase I, and the additive angiotensin-converting enzyme inhibitory effect of captopril and NO.

  • 32.
    Persson, Karin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Säfholm, A C E
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Glyceryl trinitrate-induced angiotensin-converting enzyme (ACE) inhibition in healthy volunteers is dependent on ACE genotype2005In: Canadian Journal of Physiology and Pharmacology, ISSN 0008-4212, E-ISSN 1205-7541, Vol. 83, no 12, p. 1117-1122Article in journal (Refereed)
    Abstract [en]

    Evidence concerning the importance of angiotensin-converting enzyme (ACE) genotype in cardiovascular diseases is accumulating. The aim of this study was to investigate if nitric oxide (NO), generated from glyceryl trinitrate (GTN), affects human serum ACE activity in vivo, and if so, whether this effect was dependent on ACE genotype and (or) reflected in blood pressure reduction. A tablet containing 5 mg GTN was bucally administered for 5 minutes to 17 healthy volunteers. Blood pressure (BP) was recorded, and serum ACE activity, ACE genotype, and plasma cGMP was analyzed. GTN administration significantly reduced BP only in individuals with the deletion/deletion (DD) genotype. Sixty minutes after GTN administration, serum ACE activity was reduced in individuals with the insertion/insertion (II) and insertion/deletion (ID) genotypes, but not the DD genotype. Comparing the change in ACE activity over time between the genotypes resulted in the following: II vs. DD, p < 0.01, II vs. ID, p < 0.05, and ID vs. DD, p < 0.05. There was no significant difference in plasma cGMp content neither between the ACE genotypes nor before and after GTN administration. In conclusion, GTN inhibits serum ACE in vivo in individuals with the II and ID, but not the DD genotype. © 2005 NRC Canada.

  • 33.
    Persson, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per A.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Nyhlén, Kristina
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Jacobsson-Strier, Monica
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Glindell, Maria
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    NO donors and ACE inhibitors act in concert to inhibit human ACE activity and platelet aggregation in vitroManuscript (preprint) (Other academic)
    Abstract [en]

    This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme (ACE) activity, and platelet aggregation. The NO donor S-nitroso N-acetylpenicillamine SNAP (10-8-10-6 M) significantly and dose-dependently inhibited serum ACE activity. The concomitant addition of SNAP to ACE inhibitor-treated (captopril or enalaprilat) serum, further reduced ACE activity. In cultured endothelial cells from human umbilical veins (HUVEC), both SNAP and 3-morpholinosydnonimine (SIN-1) significantly reduced ACE activity. An additative effect was seen with a combined treatment of captopril and SNAP. Treatment with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) did not affect ACE activity. Thrombin inhibited endothelial ACE activity, an effect that was abolished when cells were pretreated with L-NMMA. ADP-induced platelet aggregation was inhibited with SNAP, SIN-1 and nitroglycerine (GTN). Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M ACE inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-I and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human ACE activity. NO donors and ACE inhibitors act in concert to inhibit ACE and platelet aggregation. 

  • 34.
    Persson, Karin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Whiss, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Nyhlén, Kristina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Nursing Science.
    Jacobsson-Strier, M.
    Glindell, M.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Nitric oxide donors and angiotensin-converting enzyme inhibitors act in concert to inhibit human angiotensin-converting enzyme activity and platelet aggregation in vitro2000In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 406, no 1, p. 15-23Article in journal (Refereed)
    Abstract [en]

    This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme activity and platelet aggregation. The NO donor S-nitroso-N-acetylpenicillamine (10-8-10-6 M) significantly and dose-dependently inhibited serum angiotensin-converting enzyme activity. The concomitant addition of S-nitroso-N-acetylpenicillamine to angiotensin-converting enzyme inhibitor-treated (captopril or enalaprilat) serum, further reduced angiotensin-converting enzyme activity. In cultured endothelial cells from human umbilical veins (HUVECs), both S-nitroso-N-acetylpenicillamine and 3-morpholinosydnonimine (SIN-1) significantly reduced angiotensin-converting enzyme activity. An additative effect was seen with a combined treatment of captopril and S-nitroso-N-acetylpenicillamine. Treatment with the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) did not affect angiotensin-converting enzyme activity. Thrombin inhibited endothelial angiotensin-converting enzyme activity, an effect that was abolished when cells were pretreated with L-NMMA. Adenosine 5'-diphosphate (ADP)-induced platelet aggregation was inhibited with S-nitroso-N-acetylpenicillamine, SIN-1 and nitroglycerine. Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M angiotensin-converting enzyme inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-1 and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human angiotensin-converting enzyme activity. NO donors and angiotensin-converting enzyme inhibitors act in concert to inhibit angiotensin-converting enzyme and platelet aggregation. Copyright (C) 2000 Elsevier Science B.V.

  • 35.
    Schmekel, Birgitta
    et al.
    Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Rydberg, Irene
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Norlander, Björn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Naidu Sjöswärd, Kerstin
    Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers1999In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 13, no 6, p. 1230-1235Article in journal (Refereed)
    Abstract [en]

    Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use. Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng·mL -1. The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached. In conclusion, the clinical consequences of increasing plasma concentrations of S-salbutamol need to be further assessed.

  • 36.
    Szabó, Zoltan
    et al.
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Intraoperative muscle and fat metabolism in diabetic patients during coronary artery bypass grafting surgery: a parallel microdialysis and organ balance study2009In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 103, no 2, p. 166-172Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Surgical trauma causes stress and inflammatory reactions with elevated serum free fatty acids (FFA) and glucose levels characteristic of intraoperative insulin resistance. Our aim was to compare microdialysis findings with those using the classical organ balance technique and to test the clinical feasibility of microdialysis during cardiac surgery. METHODS: Nine diabetic and nine non-diabetic patients, undergoing routine coronary artery bypass grafting surgery, were studied using both microdialysis and the organ balance technique in the brachio-radial muscle of the forearm, and microdialysis in the pre-pectoral fat tissue. Glucose, lactate, and glycerol were measured in arterial and venous plasma and in the microdialysate before administration of heparin, at the release of the aortic cross-clamp, and before transfer to the intensive care unit. RESULTS: Glucose release from the diabetic muscle at the last sampling time was detected. This was confirmed by a negative glucose A-I (arterial-interstitial difference) in the muscle. No differences were observed regarding lipolysis in the fat tissue in terms of A-I of glycerol. Intergroup differences were detected at the first sampling time, where arterial plasma glucose and plasma insulin levels were higher and muscle interstitial glucose lower in the diabetic patients. Plasma insulin was higher in the diabetic patients even at the final measurement time. CONCLUSIONS: In terms of lipolysis in the fat tissue and glucose transport in the muscle, the non-diabetic patients were metabolically 'diabetics' during surgery. Despite strict blood glucose control, disturbances in glucose homeostasis in the diabetic muscle persist. Microdialysis was easy to use during cardiac surgery.

  • 37.
    Szabó, Zoltán
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Insulin resistance during coronary surgery in diabetic and non-diabetic patients-parallel microdialysis and organ balance technique studying skeletal muscle (preliminary results)2007In: Diabetologia(ISSN 0012-186X), vol 50, 2007, Vol. 50, p. 275-276Conference paper (Refereed)
  • 38.
    Szabó, Zoltán
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Thoracic Surgery. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Insulin resistance during coronary surgery in diabetic and non-diabetic patients-parallel microdialysis and organ balance technique studying skeletal muscle (preliminary results)2007In: European Association for the Study of Diabetes EASD,2007, 2007Conference paper (Refereed)
    Abstract [en]

        

  • 39.
    Szabó, Zoltán
    et al.
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Katkits, Kristofer
    Östergötlands Läns Landsting.
    Gabro, George
    Östergötlands Läns Landsting.
    Andersson, Rolf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    The Contractility of Isolated Rat Atrial Tissue during Hypoxia is Better Preserved in a High- or Zero-glucose Environment than in a Normal Glucose Environment2009In: International Journal of Biomedical Sciences, ISSN 1306-1216, Vol. 5, no 1, p. 12-16Article in journal (Refereed)
    Abstract [en]

    Aim: Hyperglycemia is known to be associated with an increase in mortality in myocardial infarction and intensive care patients despite the fact that glucose metabolism plays a central role in myocardial protection. We studied the effect of different glucose levels (22 Mm L-1; 5.5 mM L-1; and 0 mM L-1) on the contractile reserve of isolated rat atrial myocardium during and after hypoxia.Methods: We observed the contraction ofisolated rat atrium strips caused by electrical-field stimulation in a modified Krebs-Henseleit Buffer (KHB) organ bath oxygenated with 95% O2 + 5% CO2 at 37°C. We applied two periods of hypoxia and two periods of reoxygenation. Three glucose concentrations were used in the buffer to study the effect of glucose (high- n=6; normal- n=7; and zero-glucose n=6). The effect of isoproterenol 1 µM L-1 was tested during the second ischemic period.Results: The main finding was that both a zero-glucose (27.8 ± 5.9 vs. 14.7 ± 3 % of baseline tension) and a high-glucose environment (38.5 ± 14 vs. 14.7 ± 3 % of baseline tension) had a positive effect in terms of better contractility than the normal-glucose buffer during both the first (p=0.00062) and the second ischemic period (31.2 ± 5.9 % zero-glucose vs 14.7 ± 4.2 normal-glucose vs. 35.3 ± 15.9% high-glucose p=0.0038).Conclusion: Both zero-glucose and high-glucose environments resulted in a better contractile reserve in isolated rat atrial myocardium during hypoxia than in a normal one. The exact clinical relevance of this observation is, at present, unclear.

  • 40.
    Toll, Johan B
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Andersson, Rolf G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Effects of enprofylline and theophylline on purified human basophils1984In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 39, no 7, p. 515-520Article in journal (Refereed)
    Abstract [en]

    Extracts from purified human basophils revealed activity of cAMP-phosphodiesterase with a km-value of 0.59 microM. The enzyme was not activated by Ca-ions. Enprofylline and theophylline inhibited the enzyme in a competitive manner. Enprofylline was more potent than theophylline. These drugs did also inhibit the anti-IgE-induced histamine release from the basophils. These results favour the hypothesis that inhibition of histamine release of enprofylline is caused by an inhibition of phosphodiesterase. Although accumulating data have indicated that theophylline, at therapeutic concentrations, is a weak inhibitor of cAMP-phosphodiesterase activity, there is reason to believe that enprofylline, at therapeutic concentrations, may act at least partly as a phosphodiesterase inhibitor.

  • 41.
    Toll, Johan B
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Andersson, Rolf G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Effects of mepacrine and p-bromophenacyl bromide on anti-IgE and phospholipase A2-induced histamine release from human basophils1986In: Agents and actions, ISSN 0065-4299, Vol. 18, no 5-6, p. 518-523Article in journal (Refereed)
    Abstract [en]

    Exposure of human basophils to purified phospholipase A2 caused a release of histamine, the process could be divided in one Ca2+-independent and one Ca2+-dependent stage. Low concentrations of mepacrine and p-bromophenacyl bromide (BPB) inhibited both phospholipase A2- and anti-IgE-induced histamine release. Mepacrine was more potent than BPB when the two-stage-method was used. The inhibition of mepacrine was most effective when the drug was added in the second Ca2+-dependent stage. The effect of mepacrine in the whole reaction of the anti-IgE-induced histamine release was biphasic and mepacrine was less effective than in the inhibition of the separated stages. The effect of BPB on the whole reaction was rather similar to mepacrine, although it was not biphasic. The results presented in this work confirm a previous hypothesis suggesting that activation of phospholipase A2 is an important step in the IgE-mediated histamine release process. The results also suggest that inhibition of histamine release due to inhibition of phospholipase A2 might be of therapeutical value as the system can be inhibited at very low drug concentrations.

  • 42.
    Toll, Johan B
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Wikberg, J E
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Andersson, Rolf G
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Purification of human basophils by affinity chromatography on anti-IgE-sepharose 6MB1981In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 36, no 6, p. 411-417Article in journal (Refereed)
    Abstract [en]

    This work describes a method for the purification of basophil leukocytes from human peripheral blood by the use of a three-step separation technique including affinity chromatography on anti-IgE-sepharose 6MB. The purity of the obtained basophils was 50--95% and the recovery was 30--40%. The basophils separated by this method appeared normal and were found to be reactive with anti-IgE in subsequent tests.

  • 43.
    Whiss, Per A
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Divalent cations and the protein surface co-ordinate the intensity of human platelet adhesion and P-selectin surface expression2002In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 13, no 5, p. 407-416Article in journal (Refereed)
    Abstract [en]

    At sites of blood vessel injury, platelets adhere to exposed vessel components, such as collagen, or immobilized fibrinogen derived from plasma or activated platelets. The divalent cations Mg2+ and Ca2+ are essential for platelet adhesion and activation, but Mg2+ can also inhibit platelet activation. The present study evaluates, by an enzymatic method, the effects of various divalent cations on the adhesion of isolated human platelets to collagen, fibrinogen, albumin or plastic in vitro. By enzyme-linked immunosorbent assay, platelet surface expression of P-selectin was measured to estimate the state of activation on adherence. Mg2+ increased platelet adhesion exclusively to collagen and fibrinogen at physiologically relevant concentrations. At higher concentrations, the adhesion declined. Ca2+ induced a weak adhesion only to fibrinogen at physiological doses and a peak of increased adhesion to all protein-coated surfaces at 10 mmol/l. Mn2+ elicited dose-dependent adhesion only to collagen and fibrinogen. Zn2+, Ni2+ and Cu2+ increased the adhesion of platelets independently of the surface. Ca2+ dose-dependently inhibited adhesion elicited by Mg2+ to collagen and fibrinogen. No other combination of divalent cations elicited such an effect. Mg2+-dependent platelet adhesion to collagen and Ca2+-dependent adhesion to fibrinogen increased P-selectin expression. Thus, the present study shows that the outcome of the platelet adhesion depends on the surface and the access of divalent cations, which co-ordinate the intensity of platelet adhesion and P-selectin surface expression.

  • 44.
    Whiss, Per A.
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Kinetics of platelet P-selectin mobilization: Concurrent surface expression and release induced by thrombin or PMA, and inhibition by the NO Donor SNAP1998In: Cell Communication & Adhesion, ISSN 1541-9061, E-ISSN 1543-5180, Vol. 6, no 4, p. 289-300Article in journal (Refereed)
    Abstract [en]

    Activated platelets and endothelium surface express the cell adhesion molecule P-selectin (CD62P), which plays an important role in mediating interactions with leukocytes. Increased levels of a functional soluble form of P-selectin (sP-selectin) have been reported in several pathological states but it is not clear whether this circulating sP-selectin originates from platelets and/or endothelial cells. Here we describe the concurrent kinetics of intracellular storage, surface expression and release of platelet P-selectin induced by thrombin or the protein kinase C activator PMA. Platelet activation with submaximal concentrations of thrombin (0.1 U/ml) resulted in a rapid decrease of intracellular P-selectin. This decrease of intracellular P-selectin concurred with a gradual increase of surface expression and an initial increase of sP-selectin. Our results indicate that intracellular stores of P-selectin were only partly mobilized upon activation with submaximal concentrations of thrombin. A high concentration of thrombin (1.0 U/ml) induced a rapid and nearly total decrease of intracellular stores and a more pronounced, but transient, increase of surface expression. The release of P-selectin was fast and occurred during the initial activation phase. The NO donor SNAP inhibited both surface expression and release of platelet P-selectin in a similar manner. PMA (0.1–1.01 µM) mediated a more slow, gradual and sustained surface expression and release of P-selectin than thrombin. Thus, surface expression and release of platelet P-selectin show different kinetics depending on the mode of activation.

  • 45.
    Whiss, Per A.
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Modulation of P-selectin expression on isolated human platelets y an NO donor assessed by a novel ELISA application1997In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 200, no 1-2, p. 135-143Article in journal (Refereed)
    Abstract [en]

    Adhesion molecules such as P-selectin are potential markers for evaluating platelet activation and studying the role of cell-cell interactions in numerous biological processes related to hemostasis and inflammation. The expression of P-selectin and related molecules has previously been quantified with different techniques. As an alternative to the most common method, flow cytometry, we have developed a useful ELISA method to simultaneously analyse 96 samples for platelet expression of P-selectin. Samples may be stored for at least 7 days at 4°C prior to analysis. The method is simple, reproducible, flexible and requires only standard equipment. Washed platelets (WP) from healthy male volunteers, at a concentration of 1 × 107/microtiter plate well, were stimulated with various known platelet activators and fixed with 0.1% formaldehyde for 10 min. The fixed WP were centrifuged to form a confluent layer in the wells and then incubated with optimal dilutions of primary antibodies (1/2000) directed against P-selectin, CD41, CD9 and secondary antibodies conjugated with alkaline phosphatase. Our results show that P-selectin expression on WP increases significantly upon stimulation with thrombin (0.1–1.0 U/ml), ADP (10 μM) and epinephrine (100 μM). The induction of P-selectin expression by thrombin is fast and has different kinetics depending on the concentration of the agonist. Prior incubation with the nitric oxide donor SNAP (10 μM) inhibits the up-regulation of P-selectin induced by sub-maximal concentrations of thrombin (p < 0.05). This ELISA is suitable for studying the expression and regulation of P-selectin and other surface molecules on human platelets in various pathological states.

  • 46.
    Whiss, Per A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Uppugunduri, Srinivas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry.
    A novel ELISA application for studies of P-selectin expression on isolated human platelets1996In: World Congress of Medical Technology,1996, 1996Conference paper (Other academic)
  • 47.
    Whiss, Per A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Uppugunduri, Srinivas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry.
    Modulation of platelet P-selectin storage, surface expression and secretion by nitric oxide1997In: Cell Adhesion and Migration in Inflammation and Cancer,1997, 1997Conference paper (Other academic)
  • 48.
    Whiss, Per A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Uppugunduri, Srinivas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry.
    Modulation of P-selectin expression on isolated human platelets assessed by a novel ELISA application1996In: International Congress of clinical chemistry,1996, 1996Conference paper (Other academic)
1 - 48 of 48
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