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D Pawlak

Publications and source records attributed to D Pawlak.

At least 37 records · Page 2Linked to original sources
PubMed2000

The antithrombotic effect of angiotensin-(1-7) closely resembles that of losartan.

Angiotensin-(1-7) [Ang-(1-7)] is the bioactive peptide which may be responsible for some of the pharmacological effects of losartan. Our previous study has demonstrated the antithrombotic action of losartan in a model of experimental thrombosis. In the present study, we compared the antithrombotic action of losartan and Ang-(1-7). Acute (10 mg/kg, p.o.) and chronic (10 mg/kg, p.o., three weeks) losartan administration to spontaneously hypertensive rats (SHR) induced a decrease in thrombus weight (1.6 +/- 0.6 mg and 1.2 +/- 0.3 mg respectively vs. control 2.9 +/- 0.8 mg; p<0.05, p<0.05). A similar reduction was observed in two-kidney, one-clip hypertensive rats (2K-IC)receiving acute losartan administration (1.39 +/- 0.29 mg vs. 3.25 +/- 0.62 mg; p<0.01). Infusion of Ang-(1-7) to2K-lC rats also reduced the thrombus weight(1.01 +/- 0.34 mg, 1.23 +/- 0.38 mg and 2.17 +/- 0.36 mg for 1, 10, 100 pmol/kg/min, respectively vs. 3.58 +/- 0.6 mg control; p<0.01, p<0.01, p<0.05). Losartan produced a decrease in systolic blood pressure (BP) in SHR as well as in 2K-1C rats, while Ang-(1-7) infusion had no effect on BP. Acute losartan dosing to 2K-1C rats decreased platelet adhesion to fibrillar collagen(24.9 +/- 1.0% vs. control 31.5 +/- 1.1%, p<0.001). The incubation of platelet samples with Ang-(1-7) (10-6 and 10 5 M) also reduced adhesion to fibrillar collagen(38.4 +/- 0.1% and 33.8 +/- 0.8% respectively vs. control 40.0 +/- 0.6%; p<0.05, p<0.001). There were no apparent changes in prothrombin time, activated partial thromboplastin time and euglobulin clot lysis time in losartan and Ang-(1-7)-treated groups. We conclude that, like losartan, Ang-(1-7) is able to act as an antithrombotic agent.

Angiotensin I↗
PubMed2000

[Kynurenic pathway in health and disease].

The paper gives a review about kynurenic pathway metabolism of tryptophan. The implications of its metabolites in pathomechanism of several dysfunctions of tissues and organs as well as possibilities of therapeutic interference are described.

Animals↗
PubMed1999

Conformational analysis of a novel cyclic enkephalin analogue using NMR and EDMC calculations.

Conformational space of a novel cyclic enkephalin analogue, cyclo(N(epsilon),N(epsilon')-carbonyl-D-Lys2,Lys5)enkephalin amide, was exhaustively examined. A large number of conformations was selected and clustered into families on the basis of their structure and energy. For representative conformations ROESY spectra were generated and their linear combination was fitted to the spectra measured in water and Me2SO-d6. This procedure yielded an ensemble of most populated conformations of the peptide in the two solvents.

Amides↗
PubMed1998

A potent 5-hydroxytryptamine receptor (5-HT2A) antagonist, DV-7028, delays arterial thrombosis development in rats.

In our study, we demonstrated that DV-7028: (3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6, 7,8,9-tetrahydro-2H-pyrido [1,2,-a]-1,3,5-triazine-2, 4(3H)-dione maleate)--a selective 5-HT2A receptor antagonist, inhibited thrombus formation in the arterial thrombosis model and was completely ineffective in the prevention of venous thrombosis in the rat. In washed platelets prelabelled with 3H-serotonin, DV-7028 inhibited, in a dose-dependent manner, the collagen-induced secretion of serotonin. However, the uptake of serotonin into platelets was not affected by this substance. Administration of DV-7028 also inhibited platelet aggregation in the whole blood and platelet-rich plasma (PRP) induced by collagen, and diminished serotonin-induced aggregation of rat platelets in the presence of a sensitizing but nonaggregating amount of ADP, whereas it did not modify aggregation in PRP when induced by ADP. DV-7028 caused a concentration-dependent, almost parallel shift to the right of the concentration-response to serotonin for its pressor effect in the rat perfused tail artery. The present data demonstrate that DV-7028 exhibits 5-HT2A receptor antagonistic properties in the rat cardiovascular system, exhibits antithrombotic effect in the model of arterial but not venous thrombosis in rats. These results constitute further evidence of the possible importance of serotonin as a mediator of platelet thrombosis in arteries. Moreover, they can provide a useful tool for the prevention of various thrombotic diseases.

Animals↗
PubMed1998

Losartan inhibits experimental venous thrombosis in spontaneously hypertensive rats.

The potential antithrombotic action of losartan, the AT1 receptor antagonist, in an experimental model of venous thrombosis in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) was tested. The involvement of nitric oxide and prostacyclin in this effect was also studied. Venous stasis was induced by ligation of the vena cava. Losartan, after administration of a single, hypotensive dose (10 mg/kg, p.o.), significantly reduced the thrombus weight in SHR but not in WKY. The antithrombotic activity of losartan in SHR was abolished by NG-nitro L-arginine methyl ester (L-NAME) (30 mg/kg s.c.) but not by indomethacin (2.5 mg/kg s.c.). No changes in primary hemostasis, platelet aggregation, coagulation parameters such as activated partial thromboplastin time, prothrombin time, euglobulin clot lysis time, and fibrinogen level, either in SHR or in WKY rats, were found. Our results indicate the NO-dependent mechanism in the antithrombotic effect of losartan on venous thrombosis in SHR.

Analysis of Variance↗
PubMed1998

Vascular and cardiac effects of DV-7028, a selective, 5-HT2-receptor antagonist in rats.

The effect of 5HT2A-receptor antagonist DV-7028 (3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro - 2H-pyrido[1,2,-a]-1,3,5-triazine-2,4(3H)-dione maleate on the rat cardiovascular system was evaluated. DV-7028 (0.1 and 1.0 mg/kg), given intravenously, caused a significant, dose-dependent decrease in mean arterial blood pressure in anesthetized normotensive rats. In vagotomized rats, administration of DV-7028 resulted in a reduction of mean blood pressure, but this effect was less prominent than that seen in nonvagotomized rats. Intravenous administration of DV-7028 induced bradycardia, which was almost completely abolished by vagotomy. In pithed rats, bradycardia and hypotension were not demonstrated after DV-7028 administration. In pithed rats, serotonin administered intravenously caused a dose-dependent increase in blood pressure. In this experimental model, DV-7028 inhibited the pressor effects of serotonin at doses of 0.01 and 0.1 mg/kg, which caused neither hypotension nor bradycardia in anesthetized rats. DV-7028 strongly inhibited the pressor effects of serotonin in the isolated perfused hindlegs of the rat (IC50 = 0.032 +/- 0.004 microM) and caused a concentration-dependent, almost parallel shift to the right of the concentration-response curve to serotonin for its pressor effect in the rat perfused tail artery (pA2 value for DV-7028 was 7.92, a slope 0.94). These data demonstrate that DV-7028 exhibits 5-HT2A-receptor antagonistic property in the rat cardiovascular system. Besides this peripheral action, DV-7028, when applied in high doses, exerts hypotension and bradycardia via an unknown site and mechanism.

Animals↗
PubMed1997

[Altered circadian rhythm of platelet aggregation in patients on longterm hemodialysis].

Chronic uremia is associated with a bleeding tendency, and paradoxically with propensity for thrombotic complications. Several physiological systems are subject to circadian rhythm, including among others hemostasis, platelet aggregability and fibrinolysis. Alterations in these rhythms were suggested to be involved in the pathogenesis of sudden cardiac and cardiovascular complications of diabetes mellitus. As cardiovascular events are the most frequent cause of death in dialyzed patients, we studied circadian rhythm of platelet function in chronically hemodialyzed patients in relation to blood and plasma serotonin. We investigated 16 patients (mean age 49.7 +/- 12.2 years, 10 females, 6 males) who had been maintained on chronic hemodialysis. Control group consisted of 8 age matched healthy volunteers. Blood was collected after 15 min. rest at 8:00, 11:00, 17:30, and 23:00 from antecubital veins. Platelet aggregation was measured according to the method of Born. Following concentrations of aggregating agents were used: ADP 5 microM; collagen, 2 micrograms/ml; arachidonic acid 0.75 microM, serotonin 1 microM; and ristocetin 1.5 micrograms/ml. Serotonin was measured in whole blood and plasma by HPLC method. In PRP from healthy subjects aggregatory responses to ADP and arachidonic acid were significantly higher at 17:30 than at 8:00. In uremic patients aggregatory response to ADP and ristocetin was more intensive at 11:30 and 23:00 in comparison to 8:00. Whole blood 5-HT did not change during the day, while plasma 5-HT concentration increased significantly in uremics at 11:30 in comparison to initial value. In conclusion, our study demonstrates that in chronically dialyzed patients circadian changes in platelet aggregation are different from normal persons.

Adult↗
PubMed1996

Hemostasis, platelet function and serotonin in acute and chronic renal failure.

A pathogenetic role for fibrin deposition and platelet activation in the kidney is thought to play a role in the pathogenesis of acute renal failure (ARF). Thus, some fibrinolytic parameters and platelet function have been studied in 17 patients with ARF and compared to healthy volunteers and subjects with chronic renal failure (CRF). Since serotonin may participate in pathological processes resulting from platelet/vessel wall interactions, its level in the whole blood and plasma was also assayed. In ARF and CRF platelet aggregatory responses in both whole blood and in platelet rich plasma upon stimulation with various agonists (collagen, arachidonic acid, ADP, ristocetin) were lower than those obtained in healthy volunteers. Increased levels of lipoprotein (a), von Willebrand factor (vWF) and fibronectin were found in ARF relative to controls. Protein C activity was significantly lower in patients with ARF. Euglobulin clot lysis time was prolonged in ARF and CRF, reflecting a decreased overall fibrinolytic activity. Activity of tissue plasminogen activator (tPA) inhibitor (PAI) and PAI:Ag were higher in ARF, whereas tPA:Ag, urokinase, tPA/PAI complexes, thrombin-antithrombin complexes (TAT), plasmin-antiplasmin (PAP) complexes, fibrinogen, and F1+2 did not differ between ARF and controls. In CRF elevated levels of TAT, PAP, fibrinogen and prothrombin fragments F1+2 were found, whereas concentration of fibronectin was lowered when compared to controls. In both groups of renal failure patients increased levels of fibrin monomers and d-dimer were found relative to healthy volunteers. Whole blood serotonin was significantly lower, whereas plasma serotonin was significantly higher in patients with ARF and CRF relative to controls. Serotonin uptake and its release from platelets were markedly diminished in patients with ARF and CRF. Chronic renal failure exhibit a slightly different pattern of coagulopathies that acute renal failure.

Acute Kidney Injury↗
PubMed1996

Peripheral serotonergic system in uremia.

Several data suggest that platelet-derived serotonin (5-HT), previously classified as a trivial modulator of blood-borne cardiovascular disease (1), may play a decisive role in various pathological processes, resulting from abnormal platelet-vessel wall interactions (2). Following platelet activation upon a contact with a damaged vessel wall, 5-HT, released from platelets upon the activation of 5-HT2 receptors, may amplify the action of other agents on vascular smooth muscle cells and platelets (3,4). Platelets play a unique role in 5-HT metabolism: they take it up, store in their dense granules and release upon stimulation. Platelet dysfunction, alteration in platelet count, their consumption and turnover are common in renal diseases (5). Storage pool deficiency regarding 5-HT and ADP was reported in renal failure (6). Previously we reported that 5HT2 receptor blockers may serve as potent antiplatelet drugs in uremic patients, which are prone to thrombotic complications (7,8). Up to date there have been a few reports dealing predominantly with 5-HT levels in renal patients. Thus, we focused on peripheral serotonergic mechanisms including 5-HT uptake and release and kinetics of its uptake in uremic patients.

Adult↗
PubMed1996

[Serotonin in diabetic retinopathy].

PURPOSE: The present study was designed to evaluate a possible participation of serotonin in the development of retinopathy in diabetes mellitus. MATERIAL AND METHODS: Serotonin of whole blood and platelets was studied in 12 patients with Type I and II diabetes using high pressure liquid chromatography method. RESULTS: The concentration of serotonin in the blood was markedly increased (210 +/- 50 ng/ml in diabetes and 150 +/- 35 ng/ml in control, p < 0.01) and not changed in platelets in diabetes. There was a relation between blood serotonin level and the presence of retinopathy. CONCLUSION: These results suggest that serotonin may be involved in the pathogenesis of diabetic microangiopathy.

Aged↗
PubMed1996

Peripheral serotonergic mechanisms in the cardiovascular system of epidermoid lung cancer patients.

The aim of the work was to evaluate the peripheral serotonergic mechanisms in patients with epidermoid lung cancer. The study was performed on lung cancer patients diagnosed on the basis of histopathological findings. The subjects were treated by radiotherapy. Whole blood 5HT in patients with epidermoid lung cancer was increased, whereas uptake of 3H-5HT by platelets was diminished in these patients when compared to control group. Radiotherapy caused a lowering of serotonin in blood to levels observed in healthy subjects. Platelet aggregation induced by ADP was diminished in patients with epidermoid lung cancer, however radiotherapy resulted in an increased sensitivity of platelets to ADP (an enhanced aggregation). On the other hand, serotonergic amplification of ADP-induced platelet aggregation was higher in these patients. This effect was inhibited by radiotherapy. On the basis of our results, we may suggest that peripheral serotonergic mechanisms play an important role in pathogenesis and course of epidermoid lung cancer in humans.

Aged↗
PubMed1996

Influence of MCI-9042, a novel 5-HT2 receptor blocker on blood vessels of the rat.

We demonstrated that MCI-9042 potently inhibited the vasoconstrictory effects of serotonin in the isolated perfused hindlegs of the rat. Concentrations of MCI-9042 in the range of 0.01-1 mumol/l caused a dose-dependent inhibition of the vasoconstrictory effect of serotonin (1-30 micrograms/0.1 ml). The maximal inhibitory effect of MCI-9042 was about 97% (1 mumol/l). MCI-9042 caused a concentration-dependent shift to the right of concentration-response curve to serotonin in the rat tail artery. The present data demonstrate MCI-9042 as a potent 5-HT2 receptor antagonist.

Animals↗
PubMed1996

Effect of DV-7028, a novel serotonin 5-HT2 receptor antagonist on the cardiovascular system in rats.

The response of the cardiovascular system to DV-7028 demonstrated the complex action of this substance. In anaesthetized rats DV-7028 decreased the blood pressure and heart rate. These effects did not occur in pithed rats. The hypotensive action and bradycardia was partially reduced in vagotomized animals. DV-7028 potently inhibited the vasoconstrictory effects of serotonin in isolated perfused hindlegs of rat and caused a concentration-dependent shift to the right of response curve to serotonin in the rat tail artery. The present data demonstrate that DV-7028 is a potent 5-HT2 receptor antagonist. Besides its peripheral action, DV-7028 exerts central effects which cause hypotension and bradycardia.

Animals↗
PubMed1995

Evidence that the 50-kDa substrate of brefeldin A-dependent ADP-ribosylation binds GTP and is modulated by the G-protein beta gamma subunit complex.

Brefeldin A, a fungal metabolite that inhibits membrane transport, induces the mono(ADP-ribosyl)ation of two cytosolic proteins of 38 and 50 kDa as judged by SDS/PAGE. The 38-kDa substrate has been previously identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We report that the 50-kDa BFA-induced ADP-ribosylated substrate (BARS-50) has native forms of 170 and 130 kDa, as determined by gel filtration of rat brain cytosol, indicating that BARS-50 might exist as a multimeric complex. BARS-50 can bind GTP, as indicated by blot-overlay studies with [alpha-32P]GTP and by photoaffinity labeling with guanosine 5'-[gamma-32P] [beta,gamma-(4-azidoanilido)]triphosphate. Moreover, ADP-ribosylation of BARS-50 was completely inhibited by the beta gamma subunit complex of G proteins, while the ADP-ribosylation of GAPDH was unmodified, indicating that this effect was due to an interaction of the beta gamma complex with BARS-50, rather than with the ADP-ribosylating enzyme. Two-dimensional gel electrophoresis and immunoblot analysis shows that BARS-50 is a group of closely related proteins that appear to be different from all the known GTP-binding proteins.

Adenosine Diphosphate Ribose↗