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1.
Pharmacol Rep ; 63(5): 1169-79, 2011.
Article in English | MEDLINE | ID: mdl-22180359

ABSTRACT

SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul are recombinant proteins that are derivatives of r-SAK (recombinant staphylokinase). They are characterized by their fibrin-specific plasminogen activation properties and their antithrombin and antiplatelet activities. The difference between these proteins is the presence of the antithrombotic fragment (hirudin or hirulog) in the C-terminal portion of the r-SAK. The aim of the present study was to examine the thrombolytic potentials of SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul in an electrically induced carotid artery thrombosis model in rats and to compare the potentials to that of r-SAK. We determined that a bolus injection of SAK-RGD-K2-Hirul was more effective than one of r-SAK in the improvement and maintenance of carotid patency and in arterial thrombus weight reduction; however, it had the same potency as SAK-RGD-K2-Hir. The bleeding time, prothrombin time and activated partial thromboplastin time were significantly prolonged in the animals that were treated with either dose (1.5 or 3.0 mg/kg) of SAK-RGD-K2-Hir or SAK-RGD-K2-Hirul, whereas no changes were observed in the plasma fibrinogen concentration or the α2 plasmin inhibitor level. r-SAK alone did not change the bleeding time or coagulation parameters. In conclusion, our findings demonstrate the thrombolytic activity of intravenous bolus injection of the novel thrombolytic agent SAK-RGD-K2-Hirul in rats. Although this protein compares favorably with r-SAK, we were unable to show the presence of any beneficial effects of SAK-RGD-K2-Hirul over those of SAK-RGD-K2-Hir. Furthermore, our results suggest that high doses of SAK-RGD-K2-Hirul bear the risk of bleeding.


Subject(s)
Carotid Artery Thrombosis/drug therapy , Fibrinolytic Agents/pharmacology , Hirudins/pharmacology , Metalloendopeptidases/pharmacology , Recombinant Fusion Proteins/pharmacology , Animals , Bleeding Time/methods , Blood Coagulation/drug effects , Carotid Artery Thrombosis/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/toxicity , Hirudins/administration & dosage , Hirudins/toxicity , Injections, Intravenous , Male , Metalloendopeptidases/administration & dosage , Metalloendopeptidases/toxicity , Rats , Rats, Wistar , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/toxicity
2.
J Renin Angiotensin Aldosterone Syst ; 12(4): 430-9, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21421657

ABSTRACT

INTRODUCTION: We investigated the role of primary haemostasis, fibrinolysis, nitric oxide (NO) and oxidative stress as well as mineralocorticoid receptors (MR) in acute aldosterone prothrombotic action. MATERIALS AND METHODS: Venous thrombosis was induced by stasis in Wistar rats. Aldosterone (ALDO; 10, 30, 100 µg/kg/h) was infused for 1 h. Eplerenone (EPL; 100 mg/kg, p.o.), a selective MR antagonist, was administered before ALDO infusion. Bleeding time (BT) and platelet adhesion to collagen were evaluated. The expression of nitric oxide synthase (NOS), NADPH oxidase, superoxide dismutase (SOD) and plasminogen activator inhibitor (PAI-1) was measured. NO, malonyl dialdehyde (MDA) and hydrogen peroxide (H(2)O(2)) plasma levels were assayed. RESULTS: Significant enhancement of venous thrombosis was observed after ALDO infusion. ALDO shortened BT and increased platelet adhesion. Marked increases were observed in PAI-1, NADPH oxidase and SOD mRNA levels. MDA and H(2)O(2) levels were augmented in ALDO-treated groups, and NOS expression and NO level were decreased. EPL reduced ALDO effects on thrombus formation, primary haemostasis, PAI-1 expression and MDA level. CONCLUSION: Short-term ALDO infusion enhances experimental venous thrombosis in the mechanism involving primary haemostasis, fibrinolysis, NO and oxidative stress-dependent pathways. The MR antagonist only partially diminished the ALDO effects, suggesting the involvement of additional mechanisms.


Subject(s)
Aldosterone/metabolism , Thrombosis/pathology , Aldosterone/blood , Animals , Aorta/drug effects , Aorta/enzymology , Aorta/pathology , Biological Availability , Bleeding Time , Hemodynamics/drug effects , Hemostasis , Male , Mineralocorticoid Receptor Antagonists , Nitric Oxide/blood , Nitric Oxide Synthase/metabolism , Oxidative Stress/drug effects , Plasminogen Activator Inhibitor 1/metabolism , Platelet Adhesiveness/drug effects , Potassium/urine , Rats , Rats, Wistar , Receptors, Mineralocorticoid/metabolism , Thrombosis/blood , Thrombosis/physiopathology , Thrombosis/urine , Venous Thrombosis/pathology
3.
Postepy Hig Med Dosw (Online) ; 64: 471-81, 2010 Oct 18.
Article in Polish | MEDLINE | ID: mdl-20966505

ABSTRACT

Recent studies have focused on a new wave of interest in aldosterone due mainly to its growing profile as a local messenger in pathology of the cardiovascular system, rather than its hormonal action. In the last few years strong evidence for a correlation between raised aldosterone level and haemostasis disturbances leading to increased risk of cardiovascular events has been provided. It has been demonstrated that aldosterone contributes to endothelial dysfunction, fibrinolytic disorders and oxidative stress augmentation. It was also shown that chronic aldosterone treatment results in enhanced experimental arterial thrombosis. Our study in a venous model of thrombosis in normotensive rats confirmed that even a short-lasting increase in aldosterone level intensified thrombus formation. One-hour aldosterone infusion shortened bleeding time; increased platelet adhesion to collagen; reduced tissue factor, thrombin activatable fibrinolysis inhibitor, and plasminogen activator inhibitor; and increased plasminogen activator plasma level. A fall in plasma nitric oxide metabolite concentration with a decrease in aortic nitric oxide synthase mRNA level was also observed. Moreover, aldosterone increased hydrogen peroxide and malonyl dialdehyde plasma concentration and augmented NADPH oxidase and superoxide dismutase aortic expression. Therefore, the mechanism of aldosterone prothrombotic action is multiple and involves primary haemostasis activation, procoagulative and antifibrinolytic action, NO bioavailability impairment and oxidative stress augmentation. The effects of aldosterone were not fully abolished by mineralocorticoid receptor blockade, suggesting the involvement of alternative mechanisms in the prothrombotic aldosterone action.


Subject(s)
Aldosterone/pharmacology , Hemostasis/drug effects , Spironolactone/analogs & derivatives , Animals , Eplerenone , Platelet Adhesiveness/drug effects , Rats , Spironolactone/pharmacology , Thrombosis
4.
Postepy Hig Med Dosw (Online) ; 61: 555-64, 2007 Oct 12.
Article in Polish | MEDLINE | ID: mdl-17971759

ABSTRACT

Vascular endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing some vasodilating factors, such as prostacyclin (PGI2), nitric oxide (NO), and a yet unidentified endothelium-derived hyperpolarizing factor (EDHF). Although the nature of EDHF is still controversial, this additional endothelial pathway, endothelium-dependent hyperpolarization, has been demonstrated in many blood vessels of different species, including humans. Despite tissue- and species-specific site differences, endothelium-dependent hyperpolarization plays an important role in the regulation of resistance of vessels and microcirculation. The most probable candidates for EDHF include epoxyeicosatrienoic acids, endothelium-derived potassium ions (K+), and hydrogen peroxide (H2O2). Endothelium-dependent hyperpolarization also probably involves the activation of two populations of endothelial potassium channels, i.e. the small- and intermediate-conductance calcium-activated potassium channels (SKCa and IKCa). Electrical communication between endothelial and smooth muscle cells through gap junctions has also been suggested to be involved in endothelium-dependent hyperpolarization. EDHF-mediated responses are clearly sex-dependent and altered in aging and various pathological conditions, such as hypoxia, hypertension, atherosclerosis, and diabetes, which are mainly related to endothelial dysfunction. Suitable therapeutic treatment can restore these impaired vascular responses. Activating endothelial potassium channels or improving myo-endothelial communication could become interesting therapeutic targets.


Subject(s)
Biological Factors/physiology , Endothelium, Vascular/physiology , Endothelium, Vascular/physiopathology , Gap Junctions/physiology , Homeostasis , Age Factors , Epoprostenol/metabolism , Humans , Hydrogen Peroxide/metabolism , Nitric Oxide/metabolism , Potassium Channels, Calcium-Activated/metabolism , Sex Factors
6.
Thromb Haemost ; 97(6): 1037-45, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17549308

ABSTRACT

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. In the arterial thrombosis model, a bolus injection of SAK-RGD-K2-Hir was less effective than rt-PA and r-SAK. However, the most effective in the improvement and maintenance of carotid patency and in arterial thrombus mass reduction was SAK-RGD-K2. In contrast, all r-SAK derivatives reduced venous thrombus weight significantly in comparison to r-SAK and r-Hir. However, the most observable decrease in thrombus weight was obtained after application of recombinant proteins containing the r-Hir. The bleeding time was significantly prolonged in the animals treated with proteins containing r-Hir at a dose of 1.0 mg/kg. There were no observable changes in plasma fibrinogen concentration. In conclusion, our findings show thrombolytic activity in intravenous bolus injection of the novel thrombolytic agent SAK-RGD-K2-Hir in rats. Although this protein compares favourably with r-SAK in rat venous thrombolysis, we were unable to confirm the beneficial effects of SAK-RGD-K2-Hir over r-SAK and rt-PA in the carotid artery thrombolysis model. Furthermore, our results also suggest that SAK-RGD-K2-Hir bears a risk of bleeding, but this may be true for higher doses.


Subject(s)
Blood Coagulation/drug effects , Carotid Artery Thrombosis/drug therapy , Fibrin/metabolism , Fibrinolytic Agents/pharmacology , Hirudins/pharmacology , Metalloendopeptidases/pharmacology , Recombinant Fusion Proteins/pharmacology , Vascular Patency/drug effects , Venous Thrombosis/drug therapy , Animals , Bleeding Time , Carotid Artery Thrombosis/blood , Carotid Artery Thrombosis/metabolism , Carotid Artery Thrombosis/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Electric Stimulation , Fibrinolytic Agents/adverse effects , Fibrinolytic Agents/metabolism , Hemorrhage/chemically induced , Hirudins/adverse effects , Hirudins/metabolism , Ligation , Male , Metalloendopeptidases/adverse effects , Metalloendopeptidases/metabolism , Partial Thromboplastin Time , Rats , Rats, Wistar , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/metabolism , Thrombin Time , Time Factors , Tissue Plasminogen Activator/pharmacology , Venae Cavae/surgery , Venous Thrombosis/blood , Venous Thrombosis/metabolism
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