IN THE MIDDLE AGES

At times when Jagiellonian University was founded (1364) pharmacology was not the self-standing academic discipline. Lectures on therapy were covered under general term of Materia Medica and based on Greek and Arab classical texts. Knowledge of therapy was based on skills of preparing herbal extracts. Therefore, the first department that can be related to nowadays pharmacology was that of medical botanic, led by prof. Joannice and founded in 1602. Several textbooks on herbal drugs were issued soon after founding of the university by Marcin z Urzedowa, Schneeberger, Syreniusz, Stanko. Not surprisingly, at these times the boundaries between pharmacology and pharmacy were blurred and both these subjects were taught in one department.

In 1857, when pharmacy teaching was temporarily suspended, the Division of Pharmacology and Pharmacognosy in Poland was created for the first time at the Medical Faculty. It was led by prof. Skobel until his death in 1876. He was a very active researcher who published many articles and started publishing the journal Przeglad Lekarski (Medical Review). In 1881 prof. Lazarski became Head of the Department of Pharmacology and he remained at this position until his death in 1924. The level of teaching of pharmacology was very good under his professorship but research activities were relatively limited. After his death, pharmacology was taught temporarily by prof. Lobaczewski, who was also Head of the Department of Pharmacognosy at the Pharmacy Faculty. Prof. Lobaczewski died in 1928 and in 1929 Head of the Department of Pharmacology became prof. Janusz Supniewski.

HIGHEST PRIORITY TO SCIENCE

Prof. Supniewski started a modern era of pharmacology in Krakow. After the World War I he had an opportunity to study and work at laboratories in the United States. He brought to his work at the Jagiellonian University strong belief that he should emphasize and support research activity in the Department. Probably for the first time in the history of the Department, scientific achievements were given the highest priority. However, research interests in the Department were diverse. Before the World War II, scientists at the Department worked on the hemolytic properties of saponins (1), small intestine histaminase (2), and vitamin B1 (3). Professor Supniewski devoted most of his time to study cancerogenic substances (4) and antisterilising agents (5, 6). In the same area of interest of "antisterilising agents" several articles were published on the mechanisms of action of yohimbine (7) and stilbestrol derivatives (8, 9).

After the World War II, Department gradually regained the scientific potential. Professor Supniewski, as a scientific advisor of Pharmaceutical Company in Krakow, established collaboration with goals to improve the synthesis of chemical substances with practical applications for the therapy. The period when Prof. Supniewski was the Head of the Department of Pharmacology could be sum up as the time when skills of organic chemical synthesis were of paramount importance for the research activities in the Department.

The properties of sulfonamides (10) and cancer chemotherapeutics were among the first drugs studied. Studies on cancer chemotherapeutics were continued for the years to come (11). The new area of interest were antihistaminic drugs (12), in particular benadryl (13) and cardiologic agents. Effects of constant infusion of cardiac glycosides were studied by titration in pigeons (14).

Supniewski and Bany developed method of ephedrin synthesis (15) and described new directions in the drug synthesis, especially related to steroid drugs and polypeptides (16). Influence of nicotinic acid and isonicotinic acid on bile secretion was studied (17) and tuberculostatic properties of isonicotinic acid hydrazide were described (18). Around that time professor Supniewski developed interest in the properties of antibiotic drugs and described properties of erythromycin and tetracyclines (19, 20). He also studied drugs used to treat megaloblastic anemia (21). 1954 marked the interest in diabetes. Supniewski and Chrusciel wrote an article about the role of biguanid, oral hypoglycemic agents (22) and soon later another class of oral hypoglycemic agents - sulfonylureas was described by Gryglewski (23).

In mid-50s, the new area of research on the mechanism of action of antiatherogenic drugs was opened. Chrusciel and Chrusciel published the first in the series of articles on experimental atherogenesis (24). This work was continued for the years to come; in 1956 the method of inducing atherogenesis in pigeons was described in detail (25). In the meantime, professor Supniewski was still working on chemotherapeutic agents and he published an article on tuberculostatic properties of pyridine, hydrazides and thiosemicarbazone (26) and on antineoplastic chemotherapeutic agents (27). Ryszard Gryglewski continued his work on sulfonylurea hypoglycemic agents (28).

In the second half of 1950s the interest in pharmacology of central nervous system resulted in a series of articles on various aspects of therapy, e.g. anxiolytic drugs (29) and psychotomimetic drugs (30). Soon the interests in studying of pharmacotherapy of the central nervous system led to establishment of the Institute of Pharmacology of the Polish Academy of Sciences in Krakow. This institute, initially led by prof. Supniewski, specializes until today in pharmacology of the central nervous system.

In 1960 prof. Supniewski published a series of articles on biosynthesis of cholesterol (31-33). In these articles he suggested prophetically that inhibition of cholesterol biosynthesis pathway might be an important option to prevent and treat atherosclerosis. In the same year, in a surge of interest in biogenic amines, prof. Supniewski described synthesis and biological properties of melatonin (34).

In 1963, the article by Gryglewski on bioassay of factor I in the rat brain (35) heralded a paradigm shift in the way pharmacology was studied. Gradually, studying the mechanisms of action of the drugs in vivo or in isolated organs became more important than chemical synthesis of substances.

Professor Janusz Supniewski died in 1964. His legacy was the whole school of pharmacology teaching and research in Poland. Many of his former assistants became heads of pharmacology departments throughout the country: e.g. prof. Jozef Hano in Wroclaw, prof. Wojciech Dymek at the Faculty of Pharmacy in Krakow, prof. Chrusciel in Zabrze, prof. Andrzej Danysz in Bialystok. Prof. Wajdowa became professor of Pharmacology in New York.

PHARMACOLOGY OF CIRCULATION

The Head of the Department of Pharmacology at the Jagiellonian University became prof. Ryszard Gryglewski. Under his leadership research interests became gradually focused on various aspects of cardiovascular pharmacology. One of them was fibrynolysis and among the first articles on this subject was the one on fibrynolitic activity of anti-inflammatory drugs and of bicarboxylic acids (36, 37). The principles of bioassay were implemented in various modifications, e.g. to study influence of peptides on isolated, perfused rabbit arteries (38). Other issues studied in the late 60-s in the Department were: micronecrosis of the myocardium (39), resistography of mesenteric arteries (40). Other bioassay models used in the Department at that time were e.g. nictitating membrane of the pithed cat (used to study the effects of phentolamine) (41) and isolated guinea-pig lung (used to study the effects of adrenergic drugs, (42). It is important to add that in 1969 the Study Guide for Students of Pharmacology was published (43).

The sixties marked an era of new international connections of the Department. Dr. E. Mikos became acquainted with Dr. John Vane from England, later known as Sir John Vane, the Nobel Prize Laureate for the year 1982. Being invited by John Vane to England she published in Nature (London) (44) the paper on the effect of gastrin on isolated smooth muscles. Later on, by common effort of the above team, including prof. S. Konturek and prof. W. Pawlik, the next paper came into being in Journal of Physiology (London). In 1970 Dr. John Vane’s Polish Companionship was joined by Prof. Ryszard Grylewski and his young pharmacology team (45). In those days, from the very beginning, Sir John Vane collaborated with prof. Gryglewski’s Group mainly on the aspects of cardiovascular pharmacology and this collaboration lasted for the next few decades, actually incessantly to Sir John dying day in 2004. Sir John Vane visited Poland for numerous Congresses and he also hosted several of Prof. Gryglewski's assistants (Ryszard Korbut, Aldona Dembinska-Kiec) in his laboratories.

In the meantime, in the Department effects of angiotensin II and methylxantines on blood vessels of anaesthetized cats were studied successfully (46) and several novel articles on the mechanisms of action of b-adrenergic receptor antagonists were published in cooperation with Department of Physiology (47, 48).

Finally, collaboration with Sir John Vane resulted in an article on rabbit aorta contracting substance and suggestion that this substance may be a prostaglandin precursor (49). In the following year the article by them and co-workers on the effects of anti-inflammatory drugs on prostaglandin biosynthesis was published in Nature (London) (50) as well as several articles on the relationship between prostaglandins and rabbit aorta contracting substance (51, 52).

Further research on prostaglandin biosynthesis, being realized in friendly collaboration with prof. Andrzej Szczeklik, the Head Department of Internal Medicine in Medical Academy in Krakow, resulted in formulation of prostaglandin-hypothesis of asthma (53). The role of prostaglandins in aspirin-sensitive asthmatic patients was further studied by Szczeklik, Gryglewski, Czerniawska-Mysik (54).

1976 was marked by discovery of prostacyclin, initially known as prostaglandin X (55), and discovery of its vasoprotective, antithrombotic properties (56). At this time, interactions between the prostaglandin system and other endogeneously synthesized substances were studied parallel in London and in Krakow. Gryglewski’s Group in Poland: R. Korbut, A. Dembinska-Kiec, L. Grodzinska, J. Robak and B. Panczenko, studied generation of prostagalandins and thromboxanes in the trachea in lung strips and interactions between prostaglandins and histamine and catecholamines (57, 58).

Potential clinical significance of reduced prostacyclin synthesis was studied in a rabbit model of atherosclerosis (59). For the first time influence of steroids on prostaglandin and thromboxane biosynthesis was found (60) and modifications in bioassay of biologically active substances in a cascade of isolated organs were performed by Ryszard Korbut (61). The contradictory role of thromboxane and prostacyclin in the circulation was described in an article by Gryglewski, Dembinska-Kiec and Korbut (62).

In 1978 prostacyclin research made the next step moving from the laboratory to the clinic. Just in Poland prostacyclin was administered for the first time into humans (63) and described in Nature (London) as a circulating hormone (64). Also interactions of prostacyclin with phosphodiesterase inhibitors were studied (65). In 1978, for the first time, the role of lipid peroxides as a link between the prostacyclin deficiency and atherosclerosis was suggested (66) and the role of prostaglandins in circulatory shock (67) and in endotoxin induced hyperpyrexia (68) were studied. Lipid peroxidation was also studied in the context of adjuvant-induced and carrageenin-induced inflammation (69).

Since prostacyclin showed such promise in the protection of blood vessels, it was very important to obtain stable analogs of this short-acting substance, e.g. carboprostacyclin (70). Simultaneously, substances able to release prostacyclin, both endogenously (angiotensin), (71) and exogenously (almitrine,) (72) were searched for. Also the role of LDL as a carrier of lipid peroxides and quencher of prostacyclin biosynthesis was under investigation (73).

In 1980 cytoprotective action of prostacyclin on gastric mucosa was described in collaboration with prof. Stanislaw Konturek and co-workers from the Department of Physiology (74). Prostacyclin was used in the therapy of peripheral arterial disease (75), in central retinal vein occlusion (76) and in stroke (77). The Division of Clinical Pharmacology that opened in the late 70-s gathered significant expertise in pharmacological treatment of peripheral vascular disease. Drugs like bencyclan (78), beta-piridylcarbinol (79), pentoxyfilline (80), diprophyllin (81) were tested.

Since 1984 another branch of arachidonic acid metabolites - leukotrienes were studied (82). Influence of flavonoids with antiaggregatory effects on lipoxygenase and cyclooxygenase were studied by Swies et al. (83). Unsaturated fatty acids like dihomo-gamma-linolenic acid, potentially modulating platelet aggregation were tested in patients with atherosclerosis (84). Prostacyclin was used in a placebo-controlled trial in patients with gastric ulcer (85). Role of arachidonic acid metabolites in the mediation of pain was described by Korbut and Radomski (86).

In 1986 research interests shifted gradually from studying prostacyclin toward study of endothelium-derived relaxing factor (EDRF, later discovered to be identical with nitric oxide). Prostacyclin and EDRF were bioassayed concommittantly from porcine aortic endothelial cells (87). Mechanisms of action of EDRF inhibitors were searched by Moncada et al. (88) and the role of superoxide anion in breakdown of EDRF was discovered and published in a Nature article by Gryglewski, Palmer and Moncada (89).

Oxygen free radicals as quenchers of nitric oxide were studied by Gryglewski (90) and the impact of prostaglandins on function of polymorphonuclear leukocytes was tested in collaboration with the Department of Internal Medicine (91). Interactions between prostacyclin and nitric oxide in antiaggregatory properties of vascular endothelium were a recurrent theme in research for the next several years, e.g. (92). De Nucci G., Gryglewski R., Warner T. and Vane J. demonstrated that release of EDRF and prostacyclin from cultured endothelial cells is coupled (93). Robak and Gryglewski (94) demonstrated that flavonoids are scavengers of superoxide anions and this activity may explain their vasoprotective properties. Since similar, superoxide scavenging properties were demonstrated for calcium channel blockers (95), nitrendipine was used for the treatment of arteriosclerosis obliterans (96).

In the late 1980s, studies on the mechanisms of action of nitric oxide and prostacyclin were extended to cell cultures and isolated cells. Gryglewski, Trybulec, Radziszewski, Swierkosz, Dudek and Zembowicz studied production of EDRF in fresh and cultured endothelial cells (97). Isolated cells allowed studying intracellular signaling pathways. Gryglewski, Korbut, Kalecinska and Zembowicz studied the interaction between the stimulators of adenylate and guanylate cyclase (effectors of prostacyclin and nitric oxide stimulation, respectively) in human leukocytes, platelets and arteries (98). Gryglewski, Korbut, Trabka-Janik, Zembowicz and Trybulec studied interaction between NO donors and prostacyclin analog in these cells and additionally in arterial smooth muscle cells (99). Korbut, Trabka-Janik and Gryglewski demonstrated cytoprotection of polymorphonuclear leukocytes by stimulation of adenylate and guanylate cyclases (100). Nitric oxide released from neutrophils and mononuclear cells was found to inhibit platelet aggregation (101).

While interactions between nitric oxide and prostacyclin were at this time relatively well studied, demonstration of increased fibrinolytic potential of tissue plasminogen activator (t-PA) due to nitrovasodilators was a novel direction of research (102). In the early 1990s, effects of various NO-donors were studied in vitro and in the clinic. Dembinska-Kiec and colleagues studied the influence of SIN-1 on inflammatory cells (103). Grodzinska and colleagues used another NO-donor, molsidomine in patients with atherosclerosis obliterans of lower limbs (104). Bieron and colleagues studied synergism between prostacyclin and molsidomine in patients with peripheral arterial disease (105). In an article published in New England Journal of Medicine Korbut, Bieron and Gryglewski discussed effect of L-arginine, NO-precursor, on plasminogen-activator inhibitor (PAI-1) in hypertensive patients with hypercholesterolemia (106).

An interaction between prostanoids and other important substances secreted by endothelium - endothelins, was studied in isolated perfused rat kidney by Trybulec, Dudek and Gryglewski (107). A series of articles studied the role of endothelium in isolated perfused guinea pig hearts (Langendorff's method). Chlopicki and Gryglewski studied the role of endothelium-dependent and endothelium-independent vasodilators in the heart (108). Role of nitric oxide as a mediator of the phenomenon known as reactive hyperemia was described by Chlopicki and Gryglewski (109). Jakubowski et al. (110) and Chlopicki et al. (111) studied the pattern of purine release depending on the duration of heart ischemia and Lomnicka et al. studied the role of ischemic preconditioning on the preservation of function of endothelium and smooth muscle cells (112).

Mechanisms of action of hydroxy-arginine and hydroxy-guanidine, potential NO-carrier were studied in several articles by Zembowicz and colleagues (113-115). Collaboration with GEA pharmaceutical company resulted in the study on scavenging of superoxide anion by nitric oxide donors (116) and a study that described new NO-donors, mesoionic oxatriazole derivatives (117). Role of nitric oxide, derived from neutrophils on deformability of erythrocytes was studied by Korbut et al. (118). Dembinska-Kiec and colleagues studied the modifications exerted by iloprost and sodium nitroprusside on adhesion of platelets to neutrophils (119). An observation that hydrogen peroxide induces endothelium-dependent vasorelaxation led to a study on the role of nitric oxide in this process (120). Around that time it became evident that excessive production of nitric oxide may be harmful, e.g. in shock state, see (118, 121). This led to interest in inhibitors of nitric oxide synthase, e.g see an article on ebselen (122). Later on these studies were extended by Chlopicki et al. (123) on the role of N-iminoethyl-lysine and S-methylisothiourea as NOS inhibitors. To study the interactions between antithrombotic nitric oxide and prothrombotic thromboxane a new thromboxane synthase inhibitor with interesting properties - camonagrel was studied (124).

Fig. 1. Professor Janusz Supniewski (1899-1964) - The Dean of Medical Faculty (1939- 1945-1948).

Paradoxical thrombogenesis after administration of thrombolytic drugs was summarized in articles by Gryglewski and colleagues (125-127). Changes in the structure of platelets induced by streptokinase were described by Mackiewicz and colleagues (128). Interactions between the three major products of endothelial cells: nitric oxide, prostacyclin, and tPA were described by Gryglewski (129, 130) suggesting that in some situations they may act in alliance and sometimes they may be only neutral.

Fig. 2. Professor Janusz Supniewski at the time when "skills of organic chemical synthesis were of paramount importance for the research activities in the Department" of Pharmacology.

The second half of 1990s was marked by interest on the role of endothelium in endotoxic shock. Bartus, Chlopicki and Gryglewski described the effects of NO-deficiency in endotoxin-exposed rat lungs ex vivo (131) while Wolkow, Bartus and Gryglewski studied this effect and that of thromboxane inhibition in vivo (132). Starzyk, and Korbut described deformability of red blood cells in rat endotoxemia (133) and effects of NO and prostacyclin on the studied parameters (134). Gryglewski et al. described protective role of pulmonary nitric oxide in acute endotoxemia (135). Uracz et al. compared the role played by type II and type III nitric oxide synthase in the early protection against endotoxin-induced lung injury (136). Bochenski et al. studied the role of thromboxane and platelet activating factor in rat response to endotoxemia (137) and thienopyridines (138) were proved in a different model to be thrombolytic (139).

Fig. 3. Informal appointment with Sir John Vane (centre) in Rector’s Office of Medical College of Jagiellonian University during Prof. Stanislaw Konturek’s term of office 1996-1999. From the left: Prof. R. Korbut, Prof. J. Vetulani, Prof. A. Danysz, Prof. T. Chrusciel and his wife, Prof. S. Angielski, Sir John Vane (1927-2004)- Nobel Prize Winner, Prof. K. Ceremużyńska, Prof. R. Gryglewski, Prof. S. Konturek (The Rector), Prof. A. Szczeklik

At Division of Clinical Pharmacology, under supervision of prof. Kostka-Trabka, drugs with potential to treat peripheral ischemic disease were tested, e.g. L-arginine (140), nicotiniane xanthinol (141), misoprostol (142) and bezafibrate (143).

BEGINNING OF NEW CENTURY

At the beginning of XXI century in the Department of Pharmacology cell culture and molecular biology techniques were strongly introduced to study the effects of various drugs on endothelial cells These techniques became invaluable in search of atypical properties of drugs with well established potency in a different area, e.g. antiplatelet action of losartan (144), modulation of ticlopidine induced thrombolysis by aspirin (145) and pleiotropic actions of nebivolol, ACE inhibitors, statins and bradykinin (146-148) as well as flavonoids (149) and interleukin 1-beta (150). Interaction between two enzymes with critical importance for functioning of vascular endothelium: cyclooxygenase and hem-oxygenase was studied in collaboration with researchers from New York Medical College (151). In an attempt to study in vitro aspirin-induced asthma, an interaction between human platelets and eosinophils and epithelial cells and eosinophils were described (152, 153). These studies were later extended to probe the effects of aspirin on leukotriene production in a co-culture of eosinophils and epithelial cells (154).

Fig. 4. The Laboratory of Mass Spectrometry in Chair of Pharmacology (at the present).

In 2003 after retirement of prof. Gryglewski, Head of the Department of Pharmacology became prof. Ryszard Korbut. In addition to the topics already described above, an important aspect of research at the Department of Pharmacology becomes an analysis of the role of NAD(P)H oxidase and superoxide dysmutase in human vessels (155, 156). Molecular analyses in endotoxemia are continued by Gebska who studies rapid expression of nitric oxide synthase type II in the lung (157). Completely new area of research opens in 2004, going into problems of etiology and prevention of atherosclerosis with the use of apoE / LDL receptor double knockout mice (158).


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52. Gryglewski R, Vane JR. The release of prostaglandins and rabbit aorta contracting substance (RCS) from rabbit spleen and its antagonism by anti-inflammatory drugs. Br J Pharmacol 1972; 45: 37-47.
53. Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G. Is aspirin - sensitive asthma due to inhibition of prostaglandin biosynthesis? IXth European Congress of Allergy and Clinical Immunology 1974.
54. Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G. Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. Br Med J 1975; 1: 67-69.
55. Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which release strips of mesenteric and coeliac arteries and inhibits platelet aggregation. Prostaglandins 1976; 12: 897-913.
56. Gryglewski RJ, Bunting S, Moncada S, Flower RJ, Vane JR. Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin X) which they make from prostaglandin endoperoxides. Prostaglandins 1976; 12: 685-713.
57. Grodzińska L, Panczenko B, Gryglewski RJ. Release of prostaglandin E-like material from perfused mesenteric blood vessels of rabbits. J Pharm Pharmacol 1976; 28: 40-43.
58. Korbut R, Gryglewski RJ. Norepinephrine - stimulated generation of prostaglandin E-like substance by perfused blood vessels of the rabbit. Adv Prostaglandin Thromboxane Res 1976; 2: 917.
59. Dembińska-Kieć A, Gryglewska T, Żmuda A, Gryglewski RJ. The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits. Prostaglandins 1977; 14: 1025-1034.
60. Gryglewski RJ, Korbut R, Dembinska-Kiec A. Influence of anti-inflammatory steroids on prostaglandin and thromboxane release from tissue. Adv Study Institutes Series (A-Life Sci) - Prostaglandins and Thromboxanes 1977; 13: 363-381.
61. Korbut R. Nowy sposób oznaczania substancji biologicznie czynnych w mieszaninie, przy użyciu techniki kaskadowego omywania wyosobnionych narządów - detektorów. Folia Med Crac 1977; 19: 25-38.
62. Gryglewski RJ, Dembińska-Kieć A, Korbut R. A possible role of thromboxane A2 (TXA2) and prostacyclin (PGI2) in circulation. Acta Biol Med Germ 1978; 37: 715-723.
63. Gryglewski RJ, Szczeklik A, Niżankowski P. Anti-platelet action of intravenous infusion of prostacyclin in man. Thromb Res 1978; 13:153-163.
64. Moncada S, Korbut R, Bunting S, Vane JR. Prostacyclin is a circulating hormone. Nature 1978; 273: 767-768.
65. Moncada S, Korbut R. Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin. Lancet 1978; 17: 1286-1289.
66. Gryglewski RJ, Szczeklik A. Inhibition of prostacyclin formation by lipid peroxides in the arterial wall: hypothetical step in development of atherosclerosis. Mat Med Pol 1978; 10: 338-341.
67. Korbut R, Ocetkiewicz A, Gryglewski RJ. The influence of hydrocortisone and indomethacin on the release of prostaglandin - like substances during circulatory shock in cats, which was induced by on intravenous administration of rabbit blood. Pharmacol Res Commun 1978; 10: 371-385.
68. Spławiński JA. Rola prostaglandyn w gorączce szczurów wywołanej przez endotoksynę. Folia Med Crac 1978; 20: 171-190.
69. Robak J. Adjuvant - induced and carrageenin - induced inflammation and lipid peroxidation in rat liver, spleen and lungs. Biochem Pharmacol 1978; 27: 531-533.
70. Ceserani R, Grossoni M, Longiave D, et al. dl-9a-deoxy-9a-methylene-PGI2 (a stable prostacyclin derivative): preliminary pharmacological data. Prostaglandins Med 1980; 5: 131-139.
71. Grodzińska L, Gryglewski RJ. Angiotensin - induced release of prostacyclin from perfused organs. Pharmacol Res Commun 1980; 12: 339-347.
72. Gryglewski RJ. Almitrine, a potent releaser of prostacyclin in vivo. Rev fr Mal Resp 1980; 207-210.
73. Szczeklik A, Gryglewski RJ. Low-density lipoproteins (LDL) are carriers for lipid peroxides and invalidate prostacyclin (PGI2) biosynthesis in arteriers. Artery 1980; 7: 488-495.
74. Konturek SJ, Radecki T, Brzozowski T, Piastucki I, Dembińska-Kieć A, Żmuda A. Gastric cytoprotection by prostaglandins, ranitidine, and probanthine in rats. Scand J Gastroent 1981; 16: 7-12.
75. Szczeklik A, Gryglewski RJ. Prostacyclin in coronary and peripheral vascular diseases. Seventh Congress of the Polish Pharmacological Society 1980.
76. Żygulska-Mach H, Kostka-Trąbka E, Nitoń A, Gryglewski RJ. Prostacyclin in central retinal vein occlusion. Lancet 1980; 2(8203): 1075.
77. Gryglewski RJ, Nowak S, Kostka-Trąbka E, et al. Clinical use of prostacyclin (PGI2) in ischaemic stroke. Pharmacol Res Commun 1982; 14: 879-908.
78. Grodzińska L, Basista M, Dembińska-Kieć A, Kostka-Trąbka E. Halidor in treatment of arteriosclerosis obliterans (I and II grade). Pro Memoria 1982; 23-28.
79. Dembińska-Kieć A, Korbut R, Bieroń K, Kostka-Trąbka E, Gryglewski RJ. Beta-pyridylcarbinol (RonicolR) releases a prostacyclin - like substance into arterial blood of patients with arteriosclerosis obliterans. Pharmacol Res Commun 1983; 15: 377-385.
80. Kostka-Trąbka E, Dembińska-Kieć A, Grodzińska L, et al. Pentoxyfilline (Trental) in treatment of arteriosclerosis obliterans. Zbl Pharm 1983; 122: 763-765.
81. Kostka-Trąbka E, Grodzińska L, Dembińska-Kieć A, Basista M, Telesz E. Diprophyllinum prolongatum (Polfa, Kraków) w leczeniu zarostowej miażdżycy tętnic kończyn dolnych. Przeg Lek 1983; 40: 315-322.
82. Dembińska-Kieć A, Korbut R, Żmuda A, Kostka-Trąbka E, Simmet T, Peskar BA. Formation of lipoxygenase and cyclooxygenase metabolites of arachidonic acid by brain tissue. Biomed Biochim Acta 1984; 43: S222-S226.
83. Święs J, Robak J, Dąbrowski L, Duniec Z, Michalska Z, Gryglewski RJ. Antiaggregatory effects of flavonoids in vivo and their influence on lipoxygenase and cyclooxygenase in vitro. Pol J Pharmacol Pharm 1984; 36: 455-463.
84. Szczeklik A, Gryglewski RJ, Sladek K, Kostka-Trąbka E, Żmuda A. Dihomo-gamma-linolenic acid in patients with atherosclerosis: effects on platelet aggregation, plasma lipids and low-density lipoprotein - induced inhibition of prostacyclin generation. Thromb Haemostas 1984; 54: 186-188.
85. Dembińska-Kieć A, Kostka-Trąbka E, Kosiniak-Kamysz A, Grodzińska L, Bieroń K. Prostacyclin in patients with peptic gastric ulcers - a placebo controlled study. Hepato-gastroenterol 1986; 33: 262-266.
86. Korbut R, Radomski M. Rola metabolitów kwasu arachidonowego w mediacji bólu. Post Hig Med Dośw 1986; 40: 435-447.
87. Gryglewski RJ, Moncada S, Palmer RMJ. Bioassay of prostacyclin and endothelium - derived relaxing factor (EDRF) from porcine aortic endothelial cells. Br J Pharmacol 1986; 87: 685-694.
88. Moncada S, Palmer RMJ, Gryglewski RJ. Mechanism of action of some inhibitors of endothelium - derived relaxing factor. Proc Natl Acad Sci USA 1986; 83: 9164-9168.
89. Gryglewski RJ, Palmer RMJ, Moncada S. Superoxide anion is involved in the breakdown of endothelium - derived vascular relaxing factor. Nature 1986; 320: 454-456.
90. Gryglewski RJ. The role of oxygen free radicals in the destruction of endothelium - derived relaxing factor (EDRF). Agents Actions 1987; 22: 351-352.
91. Gryglewski RJ, Szczeklik A, Wandzilak M. The effect of six prostaglandins, prostacyclin and iloprost on generation of superoxide anions by human polymorphonuclear leukocytes stimulated by zymosan or formyl-methionyl-leucyl-phenylalanine. Biochem Pharmacol 1987; 36: 4209-4213.
92. Radomski MW, Palmer RMJ, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987; 92: 639-646.
93. DeNucci G, Gryglewski RJ, Warner TD, Vane JR. Receptor - mediated release of endothelium - derived relaxing factor (EDRF) and prostacyclin from bovine aortic endothelial cells is coupled. Proc Natl Acad Sci USA 1988; 85: 2334-2338.
94. Robak J, Gryglewski RJ. Flavonoids are scavengers of supoxide anions. Biochem Pharmacol 1988; 37: 837-841.
95. Shridi F, Robak J. The influence of calcium channel blockers on superoxide anions. Pharmacol Res Commun 1988; 20: 13-21.
96. Grodzińska L, Basista M, Ohlrogge R. Therapeutic effects of nitrendipine (BayotensinR) in patients with arteriosclerosis obliterans of lower limbs. Prostaglandins in Clinical Research: Cardiovascular System 1989; 423.
97. Gryglewski RJ, Trybulec M, Radziszewski W, Świerkosz T, Dudek R, Zembowicz A. Endothelium - derived relaxing factor (EDRF) from cultured and fresh endothelial cells. Biomed Biochim Acta 1988; 47: S61-S66.
98. Gryglewski RJ, Korbut R, Kalecińska A, Zembowicz A. Interaction between stimulators of adenylate and guanylate cyclases in human leukocytes, platelets and arteries. Int J Tiss Reac 1989; 11: 269-274.
99. Gryglewski RJ, Korbut R, Trąbka-Janik E, Zembowicz A, Trybulec M. Interaction between NO donors and iloprost in human vascular smooth muscle, platelets, and leukocytes. J Cardiovasc Pharmacol 1989; 14(suppl. 11): S124-S128.
100. Korbut R, Trąbka-Janik E, Gryglewski RJ. Cytoprotection of human polymorphonuclear leukocytes by stimulators of adenylate and guanylate cyclases. Eur J Pharmacol 1989; 165: 171-172.
101. Salvemini D, deNucci G, Gryglewski RJ, Vane JR. Human neutrophils and mononuclear cells inhibit platelet aggregation by releasing a nitric oxide - like factor. Proc Natl Acad Sci USA 1989; 86: 6328-6332.
102. Korbut R, Lidbury PS, Vane JR. Prolongation of fibrinolytic activity of tissue plasminogen activator by nitrovasodilators. Lancet 1990; 335: 669.
103. Dembińska-Kieć A, Żmuda A, Marcinkiewicz E, Sinzinger H, Gryglewski RJ. Influence of NO-donor (SIN-1) on functions of inflammatory cells. Agents Actions 1991; 32: 37-40.
104. Grodzińska L, Kostka-Trąbka E, Bieroń K, Sławiński M, Goszcz A, Ochmański W. Therapeutic effects of molsidomine, no-donor, in patients with atherosclerosis obliterans of the lower limbs. J Drug Dev 1991; 4: 39-46.
105. Bieroń K, Grodzińska L, Kostka-Trąbka E, Gryglewski RJ. Prostacyclin and molsidomine synergise in their fibrinolytic and anti-platelet actions in patients with peripheral arterial disease. Wien Klin Wochenschr 1993; 105: 7-11.
106. Korbut R, Bieroń K, Gryglewski RJ. Effect of L-arginine on plasminogen-activator inhibitor in hypertensive patients with hypercholesterolemia. New Engl J Med 1993; 328: 287-288.
107. Trybulec M, Dudek RR, Gryglewski RJ. Effects of endothelin-1 and endothelin-3 on the release of prostanoids from isolated perfused rat kidney. J Cardiovasc Pharmacol 1991; 17(suppl.7): S229-S232.
108. Chłopicki S, Gryglewski RJ. The endothelium - dependent and the endothelium - independent vasodilators in the isolated, perfused guinea pig heart. J Physiol Pharmacol 1992; 43: 353-366.
109. Chłopicki S, Gryglewski RJ. Nitric oxide is a major mediator in reactive hyperaemia evoked by a brief coronary occlusion in the guinea pig heart. Eur J Pharmacol 1993; 241: 117-120.
110. Jakubowski A, Chłopicki S, Niezabitowski P, Łomnicka M. Gryglewski RJ. The pattern of purine release from guinea-pig hearts during short and long lasting periods of ischemia. Exp Clin Cardiol 1997; 2: 98-102.
111. Chłopicki S, Jakubowski A, Niezabitowski P, Łomnicka M, Gryglewski RJ. Kinetics of purine release from ischemic isolated guinea pig heart. Exp Clin Cardiol 1998; 3: 59-64.
112. Łomnicka M, Chłopicki S, Gryglewski RJ. Ischemic preconditioning: protection against endothelial and smooth muscle cell dysfunction induced by ischemia-reperfusion in isolated guinea pig heart. Exp Clin Cardiol 2000; 5: 11-16.
113. Zembowicz A, Chłopicki S, Radziszewski W, Vane JR, Gryglewski RJ. NG-hydroxy-L-arginine and hydroxyguanidine potentiate the biological activity of endothelium - derived relaxing factor released from the rabbit aorta. Biochem Biophys Res Commun 1991; 189: 711-716.
114. Zembowicz A, Świerkosz TA, Southan GJ, Hecker M, Gryglewski RJ, Vane JR. Mechanisms of the endothelium - dependent relaxation induced by NG-hydroxy-L-arginine. J Cardiovasc Pharmacol 1992; 20(12): S57-S59.
115. Zembowicz A, Świerkosz TA, Southan GJ, Hecker M, Vane JR. Potentiation of the vasorelaxant activity of nitric oxide by hydroxyguanidine: implications for the nature of endothelium - derived relaxing factor. Br J Pharmacol 1992; 107: 1001-1007.
116. Robak J, Gryglewski RJ. Nitric oxide donors as generators and scavengers of superoxide anions. Pol J Pharmacol 1992; 45: 51-58.
117. Corell T, Pedersen SB, Lissau B, et al. Pharmacology of mesoionic oxatriazole derivatives in blood, cardiovascular and respiratory system. Pol J Pharmacol 1994; 46: 553-566.
118. Korbut R, Gryglewski RJ. Nitric oxide in regulation of endothelial thromboresistance and red blood cell deformability in vitro. Clin Hemorheology 1994; 14: A 433.
119. Dembińska-Kieć A, Żmuda A, Wenhrynowicz O, Stachura J, Peskar BA, Gryglewski RJ. Selectin-P - mediated adherence of platelets to neutrophils is regulated by prostanoids and nitric oxide. Int J Tiss Reac 1993; 15: 55-64.
120. Zembowicz A, Hatchett RJ, Jakubowski AM, Gryglewski RJ. Involvement of nitric oxide in the endothelium - dependent relaxation induced by hydrogen peroxide in the rabbit aorta. Br J Pharmacol 1993; 110: 151-158.
121. Gryglewski RJ. Nitric oxide - enemy or friend? Mag Med 1994; 5: 12-14.
122. Zembowicz A, Hatchett RJ, Radziszewski W, Gryglewski RJ. Inhibition of endothelial nitric oxide synthase by ebselen. Prevention by thiols suggests the inactivation by ebselen of a critical thiol essential for the catalytic activity of nitric oxide synthase. J Pharmacol Exp Therap 1993; 267: 1112-1118.
123. Chłopicki S, Olszanecki R, Jakubowski A, Łomnicka M, Gryglewski RJ. L-N6-(1-iminoethyl)-lysine (L-NIL) but not S-methylisothiourea sulphate (SMT) displays selectivity towards NOS-2. Pol J Pharmacol 1999; 51: 443-447.
124. Gryglewski RJ, Szczeklik A, Korbut R, et al. The mechanism of anti-thrombotic, thrombolytic and fibrinolytic actions of camonagrel - A new thromboxane synthase inhibitor. Wien Klin Wochenschr 1995; 107: 283-289.
125. Gryglewski RJ. Paradoxical thrombogenic effects of thrombolytic drugs: experimental and clinical data. Anaesthesia, Pain, Intensive Care and Emergency Medicine 1994; 713-720.
126. Gryglewski RJ, Święs J, Mackiewicz S, Uracz W. Zakrzeporodne działanie streptokinazy. Kard Pol 1995; 43: 465-470.
127. Korbut R, Gryglewski RJ. On the mechanism of thrombogenesis during pharmacological thrombolysis. Pol J Pharmacol 1996; 48: 85-88.
128. Mackiewicz Z, Gryglewski RJ, Święs J, Dąbros W, Uracz W. Streptokinase - induced changes in the structure of platelets. Ex vivo study. Acta Medica Lituanica 1996; 3-8.
129. Gryglewski R.J. Interactions between endothelial mediators. Pharmacol Toxicol 1995; 77: 1-9.
130. Gryglewski R.J. Endothelial nitric oxide, prostacyclin (PGI2) and tissue plasminogen activator (t-PA): alliance or neutrality? Pol J Pharmacol 1995; 47: 467-472.
131. Bartuś JB, Chłopicki S, Gryglewski RJ. Increased pneumotoxicity of lipopolysaccharide from E.coli in nitric oxide deficient blood-perfused rat lungs. J Physiol Pharmacol 1997; 48: 655-663.
132. Wołkow PP, Bartuś JB, Gryglewski RJ. Pneumotoxicity of lipopolysaccharide in nitric oxide - deficient rats is limited by a thromboxane synthase inhibitor. J Physiol Pharmacol 1997; 48: 645-653.
133. Starzyk D, Korbut R, Gryglewski RJ. The role of nitric oxide in regulation of deformability of red blood cells in acute phase of endotoxaemia in rats. J Physiol Pharmacol 1997; 48: 731-735.
134. Starzyk D, Korbut R, Gryglewski RJ. Effects of nitric oxide and prostacyclin on deformability and aggregability of red blood cells of rats ex vivo and in vitro. J Physiol Pharmacol 1999; 20: 629-637.
135. Gryglewski RJ, Wołkow PP, Uracz W, et al. Protective role of pulmonary nitric oxide in the acute phase of endotoxemia in rats. Circ Res 1998; 82: 819-827.
136. Uracz W, Ziemianin B, Chłopicki S, Gryglewski RJ. Role of nitric oxide synthase types II and III early protection against endotoxin-induced lung injury. Exp Clin Cardiol 1998; 3: 78-86.
137. Bocheński J, Chłopicki S, Gryglewski RJ. Role of thromboxane A2 and platelet activating factor in early haemodynamic response to lipopolysaccharide in rats. J Physiol Pharmacol 1999; 50: 287-297.
138. Ziemianin B, Olszanecki R, Uracz W, Marcinkiewicz E, Gryglewski RJ. Thienopyridines: effects on cultured endothelial cells. J Physiol Pharmacol 1999; 50: 597-604.
139. Gryglewski RJ, Dupin JP, Uracz W, et al. Thrombolysis by thienopyridines and their congeners. J Physiol Pharmacol 2000; 51(4Pt1): 683-693.
140. Sławiński M, Grodzińska L, Kostka-Trąbka E, Bieroń K, Goszcz A, Gryglewski RJ. Porównanie działania L-argininy z działaniem placebo u pacjentów chorych na miażdżycę zarostową tętnic obwodowych - wyniki wstępne. Acta Angiol 1996; 2: 1-8.
141. Bieroń K, Kostka-Trąbka E, Grodzińska L, et al. Przeciwpłytkowe i fibrynolityczne działanie nikotynianu ksantynolu (Sadamina) u chorych z miażdżycą tętnic kończyn dolnych. Probl Ter Monitor 1997; 8: 178-185.
142. Goszcz A, Grodzińska L, Kostka-Trąbka E, Bieroń K, Sławiński M, Jachym R. Misoprostol (Cytotec) on the treatment of peripheral ischaemic disease. Acta Physiol Hungar 1997; 84: 415-416.
143. Grodzińska L, Jachym R, Sławiński M, Robak J. Influence of bezafibrate on total antioxidant activity of serum and deformability of blood cells in hypercholesterolaemic patients. Pol J Pharmacol 1998; 50: 361-364.
144. Chlopicki S, Koda M, Chabielska E, Buczko W, Gryglewski RJ. Antiplatelet action of losartan involves TXA2 receptor antagonism but not TXA2 synthase inhibition. J Physiol Pharmacol 2000; 51(4Pt1): 715-722.
145. Gryglewski RJ, Uracz W, Swies J. Unusual effects of aspirin on ticlopidine induced thrombolysis. Thorax 2000; 55(Suppl.2): S17-19.
146. Gryglewski RJ, Uracz W, Marcinkiewicz E, Jakubowski A, Malinski T. Role of endothelial nitric oxide in pleiotropic action of cardiovascular drugs: nebivolol. Nitric Oxide: Basic Research and Clinical Applications 2001; 57-70.
147. Gryglewski RJ, Uracz W, Święs J, et al. Comparison of endothelial pleiotropic actions of angiotensin converting enzyme inhibitors and statins. Ann NY Acad Sci 2001; 947: 229-245.
148. Gryglewski RJ, Uracz W, Chłopicki S, Marcinkiewicz E. Bradykinin as a major endogenous regulator of endothelial function. Pediatr Pathol Mol Med 2002; 21:2 79-290.
149. Olszanecki R, Gebska A, Kozlovski VI, Gryglewski RJ. Flavonoids and nitric oxide synthase. J Physiol Pharmacol 2002; 53(4Pt1): 571-584.
150. Uracz W, Uracz D, Olszanecki R, Gryglewski RJ. Interleukin 1beta induces functional prostaglandin E synthase in cultured human umbilical vein endothelial cells. J Physiol Pharmacol 2002; 53(4Pt1): 643-654.
151. Haider A, Olszanecki R, Gryglewski R, et al. Regulation of cyclooxygenase by the heme-heme oxygenase system in microvessel endothelial cells. J Pharmacol Exp Ther 2002; 300(1): 188-194.
152. Jawien J, Chlopicki S, Olszanecki R, Lorkowska B, Gryglewski RJ. Eosinophil-epithelial cell interaction augments cysteinyl leukotrienes synthesis. J Physiol Pharmacol 2002; 53(1):127-132.
153. Jawien J, Chlopicki S, Gryglewski RJ. Interactions between human platelets and eosinophils are mediated by selectin-P. Pol J Pharmacol 2002; 54(2): 157-160.
154. Jawien J, Olszanecki R, Lorkowska B, Korbut R. Effect of aspirin on cysteinyl leukotrienes production by eosinophils co-cultured with epithelial cells. J Physiol Pharmacol 2004; 55(4): 765-772.
155. Guzik TJ, Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 2004; 54(4): 469-487.
156. Guzik TJ, Sadowski J, Kapelak B, et al. Systemic regulation of vascular NAD(P)H oxidase activity and nox isoform expression in human arteries and veins. Arterioscler Thromb Vasc Biol 2004; 24(9): 1614-1620.
157. Gebska A, Olszanecki R, Korbut R. Endotoxaemia in rats: role of leukocyte sequestration in rapid pulmonary nitric oxide synthase-2 expression. J Physiol Pharmacol 2005; 56(2): 299-311.
158. Jawien J, Gajda M, Mateuszuk L, et al. Inhibition of nuclear factor-kappaB attenuates artherosclerosis in apoE/LDLR - double knockout mice. J Physiol Pharmacol 2005; 56(3): 483-489.