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1

Pharmacology at the Jagiellonian University in Krakow, short review of contribution to global science and cardiovascular research through 400 years of history

100%

Wolkow P. P., Korbut R.

Journal of Physiology and Pharmacology. Supplement

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2006

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tom 57

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nr 1

119-136

Pharmacology at the Jagiellonian University was taught since the foundation of the University in 1364 under then used names of medical botany and pharmacognosy. The first in Poland Division of Pharmacology and Pharmacognosy was created in 1857. Modern era in the history of pharmacology in Krakow starts in 1929 when Prof. Janusz Supniewski became the Head of the Department. He was the relentless researcher whose scientific interests were as diverse as ranging from anticancer chemotherapeutics, antibiotics, and oral hypoglycemic drugs to lipid-lowering agents. Skills of organic chemistry synthesis were of paramount importance for the scientific achievements. Prof. Supniewski died in 1964, leaving the Department well equipped in instruments. He raised in his laboratory many eminent scientists who later beacame heads of pharmacology departments throughout Poland. In 1964, the Head of the Department of Pharmacology became Prof. Ryszard Gryglewski. Under his leadership the Department focused scientific efforts on various aspects of cardiovascular pharmacology. Prof. Gryglewski established collaborations with many of the best pharmacology researchers in the world, including Sir John Vane, Nobel Prize laureate. Prof. Gryglewski's assistants had ample opportunity to train in these laboratories and to bring these skills back to Krakow. Prof. Gryglewski and his team published many articles in the most prestigious scientific journals. The most important themes included discovery of prostacyclin, role of nitric oxide and of free radicals for vascular biology. Since 2003, when Prof. Gryglewski retired, the Department of Pharmacology has been led by Prof. Ryszard Korbut.

2

Anti-aggregatory prostanoids. Part II

100%

Korbut R., Gryglewski R. J.

Acta Physiologica Polonica

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1985

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tom 36

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nr 5-6

3

The current view on the role of leukotrienes in atherogenesis

100%

Jawien J., Korbut R.

Journal of Physiology and Pharmacology

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2010

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tom 61

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nr 6

4

Anti-aggregatory prostanoids. Part I

100%

Korbut R., Gryglewski R. J.

Acta Physiologica Polonica

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1985

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tom 36

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nr 5-6

5

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Platelets in fibrinolytic system

100%

Korbut R., Gryglewski R. J.

Journal of Physiology and Pharmacology

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1995

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tom 46

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nr 4

6

The effect of prostacyclin and nitric oxide on deformability of red blood cells in septic shock in rats

100%

Korbut R., Gryglewski R. J.

Journal of Physiology and Pharmacology

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1996

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tom 47

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nr 4

7

Effects of nitric oxide and prostacyclin on deformability and aggregability of red blood cells of rats ex vivo and in vitro

81%

Starzyk D., Korbut R., Gryglewski R. J.

Journal of Physiology and Pharmacology

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1999

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tom 50

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nr 4

8

The role of nitric oxide in regulation of deformability of red blood cells in acute phase of endotoxaemia in rats

81%

Starzyk D., Korbut R., Gryglewski R. J.

Journal of Physiology and Pharmacology

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1997

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tom 48

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nr 4

9

Effect of aspirin on cysteinyl leukotrienes production by eosinophils co-cultured with epithelial cells

81%

Jawien J., Olszanecki R., Lorkowska B., Korbut R.

Journal of Physiology and Pharmacology

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2004

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tom 55

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nr 4

Eosinophils have long been considered to play solely crucial role in the pathogenesis of aspirin-induced asthma, however increasing evidence suggest that the bronchial epithelium is also involved in the initiation and maintenance of allergic inflammation. Epithelial cells and eosinophils retained within airways interact reciprocally to mount and sustain inflammatory response. Recently, we have shown that eosinophil-epithelial cell interactions are capable of amplifying the production of cysteinyl leukotrienes (Cys-LTs). The aim of this study was to investigate if there is any influence of aspirin (ASA) on Cys-LTs and prostaglandin E2 (PGE2) production in the model of co-cultured human epithelial cells (line BEAS-2B) and human eosinophils. Synthesis of Cys-LTs in eosinophils was increased after incubation with ASA. At the same time the production of PGE2 was decreased by aspirin (n=32). BEAS-2B cells barely formed Cys-LTs; addition of ASA increased this production, while production of PGE2 was inhibited by aspirin (n=32). Synthesis of Cys-LTs by eosinophils co-incubated with BEAS-2B was nearly 7-fold higher than that of activated eosinophils alone (1631.5 pg/ml ± 154 vs. 258 pg/ml ± 31; p<0.05; n=32). Surprisingly, in the eosinophil-epithelial cell co-culture, aspirin inhibited both augmentation of Cys-LTs synthesis (from 1631.5 pg/ml ± 154 to 1458 pg/ml ± 137; p<0.05; n=32) and the production of PGE2 (from 2640 pg/ml ± 231 to 319 pg/ml ± 27; p<0.05; n=32). In summary, we have demonstrated that interactions between non-atopic eosinophils and epithelial cells result in augmentation of Cys-LTs production, and this augmentation could be inhibited by aspirin.

10

Endotoxaemia in rats: role of leucocyte sequestration in rapid pulmonary nitric oxide synthase-2 expression

81%

Gebska A., Olszanecki R., Korbut R.

Journal of Physiology and Pharmacology

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2005

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tom 56

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nr 2

Nitric oxide (NO), depending on the amount, time and source of generation may exert both, protective and deleterious actions during endotoxic acute lung injury (ALI). Evaluation of the expression and localization of NOS isoforms in the lung of lipopolysaccharide (LPS) - treated rats may contribute to understanding the role of NO in pathogenesis of ALI. Tissue samples (lung, heart, liver, kidney and spleen) as well as peripheral blood polymorphonuclear cells (PMNs) were collected from control male Wistar rats and LPS - treated animals, 15, 30, 60, 120 and 180 min after LPS injection (2 mg kg-1 min-1 for 10 minutes, i.v.). Levels of NOS-2 and NOS-3 mRNA and protein in tissues and PMNs were estimated by RT-PCR, Northern blotting and Western blotting. Additionally, myeloperoxidase (MPO) activity in tissue samples was assayed. NOS-3 mRNA as well as protein were detected in lungs of control animals; pulmonary NOS-3 expression was not influenced by LPS. The induction of NOS-2 mRNA in rat lungs and in PMNs isolated from peripheral blood was observed 15 minutes after LPS challenge. In contrast, increase of NOS-2 mRNA in the heart, kidneys, liver and spleen was observed 2-3 hours after LPS injection. In all tissues rise in NOS-2 mRNA was followed after 1-2 hours by increase of NOS-2 protein. Importantly, progressive leukocyte sequestration in the lung parenchyma that started as early as 15 min after LPS injection was revealed only in the lungs; in other organs no significant changes in MPO activity were detected up to 180 min after LPS injection. In conclusion, infusion of LPS caused much more rapid expression of NOS-2 in lungs as compared to the heart, kidneys, liver and spleen. Early induction of NOS-2 may depend on the LPS-stimulated rapid neutrophil sequestration within lung vasculature and fast induction of NOS-2 in sequestrated neutrophils.

11

Endothelial secretogogues and deformability of erythrocytes

81%

Korbut R. A., Adamek-Guzik T., Madej J., Korbut R.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 4,1

Many diseases of the heart and circulatory system have been linked with both dysfunction of vascular endothelium and insufficient deformability of erythrocytes. Using shear stress laser diffractometry we investigated whether deformability of erythrocytes would be regulated endogenously by generation of two endothelial secretogogues: prostacyclin and nitric oxide. Experiments were performed in rats ex vivo and with whole blood or isolated erythrocytes in vitro. Iloprost - a stable analogue of prostacyclin (10 µg/kg i.v.) and SIN-1 (NO-donor) at a dose of 2 mg/kg/min i.v induced a significant improvement of deformability of erythrocytes ex vivo. Improvements of deformability by these two compounds were also evident in vitro when they were applied at a range of concentrations of 1 µM and 3 µM, respectively. Cyclooxygenase (indomethacin 20 mg.kg i.v.) and nitric oxide synthase (L-NAME 10 mg/kg i.v.) inhibitors while worsening deformability ex vivo, they did not affect (3 mM and 10 µM, respectively) rheological functions of erythocytes in vitro. Aggravating effects of these inhibitors on erythrocyte deformability ex vivo were reversed by prostacyclin and nitric oxide supplemented exogenously. Aspirin at a low (1 mg/kg i.v.) and high dose (50 mg/kg i.v.), contrary to indomethacin and L- NAME, aggravated erythrocyte deformability either ex vivo or in vitro. It is concluded that autocrine function of vascular endothelium plays an important role in regulation of rheology of red blood cells in flowing blood. The mechanism of this phenomenon is unclear but some possible explanations are discussed. In addition, in our experiments aspirin revealed unique erythrocyte damaging properties, possibly independent of inhibition of cyclooxygenase, but related to a direct protein acetylation.

12

Bay x 1005 attenuates atherosclerosis in apoE-LDLR - double knockout mice

81%

Jawien J., Gajda M., Olszanecki R., Korbut R.

Journal of Physiology and Pharmacology

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2007

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tom 58

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nr 3

Recently, we have shown that MK-886 - an inhibitor of five lipoxygenase activating protein (FLAP) inhibits atherosclerosis in apolipoprotein E / LDL receptor - double knockout mice. We, therefore, wanted to find out if other FLAP inhibitor - BAYx1005 given at a dose of 1.88 mg per 100 mg of body weight per day during 16 weeks, could also attenuate atherogenesis. In apoE/LDLR - DKO mouse model BAYx1005 inhibited atherogenesis, measured both by "en face" method (23.84 ± 2.7% vs. 15.16 ± 1.4%) and "cross-section" method (497236 ± 31516 µm2 vs. 278107 ± 21824 µm2). This is the first report that shows the effect of BAYx1005 on atherogenesis in gene-targeted mice.

13

The involvement of adhesion molecules and lipid mediators in the adhesion of human platelets to eosinophils

81%

Jawien J., Lomnicka M., Korbut R., Chlopicki S.

Journal of Physiology and Pharmacology

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2005

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tom 56

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nr 4

Platelet-leukocyte interactions represent an important determinant of the inflammatory response. Although mechanisms of platelet-neutrophil adhesion were studied extensively, little is known on the mechanisms of platelet-eosinophil interactions. The aim of the present study was to analyze the involvement of adhesion molecules and lipid mediators in platelet-eosinophil adhesion as compared to platelet-neutrophil adhesion. For that purpose human platelets, eosinophils and neutrophils were isolated and platelet-eosinophil and platelet-neutrophil adhesion induced by thrombin (30 mU/ml), LPS (0.01 µg/ml) and fMLP (1 µM) was quantified using the "rosettes" assay. The involvement of adhesion molecules such as selectin P, glycoprotein IIb/IIIa (GPIIb/IIIa) and lipid mediators such as of thromboxane A2 (TXA2), platelet activating factor (PAF) and cysteinyl leukotrienes (cysLTs) were studied using monoclonal antibodies and pharmacological inhibitors, respectively. Thrombin (30 mU/ml), LPS (0.01 µg/ml) and fMLP (1 µM) each of them induced platelet-eosinophil adhesion that was even more pronounced as compared with platelet-neutrophil adhesion induced by the same stimulus. Anti-CD62P antibody (1 µg/ml) and anti-GP IIb/IIIa antibody (abciximab - 3 µg/ml) strongly inhibited platelet-eosinophil as well as platelet-neutrophil adhesion. Aspirin inhibited platelet-eosinophil adhesion, while MK 886 - a FLAP inhibitor (10 µM), or WEB 2170 - a PAF receptor antagonist (100 µM) were less active. On the other hand aspirin, MK 886 and WEB 2170 all three of them inhibited platelet-neutrophil adhesion. In summary, platelets adhered avidly to eosinophils both after activation of platelets by thrombin, eosinophils by fMLP or simultaneous activation of platelets and eosinophils by LPS. Similarly to platelet-neutrophil interaction adhesion of platelets to eosinophils involved not only adhesion molecules (selectin P, GPIIb/IIIa), but also lipid mediators such as TXA2. The involvement of PAF and cysteinyl leukotrienes in platelet-eosinophil adhesion was less pronounced as compared to platelet-neutrophil adhesion.

14

Production of prostacyclin and prostaglandin E2 in resting and IL-1beta-stimulated A549, HUVEC and hybrid EA.HY 926 cells

81%

Olszanecki R., Gebska A., Korbut R.

Journal of Physiology and Pharmacology

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2006

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tom 57

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nr 4

Production of arachidonic acid (AA) metabolites - prostacyclin (PGI2) in large vessels and prostaglandin E2 (PGE2) in microcirculation is intrinsically involved in maintenance of vascular wall homeostasis. EA.hy 926 is a hybrid cell line, is derived by fusion of HUVEC with A549 cells. The aim of this study was to examine the production of prostacyclin and PGE2 in resting and IL-1ß-stimulated EA.ha 926 cells, in comparison with its progenitor cells. Non-stimulated EA.hy 926 cells has been found to produce much lower amounts of prostacyclin than resting HUVEC. Resting hybrid cells produced more PGE2 than prostacyclin, despite they expressed high levels of COX-1 and PGI2 synthase. On the contrary to HUVEC and A549, EA.hy 926 cells did not respond to IL-1ß with COX-2 induction and increase of prostaglandin production, however they did it in response to lysophosphatidylcholine (LPC). The characteristics of EA.hy 926 cells in terms of the pattern of prostanoid formation could facilitate studies on endothelial metabolism and role of these important lipid mediators.

15

Adipocytokines - novel link between inflammation and vascular funktion?

81%

Guzik T. J., Mangalat D., Korbut R.

Journal of Physiology and Pharmacology

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2006

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tom 57

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nr 4

Obesity and obesity related diseases are a major public health problem. Recent studies have shown that fat tissue is not a simple energy storage organ, but exerts important endocrine and immune functions. These are achieved predominantly through release of adipocytokines, which include several novel and highly active molecules released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines released possibly by inflammatory cells infiltrating fat, like TNF-alpha, IL-6, MCP-1 (CCL-2), IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation and may also affect vascular (endothelial) function by modulating vascular nitric oxide and superoxide release and mediating obesity related vascular disorders (including hypertension, diabetes, atherosclerosis, and insulin resistance) but also cancer or non-alcoholic fatty liver diseases. Present review, in a concise form, focuses on the effects of major adipocytokines, characteristic for adipose tissue like leptin, adiponectin, resistin and visfatin on the immune system, particularly innate and adaptive immunity as well as on blood vessels. Macrophages and T cells are populating adipose tissue which develops into almost an organized immune organ. Activated T cells further migrate to blood vessels, kidney, brain and other organs surrounded by infiltrated fat leading to their damage, thus providing a link between metabolic syndrome, inflammation and cardiovascular and other associated disorders. Ceretain treatments may lead to significant changes in adipocytokine levels. For example include beta-2 adrenoreceptor agonists, thiazolidinediones as well as androgens lead to decrease of plasma leptin levels. Moreover future treatments of metabolic system associated disorders should focus on the regulation of adipocytokines and their modes of action.

16

The effect of nitric oxide donors on the release of plasminogen activator inhibitor [PAI] from rabbit platelets in vitro

81%

Korbut R., Marcinkiewicz E., Cieslik K., Gryglewski R. J.

Journal of Physiology and Pharmacology

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1995

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tom 46

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nr 1

17

Mouse models of experimental atherosclerosis

81%

Jawien J., Nastalek P., Korbut R.

Journal of Physiology and Pharmacology

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2004

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tom 55

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nr 3

Since 1992 the mouse has become an excellent model for experimental atherosclerosis research. Until 1992, the diet - induced atherosclerosis mouse model has been used effectively, but the lesions tended to be small and were limited to early fatty-streak stage. This model was also criticized because of the toxicity and inflammatory responses due to the diet. In 1992 the first line of gene targeted animal models, namely apolipoprotein E - knockout mice was developed. Of the genetically engineered models, the apoE - deficient model is the only one that develops extensive atherosclerotic lesions on a chow diet. It is also the model in which the lesions have been characterized most thoroughly. The lesions develop into fibrous plaques; however, there is no evidence that plaque rupture occurs in this model. The LDL receptor - deficient model has elevated LDL levels, but no lesions, or only very small lesions, form on the chow diet, however, robust lesions do form on the western-type diet. The creation of apoE - knockout mice has changed the face of atherosclerosis research.

18

Secretory dysfunction of vascular endothelium limits the effect of angiotensin converting enzyme inhibitor quinapril on aggregation of erythrocytes in experimental hypertension

81%

Korbut R. A., Madej J., Adamek-Guzik T., Korbut R.

Journal of Physiology and Pharmacology

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2003

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tom 54

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nr 3

Using automatic erythrocyte aggregometer type MA-1 (Myrenne gmbh, Germany), we investigated the hypothesis that therapeutic effectiveness of quinapril - angiotensin converting enzyme inhibitor (ACEI) - in the treatment of hypertension would correlate with improvement of red blood cell (RBC) aggregability. Experiments were performed on commercially available inbred strain of spontaneously hypertensive male rats (SHR) aged 19-21 weeks. Age-matched normotensive Wistar-Kyoto (WKY) rats genetically related to SHR were used as a control. Aggregability of RBC in hypertensive rats was significantly higher than in control WKY animals. Quinapril (100 µg/kg) administered i.p. for 8 days improved RBC aggregability in normotensive rats but surprisingly not in SHR animals. Beneficial effect of quinapril on RBC aggregation observed in normotensive animals did not occur when this drug was injected in combination with aspirin (1 or 50 mg/kg) or with indomethacin (20 mg/kg) or with L-NAME (10 mg/kg). However, much the same damaging effects on RBC aggregability were observed when aspirin, indomethacin or L-NAME were each administered into normotensive animals without quinapril. In contrast with normotensive rats, aggregability of RBC in SHR was not affected either by quinapril or by indomethacin and by L-NAME, given separately or in combination. The only compound significantly worsening RBC aggregability in SHR was aspirin but this effect was not dose-dependent. Quinapril-induced improvement of RBC aggregability in normotensive rats (but not in SHR) was completely abolished by simultaneous administration of B2 receptor antagonist icatibant and successfully mimicked by 8 days of treatment with bradykinin. In vitro aggregability of RBC isolated from WKY was not affected by previous incubation (30 min at 37°C) with quinapril, indomethacin or L-NAME. Only aspirin (3 mM) significantly increased RBC aggregability as compared to placebo. It is concluded that under physiological conditions quinapril efficiently inhibits RBC aggregability and this effect is modulated by secretion of endothelial mediators, mainly prostacyclin and nitric oxide. In hypertension quinapril, in spite of lowering of arterial blood pressure, is unable to display its beneficial effects on RBC aggregability possibly due to the hypertension-induced/accompanied dysfunction of vascular endothelium. Aspirin revealed unique erythrocyte damaging properties, presumably independent of inhibition of cyclooxygenase but related to a direct membrane protein acetylation.

19

Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction

81%

Guzik T. J., Marvar P. J., Czesnikiewicz-Guzik M., Korbut R.

Journal of Physiology and Pharmacology

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2007

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tom 58

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nr 4

20

Nitric oxide and superoxide in inflammation and immune regulation

81%

Guzik T. J., Korbut R., Adamek-Guzik T.

Journal of Physiology and Pharmacology

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2003

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tom 54

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nr 4

Nitric oxide (NO) and reactive oxygen species exert multiple modulating effects on inflammation and play a key role in the regulation of immune responses. They affect virtually every step of the development of inflammation. Low concentrations of nitric oxide produced by constitutive and neuronal nitric oxide synthases inhibit adhesion molecule expression, cytokine and chemokine synthesis and leukocyte adhesion and transmigration. Large amounts of NO, generated primarily by iNOS can be toxic and pro-inflammatory. Actions of nitric oxide are however not dependent primarily on the enzymatic source, but rather on the cellular context, NO concentration (dependent on the distance from NO source) and initial priming of immune cells. These observations may explain difficulties in determining the exact role of NO in Th1 and Th2 lymphocyte balance in normal immune responses and in allergic disease. Similarly superoxide anion produced by NAD(P)H oxidases present in all cell types participating in inflammation (leukocytes, endothelial and other vascular cells etc) may lead to toxic effects, when produced at high levels during oxidative burst, but may also modulate inflammation in a far more discrete way, when continuously produced at low levels by NOXs (non-phagocytic oxidases). The effects of both nitric oxide and superoxide in immune regulation are exerted through multiple mechanisms, which include interaction with cell signalling systems like cGMP, cAMP, G-protein, JAK/STAT or MAPK dependent signal transduction pathways. They may also lead to modification of transcription factors activity and in this way modulate the expression of multiple other mediators of inflammation. Moreover genetic polymorphisms exist within genes encoding enzymes producing both NO and superoxide. The potential role of these polymorphisms in inflammation and susceptibility to infection is discussed. Along with studies showing increasing role of NO and free radicals in mediating inflammatory responses drugs which interfere with these systems are being introduced in the treatment of inflammation. These include statins, angiotensin receptor blockers, NAD(P)H oxidase inhibitors, NO-aspirin and others. In conclusion in this mini-review we discuss the mechanisms of nitric oxide and superoxide dependent modulation of inflammatory reactions in experimental animals and humans. We also discuss potential roles of nitric oxide as a mediator of allergic inflammation.

Ograniczanie wyników

Pharmacology at the Jagiellonian University in Krakow, short review of contribution to global science and cardiovascular research through 400 years of history

Anti-aggregatory prostanoids. Part II

The current view on the role of leukotrienes in atherogenesis

Anti-aggregatory prostanoids. Part I

Platelets in fibrinolytic system

The effect of prostacyclin and nitric oxide on deformability of red blood cells in septic shock in rats

Effects of nitric oxide and prostacyclin on deformability and aggregability of red blood cells of rats ex vivo and in vitro

The role of nitric oxide in regulation of deformability of red blood cells in acute phase of endotoxaemia in rats

Effect of aspirin on cysteinyl leukotrienes production by eosinophils co-cultured with epithelial cells

Endotoxaemia in rats: role of leucocyte sequestration in rapid pulmonary nitric oxide synthase-2 expression

Endothelial secretogogues and deformability of erythrocytes

Bay x 1005 attenuates atherosclerosis in apoE-LDLR - double knockout mice

The involvement of adhesion molecules and lipid mediators in the adhesion of human platelets to eosinophils

Production of prostacyclin and prostaglandin E2 in resting and IL-1beta-stimulated A549, HUVEC and hybrid EA.HY 926 cells

Adipocytokines - novel link between inflammation and vascular funktion?

The effect of nitric oxide donors on the release of plasminogen activator inhibitor [PAI] from rabbit platelets in vitro

Mouse models of experimental atherosclerosis

Secretory dysfunction of vascular endothelium limits the effect of angiotensin converting enzyme inhibitor quinapril on aggregation of erythrocytes in experimental hypertension

Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction

Nitric oxide and superoxide in inflammation and immune regulation