Pharmacological modulation of fibrinolytic response - In vivo and in vitro studies.

Fibrinolysis is an action of converting plasminogen by its activators, like tissue- or urokinase-type plasminogen activators (t-PA, u-PA), to plasmin, which in turn cleaves fibrin, thereby causing clot dissolution and restoration of blood flow. Endothelial cells release t-PA, prostacyclin (PGI2) and nitric oxide (NO), the potent factors playing a crucial role in regulation of the fibrinolytic system. Since blood platelets can release not only prothrombotic, but also antifibrinolytic factors, like plasminogen activator inhibitor type-1 (PAI-1), they are involved in fibrynolysis regulation.

Impact of aliskiren on some hemostatic parameters in experimental arterial thrombosis in rats.

Background: Aliskiren is the first orally active inhibitor of renin to be approved for clinical use as an antihypertensive agent. A number of studies show a link between aliskiren and intravascular thrombosis.

Materials And Methods: The goal of the present study was to investigate the impact of aliskiren on arterial thrombosis in normotensive and renovascular hypertensive rats.

Antithrombotic effects of pyridinium compounds formed from trigonelline upon coffee roasting.

Coffee may exert a preventive effect on arterial thrombosis. Trigonelline is one of the most abundant compounds in coffee that undergoes pyrolysis upon roasting of coffee beans. The aim of the present study was to identify pyridinium compounds formed upon trigonelline pyrolysis and coffee roasting and to investigate the effect of three of them, i.

Aliskiren inhibits experimental venous thrombosis in two-kidney one- clip hypertensive rats.

A substantial amount of evidence links the renin-angiotensin system with thrombosis. For example, ACE inhibitors and angiotensin receptor blockers possess independent of the hemodynamic changes, antithrombotic activity. Aliskiren direct renin inhibitor belongs to a new very promising antihypertensive drug that effectively inhibits the renin-angiotensin system.

Antithrombotic properties of water-soluble carbon monoxide-releasing molecules.

Objective: We compared the antithrombotic effects in vivo of 2 chemically different carbon monoxide-releasing molecules (CORM-A1 and CORM-3) on arterial and venous thrombus formation and on hemostatic parameters such as platelet activation, coagulation, and fibrinolysis. The hypotensive response to CORMs and their effects on whole blood gas analysis and blood cell count were also examined.

Methods And Results: CORM-A1 (10-30 µmol/kg, i.

Cationic derivative of dextran reverses anticoagulant activity of unfractionated heparin in animal models of arterial and venous thrombosis.

Heparin is a natural polymer widely used in medicine especially during the treatment of cardiovascular diseases since it is a potent blood anticoagulant. In case of emergency, e.g.

Inhibition of platelet aggregation by carbon monoxide-releasing molecules (CO-RMs): comparison with NO donors.

Carbon monoxide (CO) and CO-releasing molecules (CO-RMs) inhibit platelet aggregation in vitro. Herein, we compare the anti-platelet action of CORM-3, which releases CO rapidly (t (½) 1 min), and CORM-A1, which slowly releases CO (t(½) = 21 min). The anti-platelet effects of NO donors with various kinetics of NO release were studied for comparison.

Effect of erythropoietin, 5-fluorouracil and SN-38 on the growth of DLD-1 cells.

Supplementation of recombinant human erythropoietin (rHuEpo) is one of the methods for the treatment of anemia. The influence of rHuEpo on proliferation or clonogenic growth of cancer cells is not clear and some of the published results are conflicting. The aim of this work was to study the effect of rHuEpo on colon cancer cells when given alone or in combination with cytostatics.

[Tryptophan and its metabolites in renal allograft recipients].

Aim: Disturbances in amino acids metabolism are common in chronic renal failure and subside partially after renal tranplantation. Tryptophan (TRP) is one of the most important exogenous amino acids. Its main derivative is L-kynurenine (KYN).

N-methylnicotinamide failed to induce endothelial prostacyclin release in perfused rat hindquarters.

N-methylnicotinamide, a nicotinamide derivative, possesses anti-thrombotic activity, although the mechanism of its action is unclear. Using a rat model of isolated perfused hindlimb, we tested whether this metabolite of nicotinamide is able to inhibit the vasoconstrictive effects of epinephrine, norepinephrine, and angiotensin II, thereby releasing prostacyclin from the endothelium. We found that N-methylnicotinamide administration by infusion or bolus injection did not change the course of perfusion pressure and did not inhibit the vasoconstrictive action of epinephrine, norepinephrine, or angiotensin II.

Experimental asthma in rats.

Animal models of asthma have been used for over 100 years. The accuracy of extrapolations from animal models to human asthmatics is highly dependent on the species of animal selected. The rat, in comparison with other animals, demonstrates many features of airway allergy and allergic asthma that are similar to the human conditions.

Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor.

Intensive efforts have been spent to discover therapeutic, non-peptide and orally effective hypertensive drugs. One drug that emerged from this effort is aliskiren, a direct human renin inhibitor that blocks the conversion of angiotensinogen to angiotensin I (Ang I). In contrast to other antihypertensive agents, aliskiren decreases plasma renin activity (PRA).

The concentration of kynurenine in rat model of asthma.

Asthma is a chronic inflammatory disease that involves the immune system activation. Evidence is accumulating about the role of kynurenine pathway in the immune system regulation. The kynurenine pathway includes several metabolites of tryptophan, among others kynurenine (KYN).

A new recombinant thrombolytic and antithrombotic agent with higher fibrin affinity - a staphylokinase variant. An in-vivo study.

The recombinant protein SAK-RGD-K2-Hir is characterized by its fibrin-specific properties of plasminogen activation combined with antithrombin and antiplatelet activities. It was previously shown in our in-vitro studies to be a more potent and faster-acting thrombolytic agent compared with standard r-SAK. In order to document the effects of the thrombolytic potential of SAK-RGD-K2-Hir we examined this protein in an electrically induced carotid artery thrombosis model and stasis-induced venous model in rats.

Are the endothelial mechanisms of ACE-Is already established?

The endothelial mechanism of ACE-Is action is multifaceted. On the one hand, by inhibiting ACE, ACE-Is diminish Ang II synthesis, one of the best known active peptides. On the other hand, they modify synthesis and release of PGI(2) and NO via increasing production of other biologically important peptides like bradykinin, Ang-(1-7) or Ang-(1-9).

Tissue distribution of a menthyl-conjugated oligodeoxyribonucleotide antisense to PAI-1 mRNA.

The inhibitory effect of numerous analogues of PO-16, an hexadecadeoxyribonucleotide antisense to sequences -22 to -17 of PAI-1 mRNA coding for a fragment of the signal peptide, on the expression of PAI-1 in endothelial cells, and physiological consequences of the subsequently reduced PAI-1 activity tested in vitro and in vivo, were described in our previous studies. Of particular interest was PO-16 5'-O-conjugated with menthyl phosphorothioate (MPO-16R). In this work, tissue localisation of MPO-16R labelled with [(35)S] phosphorothioate at the 3'-end, was determined.

[Metabolism of tryptophan via the kynurenine pathway in saliva].

In this review, the role of the kynurenine pathway enzymes TDO (tryptophan 2,3 dioxygenase) and IDO (indoleamine 2,3 -dioxygenase) as well as the properties of the metabolites of kynurenine degradation present in human saliva described. The implications of these metabolites in the pathomechanism of tissue and organs dysfunction are demonstrated. The authors also describe at length the role of saliva kynurenine derivatives in the onset and development of periodontal disease in humans.

Angiotensin II enhances thrombosis development in renovascular hypertensive rats.

There is an increased number of in vitro evidence that angiotensin II (Ang II) may promote thrombosis. However there are no in vivo experiments exploring the effect of Ang II on thrombus formation. In the present study we have investigated the influence of Ang II on venous thrombosis in renovascular hypertensive rats.

[Hypoxia involvement in erythropoiesis regulation--a new insight].

Oxygen, carried mainly by erythrocytes, plays a crucial role in human organisms--as the terminal electron acceptor enables mitochondria functioning and energy production. Oxygen excess may be a cause of the damage of basic structural organism components--proteins, lipids and nucleinic acids. Thus, from the biological point of view, regulation of oxygen supply with its detection mechanisms is a critical process.

Antithrombotic effect of captopril and enalapril in old rats.

In the present study, we have shown considerably accelerated thrombosis in old rats in comparison with adult rats, which may be related to the impaired hemostatic balance in these animals. In old rats, captopril and enalapril caused a marked reduction of venous thrombus weight. The mechanism of antithrombotic action of these drugs seems to be dependent on the suppression of coagulation cascade and the enhancement of the fibrinolytic processes.

L-arginine and cardiovascular system.

L-arginine is a basic endogenous amino acid. Its significant metabolic role as the product of ammonia detoxification, the urea cycle metabolite, the precursor of proteins, ornithine, urea and creatinine, and the amino acid involved in the formation of active enzyme centers was very well established. The current interest in this amino acid refers mainly to its close relation with an important signal molecule nitric oxide (NO).

Ebelactone B, an inhibitor of extracellular cathepsin A-type enzyme, suppresses platelet aggregation ex vivo in renovascular hypertensive rats.

The present study was undertaken to investigate whether ebelactone B, an inhibitor of bradykinin and angiotensin I hydrolysis by serine carboxypeptidase Y-like enzymes, could influence platelet aggregation ex vivo in renovascular hypertensive rats (2-kidney, 1-clip Goldblatt model, 2K1C). We found that ebelactone B (5 mg/kg) administrated subcutaneously once a day for 5 days, 5 weeks after the development of hypertension, or a single dose of ebelactone B (0.5 mg/kg) injected intravenously into 2K1C hypertensive rats before the induction of arterial thrombosis, both markedly suppressed collagen-induced platelet aggregation in whole blood.

Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats.

Recent studies indicate that highly selective proteasome inhibitors can be useful in prevention of some cardiovascular events. Here we demonstrate that proteasome inhibitor, Z-Ile-Glu (Ot-Bu) Ala-Leucinal (PSI), is active in the prevention of platelet-dependent arterial thrombosis induced in renovascular hypertensive rats (two-kidney, one clip Goldblatt model, and 2K1C, n=5). The administration of PSI intravenously at a single dose of 0.

Kidney and liver kynurenine pathway enzymes in chronic renal failure.

It has been suggested that kynurenine pathway may be an important pathological factor during the chronic renal failure (CRF) development. Therefore in the present study, in rats with end-stage of chronic renal failure, we measured the plasma and tissues (kidney and liver) concentrations of tryptophan, kynurenine, 3-hydroxykynurenine. We also evaluated the activity of tryptophan 2,3-dioxygenase in the liver (TDO), indoleamine 2,3-dioxygenase in kidney (IDO) and kynurenine 3-hydroxylase (HK) in the liver and in the kidney.