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  • 1.
    Asplund Persson, Anna
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Zalavary, Stefan
    Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per A
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets2005In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 517, no 3, p. 149-157Article in journal (Refereed)
    Abstract [en]

    We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3′5′-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3′5′-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx.

    In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.

  • 2. Axelsson Rosén, Stina
    et al.
    Hägg, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Eriksson, Andreas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lindahl, Tomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    In vitro effects of antipsychotics on human platelet adhesion and aggregation and plasma coagulation2007In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 34, no 8, p. 775-780Article in journal (Refereed)
    Abstract [en]

    1. Several studies suggest an association between venous thromboembolism and the use of antipsychotic drugs, especially clozapine, but the biological mechanisms are unknown. It has been suggested that antipsychotic drugs enhance aggregation of platelets and thereby increase the risk of venous thrombosis. The purpose of the present study was to examine the effects of clozapine and its main metabolite, N-desmethyl clozapine, as well as olanzapine, risperidone and haloperidol, on platelet adhesion and aggregation and on plasma coagulation in vitro. 2. Blood was collected from healthy subjects free of medication. Platelet adhesion to different protein surfaces and aggregation were measured in microplates. The coagulation methods of activated partial thromboplastin time (APTT) and prothrombin time were performed in platelet-poor plasma. 3. Clozapine was the only compound that increased platelet adhesion and aggregation and shortened APTT. The effect appeared at therapeutic concentrations and was significant but weak. 4. This weak effect of clozapine on haemostasis may explain, in part, the association of this compound and venous thromboembolism. © 2007 The Authors.

  • 3.
    Bengtsson, Torbjörn
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Frydén, A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Zalavary, S
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Orselius, Kristina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Grenegård, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Platelets enhence neutrophil locomotion: evidence for a role of P-selectin1999In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 59, p. 439-450Article in journal (Refereed)
  • 4.
    Désilets, Stéphanie
    et al.
    Linköping University, Department of Medicine and Care.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Eriksson, Andreas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Nilsson, Ulrika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Grenegård, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lysophosphatidic acid inhibits ADP-activated platelets2004In: 10th Annual Scandinavian Atherosclerosis Conference and International Meeting,2004, 2004Conference paper (Other academic)
  • 5.
    Eriksson, Andreas C
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Whiss, Per A
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Enhanced platelet adhesion in essential thrombocythemia after in vitro activation2010In: TURKISH JOURNAL OF HEMATOLOGY, ISSN 1300-7777, Vol. 27, no 2, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Objective: Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by elevated platelet counts and increased risk of thrombosis. Ex vivo data suggest increased platelet reactivity in agreement with the increased thrombosis risk, while in vitro tests often detect decreased platelet activity. The present study aimed to investigate adhesion of ET-platelets in vitro, which is an aspect of platelet function that has been addressed in only a few studies on ET patients. Material and Methods: The study included 30 Er patients and 14 healthy controls. Platelet adhesion was measured with a static platelet adhesion assay. Results: The main finding was that ET-platelets were more readily activated by adhesion-inducing stimuli in vitro than control platelets. This was particularly evident in elderly patients and when using multiple stimuli, such as surfaces of collagen or fibrinogen combined with addition of adenosine 5-diphosphate or ristocetin. Such multiple stimuli resulted in adhesion above the control mean +2 standard deviations for approximately 50% of the patients. Conclusion: The results are in accordance with the concept of increased platelet activity in ET, but opposite to most other in vitro studies. We suggest that the conditions in the adhesion assay might mimic the in vivo situation regarding the presence of chronic platelet activation. (Turk J Hematol 2010; 27: 82-90)

  • 6.
    Eriksson, Andreas C
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Whiss, Per A
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Measurement of adhesion of human platelets in plasma to protein surfaces in microplates2005In: Journal of Pharmacological and Toxicological Methods, ISSN 1056-8719, Vol. 52, no 3, p. 356-365Article in journal (Refereed)
    Abstract [en]

    Introduction

    Platelet adhesion is an initial, crucial and complex event for inhibiting blood loss upon vascular injury. Activation and adhesion of platelets also play a fundamental role in the development of thrombosis. A combination of exposed extracellular matrix proteins in the vascular wall and release of activating compounds from the participating cells activate the platelets. New potent anti-platelet agents are in progress but there is a shortage of methods that measure the concerted action of adhesive surfaces and soluble compounds upon platelet adhesion in vitro. The aim of this work was to develop a method to measure adhesion of platelets in plasma with standard laboratory equipment.

    Methods

    Platelet-rich plasma from healthy humans was used in studies to optimise the conditions of the present assay. Different proteins were coated in microplate wells and various soluble platelet activators and inhibitors were added to establish the ability of the current method to detect increased as well as decreased platelet adhesion. The amount of platelet adhesion was measured by the reaction between p-nitrophenyl phosphate and the intracellular enzyme acid phosphatase.

    Results

    Adhesion of platelets in plasma to microplate wells coated with albumin, collagen, fibrinogen and activated plasma showed significant surface dependency. The known soluble platelet activators adenosine diphosphate, adrenaline and ristocetin enhanced the levels of adhesion. Available anti-platelet agents such as prostacyclin, forskolin, acetylsalicylic acid and RGD containing peptides caused dose-dependent inhibition of platelet adhesion.

    Discussion

    This report describes a further development of a previously described method and offers the advantage to use platelets in plasma to measure platelet adhesion to protein surfaces. The assay is simple and flexible and is suitable in basic research for screening and characterisation of platelet adhesion responsiveness.

  • 7.
    Eriksson, Andreas C.
    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.
    Nanomolar concentrations of adrenaline induce platelet adhesion in vitro.2013In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 24, no 2, p. 129-135Article in journal (Refereed)
    Abstract [en]

    Adrenaline is a platelet activator having a resting plasma concentration of <1 nmol/l that increases to a few nmol/l during stress. However, most in vitro assays only detect effects of adrenaline in micromolar concentrations. This makes it difficult to estimate the relevance of in vitro data for the in vivo situation. The aim of this study was to investigate experimental conditions in vitro that could detect platelet effects of adrenaline in nanomolar concentrations. Platelet adhesion to albumin and collagen was evaluated with a static platelet adhesion assay. Our results show that 10 nmol/l adrenaline induced platelet adhesion to albumin in platelet-rich plasma (PRP) prepared at 140 × g, while 100 nmol/l was necessary in order to increase adhesion of platelets prepared at 220 × g. The mean platelet volume was increased after preparation at 140 × g, suggesting that large reactive platelets contributed to the increased adrenaline sensitivity. At optimal Mg(2+)-concentration, adhesion to collagen was increased by 10 nmol/l adrenaline irrespective of centrifugal force applied during PRP preparation. More specifically, we defined two populations where adhesion to collagen was increased by 10 nmol/l adrenaline either upon centrifugation at 140 × g but not 220 × g or vice versa. In some experiments, platelet adhesion to collagen was induced by 3 nmol/l adrenaline, which corresponds to concentrations achieved during stress in vivo. In summary, the static adhesion assay is able to detect platelet activating effects of adrenaline very close to physiological concentrations. This is rare for in vitro assays and motivates further research about adrenergic signalling in platelets.

  • 8.
    Eriksson, Andreas C
    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.
    Nilsson, Ulrika K
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Adhesion of human platelets to albumin is synergistically increased by lysophosphatidic acid and adrenaline in a donor-dependent fashion2006In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, Vol. 17, no 5, p. 359-368Article in journal (Refereed)
    Abstract [en]

    Lysophosphatidic acid (LPA) and adrenaline are weak platelet activators considered important for thrombus formation, and were previously shown to synergistically increase platelet aggregation. Here we investigate synergistic activation by LPA and adrenaline when measuring platelet adhesion. Platelet-rich plasma from healthy blood donors together with adrenaline and/or LPA were added to protein-coated microplates. Platelets were allowed to adhere and the amount of adhesion detected enzymatically. The LPA and adrenaline combination induced a synergistic increase of platelet adhesion to a normally non-adhesive albumin surface. The degree of synergy varied markedly between individuals; these variations could not be explained by age, gender, blood type or different amounts of platelets, oxidized low-density lipoprotein, insulin or glucose in plasma. There was a trend indicating increased synergistic effect for platelets sensitive to adrenaline stimulation. The synergistic effect was blocked by the α2-adrenoceptor antagonist yohimbine and inhibited by the ADP scavenger system creatine phosphate/creatine phosphokinase and antibodies against αIIbβ3. Furthermore, platelets adhering to albumin after adrenaline and LPA treatment expressed P-selectin. In conclusion, LPA and adrenaline act synergistically to increase αIIbβ3-mediated platelet adhesion to albumin, dependent on α2-adrenoceptor signalling and platelet secretion. We also confirm that synergistic platelet activation achieved with LPA and adrenaline is highly donor dependent.

  • 9.
    Eriksson, Andreas
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Hedbäck, Bo
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Whiss, Per A.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Monitoring platelet inhibiting treatment in coronary heart disease by static platelet adhesion2007Conference paper (Other academic)
  • 10.
    Eriksson, Andreas
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Hedbäck, Bo
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study2009In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 7, no 42Article in journal (Refereed)
    Abstract [en]

    Background: Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA) and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment. Methods: With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B-2 (TXB2)-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis. Results: The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r(2) = 0.49). In opposite, TXB2-levels decreased with ASA compared to clopidogrel. Serum TXB2 and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow cytometry were lower for clopidogrel compared to ASA. Furthermore, adhesion to collagen was lower for ASA and clopidogrel combined compared with either drug alone. Conclusion: The indirect pharmacodynamic measures of the effects of ASA and clopidogrel might be used together with ADP-induced activation and serum TXB2 for evaluation of anti-platelet treatment. This should be further evaluated in future clinical studies where screening opportunities with the adhesion assay will be optimised towards increased sensitivity to anti-platelet treatment.

  • 11.
    Eriksson, Andreas
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Correction: Enhanced platelet adhesion in essential thrombocythemia after in vitro activation (vol 27 pg 82, 2010)2010In: Turkish Journal of Hematology, ISSN 1300-7777, E-ISSN 1308-5263, Vol. 27, no 3, p. 223-223Article in journal (Other academic)
    Abstract [en]

    n/a

  • 12.
    Eriksson, Andreas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Enhanced platelet adhesion in essential thrombocythemia assessed by a novel platelet function assay2005In: Congress of the European hematology association,2005, 2005Conference paper (Other academic)
  • 13.
    Eriksson, Andreas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Nilsson, Ulrika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Adrenaline and lysophosphatidic acid acts synergistically to increase platelet adhesion to Albumin2004In: Annual Scandinavian atherosclerosis conference,2004, 2004Conference paper (Other academic)
  • 14.
    Eriksson, Andreas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Nilsson, Ulrika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Adrenaline and lysophosphatidic acid acts synergistically to increase platelet adhesion to Albumin2004In: Congress of the European hematology association,2004, 2004Conference paper (Other academic)
  • 15.
    Eriksson, Andreas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Nilsson, Ulrika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    The extra cellular ion environment modulates platelet adhesion after lysophosphatidic acid treatment in vitro2006In: XIV International symposium on atherosclerosis,2006, 2006Conference paper (Other academic)
  • 16.
    Eriksson, Andreas
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Whiss , Per
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Characterization of static adhesion of human platelets in plasma to protein surfaces in microplates2009In: BLOOD COAGULATION and FIBRINOLYSIS, ISSN 0957-5235 , Vol. 20, no 3, p. 197-206Article in journal (Refereed)
    Abstract [en]

    Platelet adhesion is a complex and important event for prevention of blood loss after vessel injury. This study investigated fundamental adhesive mechanisms occurring in an in-vitro assay developed for the measurement of static adhesion of human platelets in plasma. The aim was to gain methodological knowledge that could be used for interpretations of results from other studies using this specific assay. Involvement of adhesive receptors was investigated by the use of various antibodies as well as therapeutic drugs (abciximab, eptifibatide and tirofiban). Inhibitors of adenosine 5-diphosphate receptors (cangrelor, MRS2179) and of thromboxane A(2) signalling (BM-531) were used to estimate the role of autocrine activation. Adhesion to collagen was found to be mainly mediated by alpha(2)beta(1) and to some extent by alpha(IIb)beta(3) Adhesion to fibrinogen was mediated by alpha IIb beta 3. In addition, adenosine 5-diphosphate-induced adhesion to albumin was dependent on alpha(IIb)beta(3). Furthermore, experiments with cangrelor and BM-531 showed that the majority of the adhesive interactions tested were dependent on adenosine 5-diphosphate or thromboxane A(2). We conclude that the mechanisms of adhesion measured by the static platelet adhesion assay are in accordance with the current knowledge regarding platelet activation and adhesion. Despite its simplicity, we suggest that this adhesion assay could be used as a screening device for the study of the influence of various surfaces and soluble substances on platelet adhesion.

  • 17.
    Eriksson, Andreas
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet adhesion to proteins in microplates: from experimental research to clinical evaluation of platelet function2009Conference paper (Refereed)
    Abstract [en]

     Available platelet function assays differ with respect to the response they measure as well as in applicability, which range from experimental research to clinical evaluation of platelet function. This study focuses on the measurement of static adhesion of platelets in plasma to proteins in microplates. The aim was to describe fundamental adhesive events occurring in the assay and to investigate the ability to detect effects of factors acting both in vitro and in vivo. This communication combines several studies and presents novel interpretations. First of all, in vitro studies showed that platelets adhered to collagen via integrin alpha2beta1 whereas adhesion to surfaces coated with fibrinogen or albumin were dependent on alphaIIbbeta3. Elevated platelet adhesion, dependent on in vitro effects, was detected after addition of known platelet activators. The sensitivity of the assay is illustrated by significantly increased adhesion induced by 30 nmol/L epinephrine. Further in vitro studies showed that inhibition of autocrine activation decreased platelet adhesion. Also, adhesion was synergistically increased when combining two platelet activators at subthreshold levels. The detection of in vivo effects is illustrated by increased platelet adhesion for patients with the thrombosis prone disease essential thrombocythemia compared to healthy controls. The adhesion assay was reproducible in controls over time denoting that the assay can monitor platelet function. Decreased platelet adhesion was observed in vitro after addition of known platelet inhibitors and ex vivo after treatment with clopidogrel alone or in combination with acetylsalicylic acid in patients with a recent acute coronary syndrome. In conclusion, our studies show that this simple and flexible in vitro assay is able to detect elevated as well as decreased platelet adhesion both in vitro and ex vivo.

     

     

  • 18.
    Eriksson, Andreas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Pharmacology.
    Whiss, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Pharmacology.
    Platelets and Epinephrine2008In: Research Progress on Epinephrine / [ed] Arnold G. Lawson, Hauppauge, NY, USA: Nova Science Publishers Inc. , 2008, 1, p. 73-94Chapter in book (Other academic)
    Abstract [en]

         This new book is devoted to new research on epinephrine (INN) sometimes spelled "epinephrin" or "adrenalin" respectively, which is a hormone when carried in the blood and a neurotransmitter when it is released across a neuronal synapse. It is a catecholamine, a sympathomimetic monoamine derived from the amino acids phenylalanine and tyrosine.When secreted into the bloodstream, it rapidly prepares the body for action in emergency situations. The hormone boosts the supply of oxygen and glucose to the brain and muscles, while suppressing other non-emergency bodily processes (digestion in particular). It increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gut while dilating arterioles in skeletal muscles. It elevates the blood sugar level by increasing catalysis of glycogen to glucose in the liver, and at the same time begins the breakdown of lipids in fat cells. Like some other stress hormones, epinephrine has a suppressive effect on the immune system. Although epinephrine does not have any psychoactive effects, stress or arousal also releases norepinephrine in the brain. Norepinephrine has similar actions in the body, but is also psychoactive. Epinephrine is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output; its action is to increase peripheral resistance via á±­adrenoceptor vasoconstriction, so that blood is shunted to the body's core, and the â±­adrenoceptor response which is increased cardiac rate and output (the speed and pronouncement of heart beats). This beneficial action comes with a significant negative consequence?increased cardiac irritability?which may lead to additional complications immediately following an otherwise successful resuscitation. Alternatives to this treatment include vasopressin, a powerful antidiuretic which also increases peripheral vascular resistance leading to blood shunting via vasoconstriction, but without the attendant increase in myocardial irritability.

  • 19.
    Eriksson, Andreas
    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.
    Platelets and Epinephrine2008In: Research Progress on Epinephrine / [ed] Lawson, A. G., Gorman, R. I., Nova Science Publishers, Inc , 2008, 1, p. 73-94Chapter in book (Other academic)
    Abstract [en]

    This new book is devoted to new research on epinephrine (INN) sometimes spelled "epinephrin" or "adrenalin" respectively, which is a hormone when carried in the blood and a neurotransmitter when it is released across a neuronal synapse. It is a catecholamine, a sympathomimetic monoamine derived from the amino acids phenylalanine and tyrosine.When secreted into the bloodstream, it rapidly prepares the body for action in emergency situations. The hormone boosts the supply of oxygen and glucose to the brain and muscles, while suppressing other non-emergency bodily processes (digestion in particular). It increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gut while dilating arterioles in skeletal muscles. It elevates the blood sugar level by increasing catalysis of glycogen to glucose in the liver, and at the same time begins the breakdown of lipids in fat cells. Like some other stress hormones, epinephrine has a suppressive effect on the immune system. Although epinephrine does not have any psychoactive effects, stress or arousal also releases norepinephrine in the brain. Norepinephrine has similar actions in the body, but is also psychoactive. Epinephrine is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output; its action is to increase peripheral resistance via á±­adrenoceptor vasoconstriction, so that blood is shunted to the body's core, and the â±­adrenoceptor response which is increased cardiac rate and output (the speed and pronouncement of heart beats). This beneficial action comes with a significant negative consequence?increased cardiac irritability?which may lead to additional complications immediately following an otherwise successful resuscitation. Alternatives to this treatment include vasopressin, a powerful antidiuretic which also increases peripheral vascular resistance leading to blood shunting via vasoconstriction, but without the attendant increase in myocardial irritability.

  • 20.
    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.

  • 21.
    Fägerstam, Patrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Higher platelet P-selectin in male patients with inflammatory bowel disease compared to healthy males2006In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 12, no 8, p. 1270-1272Article in journal (Refereed)
    Abstract [en]

    Aim: To observe if the total amount of platelet P-selectin (tP-selectin) in patients with inflammatory bowel disease (IBD) was related to disease entity or activity, 5-aminosalicylic acid (5-ASA) medication or gender. Methods: tP-selectin was measured by immunoassay in seventeen IBD patients and twelve healthy controls. Results: Compared to controls, there was no difference of tP-selectin in patients related to disease entity or activity and 5-ASA medication. When the groups were split according to gender the male patient group showed higher levels of tP-selectin compared to male controls (153 ng/mL vs 94 ng/mL, P<0.05). Conclusion: Increased tP-selectin levels may alter the inflammatory response and susceptibility to thromboembolic disease. As previously shown with soluble P-selectin, tP-selectin shows gender dependent differences important to consider in future studies. © 2006 The WJG Press. All rights reserved.

  • 22.
    Fägerstam, Patrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Östberg, Anna Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Eriksson, Andreas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Fransson, Sven Göran
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Ex vivo and in vitro effects of iodinated contrast agents on platelet adhesion and platelet P-selectin2007In: Svensk och nordisk Röntgenvecka,2007, 2007Conference paper (Other academic)
  • 23.
    Fägerstam, Patrik
    et al.
    Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping. Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Östberg, Anna Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Eriksson, Andreas
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Fransson, Sven-Göran
    Linköping University, Department of Medicine and Health Sciences, Radiology . Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping. Linköping University, Faculty of Health Sciences.
    Whiss, Per
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Similar inhibition of platelet adhesion, P-selectin expression and plasma coagulation by ioversol, iodixanol and ioxaglate2010In: The British Journal of Radiology, ISSN 0007-1285, Vol. 83, no 989, p. 401-410Article in journal (Refereed)
    Abstract [en]

    Contrast media (CM) are reported to possess both pro-thrombotic and anticoagulant properties. The mechanisms are not clearly understood and early reports are contradictory. To study the effects of CM on haemostasis, we analysed the ex vivo effects of ioversol and iodixanol on platelet adhesion and P-selectin expression, and the in vitro effects of ioversol, iodixanol and ioxaglate on platelet adhesion, P-selectin expression and plasma coagulation. A novel enzymatic assay was used to measure platelet adhesion to protein surfaces and an enzyme-linked immunosorbent assay was used to measure platelet P-selectin surface expression. Pro-thrombin time (PT) and activated partial thromboplastin time (APTT) were used to measure plasma coagulation. The ex vivo study consisted of blood from 27 outpatients administered ioversol and 9 patients administered iodixanol intravenously. Samples were collected before and 5 min after CM administration. Healthy donors were used for the in vitro studies on the effects of CM. The ex vivo study showed significantly (p<0.05) decreased platelet adhesion and P-selectin expression after administration of ioversol and iodixanol. Adhesion was more affected than P-selectin expression. The in vitro study showed that ioversol, iodixanol and ioaxaglate significantly (p<0.05) and dose dependently (beginning at 3 mg ml(-1)) decreased platelet adhesion and P-selectin expression. APTT and PT were significantly (p<0.01) prolonged at concentrations of 10 mg ml(-1) and 30 mg ml(-1), respectively. In conclusion, ioversol, iodixanol and ioxaglate inhibit platelet adhesion and P-selectin expression, as well as plasma coagulation. Platelets are more sensitive in relation to the inhibiting effect on plasma coagulation.

  • 24.
    Grenegård, Magnus
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Svensson, Samuel
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    The novel nitric oxide-donor GEA 3175 and adenosine inhibit intracellular responses in thrombin-activated platelets1997In: FEBS special meeting: Cell Signalling Mechanisms, From Membrane to Nucleus,1997, 1997Conference paper (Other academic)
  • 25.
    Hallbäck, Ida
    et al.
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Eriksson, Andreas
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation2012In: Pharmacological Reports, ISSN 1734-1140, Vol. 64, no 4, p. 979-983Article in journal (Refereed)
    Abstract [en]

    Background: Although several studies show that there is an increased risk of bleeding events during antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs), few studies show direct effects in vitro of SSRIs on hemostasis. less thanbrgreater than less thanbrgreater thanMethods: This study was undertaken to investigate the effects on platelet adhesion and plasma coagulation (APTT and PT) of two common SSRIs, citalopram and sertraline, the selective noradrenaline reuptake inhibitor reboxetine, and the serotonin and noradrenaline reuptake inhibitor venlafaxine. less thanbrgreater than less thanbrgreater thanResults: None of the compounds affected plasma coagulation significantly but all compounds except for venlafaxine inhibited platelet adhesion by approximately 50% or more at the highest concentration (100 mu g/l, p andlt; 0.01). The potency of respective compound to inhibit platelet adhesion to both collagen and fibrinogen surfaces was in the following order; citalopram andgt; sertraline andgt; reboxetine. In contrast, venlafaxine caused a weak but statistically significant increased platelet adhesion to fibrinogen. less thanbrgreater than less thanbrgreater thanConclusion: This study showed that sertraline, citalopram and reboxetine direct and acutely decrease platelet adhesion to both collagen and fibrinogen in vitro. These results also indicate that increased risk for bleeding complications in antidepressant users may not only be explained by depletion of serotonin in platelets.

  • 26.
    Johansson, Mona
    et al.
    Jönköping.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Weak relationship between ionized and total magnesium in serum of patients requiring magnesium status2007In: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720, Vol. 115, no 1, p. 13-21Article in journal (Refereed)
    Abstract [en]

    Measurement and monitoring of magnesium (Mg) are important to prevent the development of serious and potentially fatal complications in critically ill patients. Although ion-selective electrodes are available and earlier reports suggest that free ionized magnesium (iMg2+) is the most useful test to estimate Mg status, most clinical laboratories still only measure total Mg. To compare the relationship among iMg2+, total Mg, and albumin in serum, samples were collected from 48 consecutive patients admitted to an intensive care unit or a primary health center. The mean serum level of iMg2+ in 44 patients was 0.53 mmol/L, the total Mg was 0.96 mmol/L, and the albumin was 34.93 g/L. The correlation between iMg2+ and total Mg in serum was r=0.585, the correlation between iMg2+ and albumin in serum was r=378, and the correlation between total Mg and albumin in serum was r=0.340. The mean percent iMg2+ in relation to total Mg in serum was calculated to be 55% in the patient samples. The important level of biologically active iMg2+ was not reflected upon analysis of total Mg in 25% of consecutive patients. This report shows that the correlation of iMg2+ and total Mg is weak, not only in critically ill patients but also in patients in whom Mg status is inquired as a whole.

  • 27.
    Lindh Falk, Annika
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Medicine and Health Sciences.
    Dahlberg, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Heslyk, Annika
    Linköping University, Department of Medical and Health Sciences, Division of Physiotherapy. Linköping University, Faculty of Medicine and Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Abrandt Dahlgren, Madeleine
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Creating spaces for interprofessional learning: Strategic revision of a common IPL curriculum in undergraduate programs2015In: Interprofessional Education in Europe: Policy and Practice / [ed] Andre Vyt, Majda Pahor, Tiina Tervaskanto-Maentausta, Antwerpen: Garant Publishers Limited , 2015, p. 49-66Chapter in book (Refereed)
  • 28.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Eriksson, Andreas
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, p. 932-938Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent.

    The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets.

    None of the metabolites cotinine, cotinine-N-oxide, nicotine-1′-N-oxide or trans-3′-hydroxycotinine (0.1–10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3′-hydroxycotinine (0.1 μM) and nicotine-1′-N-oxide (1–10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor.

    Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 29. Lundahl, TH
    et al.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Larsson, R
    Lindahl, TL
    Platelet activation before and after hemodialysis measured utilising flow cytometry and aggregometry1997In: Congress of the international society of thrombosis and haemostasis,1997, 1997Conference paper (Other academic)
  • 30.
    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. 

  • 31.
    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.

  • 32. Samuelsson, U
    et al.
    Hanås, Ragnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Ludvigsson, J
    Blood glucose peaks give high HbA1c2004In: International Society for Pediatric and Adolescent Diabetes ISPAD,2004, 2004Conference paper (Other academic)
  • 33.
    Samuelsson, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hanås, Ragnar
    Barnkliniken NÄL, Uddevalla.
    Whiss, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Do high blood glucose peaks contribute to higher HbA1c? Results from repeated continuous glucose measurements in children2008In: World Journal of Pediatrics, ISSN 1708-8569, Vol. 4, no 3, p. 215-221Article in journal (Refereed)
    Abstract [en]

    Background: HbA1c levels are infl uenced by the glycemic control of previous 2-3 months. Sometimes patients have surprisingly low HbA1c in spite of many correctly measured high blood glucose values, which is diffi cult to explain. As glucose sensors give an objective picture based on glucose readings several times per minute over 24 hours, we used the area under the curve (AUC) of such subcutaneous glucose profi les to evaluate their relationship with HbA1c. Methods: Thirty-two patients were randomized into two study arms, one open and the other blinded. Both arms had 8 pump users and 8 patients with multiple daily injections (MDI). After three months the two arms crossed over. Both study arms wore a continuous glucose monitoring system (CGMS) for 3 days every 2 weeks. HbA1c was determined before and after each 3-month study period. Results: There was no relationship between HbA1c and s.c. glucose AUC or between HbA1c and the number of peaks >15.0 mmol/L when all CGMS profi les during the 6 months were taken together. Children on MDI showed a positive relationship between HbA1c and AUC (P<0.01) as well as the number of peaks (P<0.01). Children with a negative relationship between HbA1c and AUC generally had fewer fluctuations in blood glucose values, whereas children with a positive relationship had wide fluctuations. Conclusions: Although there was no relationship between s.c. glucose AUC and HbA1c, the results indicate that wide blood glucose fluctuations may be related to high HbA1c values. Therefore, complications and therapeutic interventions should aim at reducing such fluctuations. © Springer 2008.

  • 34.
    Whiss, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Analyses of surface receptors on isolated platelets upon adhesion to protein surfaces: Platelet adhesion to collagen induces more P-selectin expression than adhesion to fibrinogen1999In: Thrombosis and Haemostasis, ISSN 0340-6245, p. 501-Conference paper (Other academic)
  • 35.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Analyses of surface receptors on isolated platelets upon adhesion to protein surfaces: Platelet adhesion to collagen induces more P-selectin expression than adhesion to fibrinogen1999In: XVIIth Congress of the International Society of Thrombosis and Haemostasis,1999, 1999Conference paper (Other academic)
  • 36.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    CTC-111 Teijin2001In: IDrugs. The Investigational Drugs Journal, ISSN 1369-7056, E-ISSN 2040-3410, Vol. 4, p. 1178-1185Article in journal (Other academic)
  • 37.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Pexelizumab Alexion2002In: Current Opinion in Investigational Drugs, ISSN 1472-4472, Vol. 3, no 6, p. 870-877Article in journal (Refereed)
  • 38.
    Whiss, Per A.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet adhesion and P-selectin surface expression2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Upon injury in a blood vessel, platelets become activated and adbere to prevent blood loss. Activated platelets express adhesion molecules on their surface that also make leukocytes adhere to the injury. One such molecule, which also is expressed on endothelium, is the glycoprotein P-selectin. The present studies were focused on how soluble factors and surfaces can affect P-selectin surface expression on human platelets.

    This thesis presents an enzyme-linked immunosorbent assay (ELISA) application to study platelet expression and release of P-selectin. The well-known platelet activators collagen, epinephrine, ADP, ristocetin, PMA, and thrombin induced surface expression of P-selectin with different potency and time-dependency in vitro. One of the most powerful platelet activators, thrombin, rapidly mediated both surface expression and release. The surface expression decreased after a short peak upon maximal thrombin-activation. The protein kinase C activator PMA induced surface expression equivalently to thrombin but the release of Pselectin was less as compared to thrombin. Nitric oxide (NO) donors, which mimic a vessel wall mechanism to inhibit platelet activation, decreased expression and release of P-selectin upon activation. Adenosine, another agent that is produced in vivo, acted in concert with NO and totally inhibited P-selectin expression induced by thrombin. NO and adenosine act by increasing the second messengers cGMP and cAMP, respectively.

    The effects of an infusion of nicotine on platelet P-selectin expression were studied in nicotine users with normal and impaired renal function. After a peak directly after infusion, the plasma concentration of nicotine declined towards the basal level and the level of NO-products was lower as compared to baseline 2 h after infusion. At the same time, P-selectin expression induced by weak activators, but not by thrombin, increased in both groups. A transient and weak inhibition of collagen-induced platelet aggregation was observed directly after infusion. Studies in vitro showed that nicotine per se inhibits P-selectin expression. Thus, nicotine appears to initially inhibit and then increase platelet activation in vivo.

    The adhesion of platelets to surfaces that can be exposed upon vessel wall injury and the subsequent expression of P-selectin were found to be dependent on divalent cations. Mg2+ dose-dependently increased platelet adhesion to both collagen and fibrinogen in the physiological range, but supraphysiological concentrations decreased the adhesion to fibrinogen. Ca2+ did only increase platelet adhesion to fibrinogen. Platelet adhesion to collagen caused more expression of P-selectin than adhesion to fibrinogen. Thus, the surface and the access of divalent cations regulate platelet adhesion and P-selectin surface expression.

    In summary, multiple factors rep1late and affect platelet adhesion and P-selectin surface expression. The methods presented in this thesis are suitable for studies to further understand and make pharmacological modulation possible of these complex mechanisms and consequences.

    List of papers
    1. Modulation of P-selectin expression on isolated human platelets y an NO donor assessed by a novel ELISA application
    Open this publication in new window or tab >>Modulation of P-selectin expression on isolated human platelets y an NO donor assessed by a novel ELISA application
    1997 (English)In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 200, no 1-2, p. 135-143Article in journal (Refereed) Published
    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.

    Keywords
    Platelet, Adhesion molecule, P-selectin, CD62P, ELISA, Nitric oxide
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79738 (URN)10.1016/S0022-1759(96)00198-6 (DOI)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2017-12-07Bibliographically approved
    2. Kinetics of platelet P-selectin mobilization: Concurrent surface expression and release induced by thrombin or PMA, and inhibition by the NO Donor SNAP
    Open this publication in new window or tab >>Kinetics of platelet P-selectin mobilization: Concurrent surface expression and release induced by thrombin or PMA, and inhibition by the NO Donor SNAP
    1998 (English)In: Cell Communication & Adhesion, ISSN 1541-9061, E-ISSN 1543-5180, Vol. 6, no 4, p. 289-300Article in journal (Refereed) Published
    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.

    Keywords
    P-selectin mobilization, kinetics, human platelets, thrombin, phorbol ester, nitric oxide
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79742 (URN)10.3109/15419069809010788 (DOI)
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2017-12-07Bibliographically approved
    3. Acute Effects of Nicotine Infusion on Platelets in Nicotine Users with Normal and Impaired Renal Function
    Open this publication in new window or tab >>Acute Effects of Nicotine Infusion on Platelets in Nicotine Users with Normal and Impaired Renal Function
    Show others...
    2000 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 163, no 2, p. 95-104Article in journal (Refereed) Published
    Abstract [en]

    The role of platelets in cardiovascular disease associated with smoking is becoming more established, but the effects of nicotine on platelets are unclear. Nicotine therapy is used for smoking cessation in both health and disease. Consequently, the effects of nicotine on platelets are of particular significance in disorders such as renal disease, which is associated with defective platelet function, increased cardiovascular morbidity, and altered nicotine metabolism. Thus, the aim of the present study was to investigate the acute effects of nicotine infusion (NI) on platelets in seven healthy subjects (HS) and seven patients with renal failure (RF). All subjects were nicotine users and had refrained from using nicotine for 36 h before NI. Blood was collected before, immediately after, and 2 h after NI. The plasma concentrations of nicotine and its main metabolite cotinine were determined by gas chromatography. Platelet responsiveness was assessed by aggregometry and flow cytometry in whole blood (P-selectin surface expression, fibrinogen- and von Willebrand factor-binding), P-selectin expression in isolated platelets, and immunoassays of platelet release (β-thromboglobulin, platelet factor 4, and soluble P-selectin) and nitric oxide (NO) products. The plasma levels of cotinine, but not nicotine, were significantly higher in RF compared to HS at all time points. In both groups, collagen-induced platelet aggregation was restrained immediately after NI, when the plasma concentration of nicotine was maximal, and was restored after 2 h. Two hours after NI, activation-dependent P-selectin surface expression in isolated platelets increased in both groups. This increased platelet responsiveness occurred simultaneously with a significant increase of plasma cotinine and a decrease of NO products. Thus, the present study suggests that nicotine, directly or through some secondary mechanism or metabolite, only slightly potentiates some of the platelet responses. Renal failure appears not to influence the effects of nicotine on platelets.

    Keywords
    Nicotine, cotinine, platelets, P-selectin, nitric oxide, healthy subjects, renal failure
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25232 (URN)10.1006/taap.1999.8853 (DOI)9671 (Local ID)9671 (Archive number)9671 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Divalent cations and the protein surface co-ordinate the intensity of human platelet adhesion and P-selectin surface expression
    Open this publication in new window or tab >>Divalent cations and the protein surface co-ordinate the intensity of human platelet adhesion and P-selectin surface expression
    2002 (English)In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 13, no 5, p. 407-416Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26773 (URN)10.1097/00001721-200207000-00005 (DOI)11377 (Local ID)11377 (Archive number)11377 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 39.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Platelet P-selectin (CD62P): A link between outflow and inflow defence.2000In: Research Signpost, Linköping: Linköpings universitet , 2000, p. 11-40Chapter in book (Other academic)
  • 40.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Trombocyters adhesion och membranuttryck av adhesionsmolekylen P-selektin2001In: Laboratoriet, ISSN 0345-696X, Vol. 1Article in journal (Other (popular science, discussion, etc.))
  • 41.
    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.

  • 42.
    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.

  • 43.
    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.

  • 44.
    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)
  • 45.
    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)
  • 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.
    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)
  • 47.
    Whiss, Per A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Larsson, Rutger
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Comparison of plasma levels of cytokines and in vitro generation of reactive oxygen species after nicotine infusion in nicotine users with normal and impaired renal function2003In: Immunopharmacology and immunotoxicology, ISSN 0892-3973, E-ISSN 1532-2513, Vol. 25, no 2, p. 131-144Article in journal (Refereed)
    Abstract [en]

    Several in vitro and animal studies suggest effects of nicotine on the immune system, but little evidence exists regarding the in vivo immunomodulation of nicotine in humans. The increased use of nicotine replacement therapy to aid smoking cessation claims further understanding of how nicotine affects blood leukocytes. This is of particular importance when nicotine therapy is used in diseases associated with alterations of the immune system, such as chronic renal failure. The present study evaluates the acute effects of nicotine infusion (NI) on some immunoregulatory functions in seven healthy subjects and seven patients with renal failure. All subjects were nicotine users and had refrained from using nicotine for 36h before NI. Blood was collected before, immediately after, and 2h after NI. Plasma concentrations of intercellular adhesion molecule-1 (ICAM-1) and the cytokines interleukin-2 (IL-2), IL-4, IL-10, interferon-? and RANTES were measured using specific immunoassays. The generation of reactive oxygen species (ROS) induced by formyl-methionyl-leucyl-phenylalanine (fMLP), Ristocetin, adenosine 5'-diphosphate, or collagen was registered in whole blood as luminol-dependent chemiluminescence. Except for fMLP, these compounds induce leukocyte ROS generation by platelet mediated mechanisms. NI did not significantly affect the levels of the cytokines and ICAM-1 in any group. The peak and the persistent ROS production, induced by collagen and Ristocetin, was lower at some time points in patients with renal failure as compared to healthy subjects. Also in patients with renal failure, both peak height and persistent ROS generation induced by Ristocetin were reduced immediately after NI. Thus, nicotine inhibits some of the platelet-mediated activation of leukocyte ROS generation, and may be associated with platelet defects in renal failure.

  • 48.
    Whiss, Per A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Larsson, Rutger
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Adenosine 5' -Diphosphate-induced platelet aggregation in uremia shows resistance til inhibition by the novel nitric oxide donor GEA 31 75 but not by S-Nitro-N-acetylpenicillamine.1999In: Haemostasis, ISSN 0301-0147, E-ISSN 1423-0038, Vol. 28, p. 260-267Article in journal (Refereed)
  • 49.
    Whiss, Per A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lundahl, TH
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lindahl, TL
    Lunell, E
    Larsson, R
    Acute effects of nicotine on platelets in healthy and renal impaired nicotine users1998In: XIIIth International Congress of Pharmacology,1998, 1998Conference paper (Other academic)
  • 50.
    Whiss, Per A
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lundahl, Tom
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry.
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Lunell, Erik
    Larsson, Rutger
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Effekter av nikotin på trombocyter vid normal och nedsatt njurfunktion2001In: Vårdfacket, ISSN 0347-0911, Vol. 163, p. 63-63Article in journal (Other (popular science, discussion, etc.))
12 1 - 50 of 51
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