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R Korbut

Publications and source records attributed to R Korbut.

At least 37 records · Page 2Linked to original sources
PubMed1999

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

Although many diseases of the heart and circulatory system have been linked with insufficient deformability and increased aggregability of red blood cells, there are only a few drugs which can modulate these biological functions of erythrocytes. Here, we show evidences that iloprost, stable prostacyclin analogue and SIN-1, active metabolite of molsidomine which spontaneously releases NO, may be sufficient pharmacological tools for modulating red blood cell deformability and aggregability. Deformability of red blood cells was measured by shear stress laser diffractometer (Rheodyn SSD) and expressed in percent of red blood cell deformability index (DI). MA-1 (Myrenne) erythrocyte aggregometer was used for photometric measurements of aggregability in arbitrary units (MEA) of mean extent of aggregation. Experiments were carried out on rats ex vivo and in vitro using whole rat blood or isolated erythrocytes. Ex vivo SIN-1 (infusion 2 mg/kg/min i.v.) and iloprost (bolus injection 10 microg/kg i.v.) significantly improved erythrocyte deformability and aggregability at 5-15 min after administration. L-NAME (10 mg/kg i.v.)- inhibitor of nitric oxide synthase, and aspirin (1 mg/kg i.v.) caused worsening of deformability of erythrocytes in experiments ex vivo. Studies in vitro also revealed improvement of red blood cell deformability and aggregability by SIN-1 (3 microM, 15 min incubation at 22 degrees C) or iloprost (1 microM, 15 min incubation at 22 degrees C) and this phenomenon appeared not only in whole blood but also in isolated red cells. It is concluded that NO- and prostacyclin-induced improvement of red blood cell deformability and aggregability results from direct action of these compounds on erythrocytes. NO-donors and iloprost could be useful in the treatment of disorders of blood fluidity.

Animals↗
PubMed1998

Thrombolytic activity of beta-adrenolytic drug, sotalol.

Sotalol is a beta-adrenoreceptor blocking drug, the clinical efficacy of which has been linked up to its negative chrono- and inotropic effects and its hypotensive action. In addition, beta-adrenolytic drugs are known to inhibit platelet aggregation in vitro possibly through lowering of calcium ions level. Here, we report that in rats sotalol at a dose of 10-20 mg/kg i.v., apart from hypotension, evokes instantaneous thrombolytic effect. This is associated with an increase in plasma level of tissue plasminogen activator (t-PA). In vitro, sotalol at a concentration of 1-100 microM inhibits thrombogenesis on surface of rabbit aorta endothelium superfused with blood. Sotalol also has a weak anti-aggregatory activity (IC50 approximately 500-1000 microM) in human platelet rich plasma (PRP). Since the thrombolytic and fibrinolytic but not hypotensive effects of sotalol were inhibited by cyclooxygenase inhibitor, indomethacin, while its hypotensive but not thrombolytic potency was dimished by an inhibitor of nitric oxide synthase, NG-nitro-L-arginine (L-NNA), we have linked up the sotalol-induced effects in vivo with the release of prostacyclin and nitric oxide. Our data point out to a possibility that prostacyclin and nitric oxide concomitantly released from endothelium and/or from other blood cells after administration of sotalol, may play different roles: prostacyclin may be responsible for fibrinolytic, thrombolytic and antithrombotic properties, while nitric oxide may take part in the mechanism of sotalol-induced hypotension.

Adrenergic beta-Antagonists↗
PubMed1998

Influence of cadmium intoxication on thromboresistance of vascular endothelium in rabbits.

Here, using our original technique for measuring of thrombogenesis on the surface of rabbit aorta endothelium superfused with whole blood, we demonstrate that the thrombogenic property of endothelium is potentiated in the course of 3 months cadmium intoxication. The loss of endothelial thromboresistance is accompanied by suppressed generation of endogenous prostacyclin, leukopenia, increased platelet aggregability and by the presence of quasi-atherosclerotic, focal proliferative, glassy-protein lesions formed in aortic endothelium. We hypothesize that the final loss of vessel thromboresistance with all sequence of events that accompany cadmium intoxication, may result from the cadmium-induced inhibition of the generation of endothelial prostacyclin. However, the exact mechanism by which cadmium intoxication may affect the generation of prostacyclin and, then, functioning of blood platelets and vascular endothelium requires further investigations.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

[Wound repair].

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Adult↗
PubMed1997

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

Using the shear stress laser diffractometer (Rheodyn) we have studied the role of nitric oxide on erythrocyte deformability during the initial 10 min after the i.v. administration of LPS at a dose of 5 mg/kg. At the stress shear force of 30 Pa the control erythrocytes elongation index (Ei) of untreated animals was 38% +/- 1.5 (mean +/- SD, n = 6) while in LPS treated animals it was decreased to 33% +/- 1.8 (n = 6) indicating significant (p < 0.01) loos of red blood cell deformability. The loss of deformability was accompanied by increased fragility of erythrocyte membranes as measured by enhanced release of free hemoglobin (E lambda 420 = 0.43 +/- 0.05 in control vs. E lambda 420 = 0.65 +/- 0.07 in LPS group) from isolated erythrocytes exposed to centrifuging at a speed of 3000 rpm for 10 min. Inhibitor of NO-synthase, NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg i.v.), significantly decreased deformability (Ei = 33.5- +/- 4.6, n = 6, p < 0.01) but did not influence fragility (E lambda 420 = 0.36 +/- 0.14, n = 6) of erythrocytes. However, when L-NAME was administered 10 min. prior to LPS it significantly improved the LPS-impaired fragility (E lambda 420 = 0.38 +/- 0.1, n = 6, p < 0.01) as compared to rats treated with LPS-alone (E lambda 420 = 0.65 +/- 0.07, n = 6). A similar protective effect of L-NAME was observed for LPS-induced impairment of erythrocyte deformability. It is concluded that NO seems to influence deformability and fragility of erythrocytes at the first stage of sepsis. During an acute phase of LPS action, possibly reflected by stimulation of endothelial constitutive (ecNOS) but not inducible NO-synthase (iNOS), the excessive amount of NO leads to a damage of erythrocyte plasticity and then the pretreatment with L-NAME exerts a protective action of LPS-impaired deformability and fragility of erythrocytes. On the other hand, basal release of NO maintains erythrocyte deformability at the physiological range and lowering of the basal level of NO by NOS-inhibitors leads to impairment or erythrocyte deformability.

Animals↗
PubMed1996

Thrombolytic action of ticlopidine: possible mechanisms.

Ticlopidine (Ticlide), an anti-platelet drug with a broad scope of clinical applications, is claimed to be an antagonist of adenosine diphosphate on platelet receptors. In vitro this antagonism cannot be demonstrated. Ex vivo it is detectable many hours after oral administration of the drug, perhaps subsequently to its biotransformation to an unknown metabolite. Here, we report for the first time that in patients with peripheral arterial disease and in cats with extracorporal circulation ticlopidine evokes instantaneous thrombolytic or fibrinolytic effects which are not associated with inhibition of platelet aggregation. Shortening of euglobulin clot lysis time and increase in plasma levels of tissue plasminogen activator were observed 1-2 h after oral ingestion of ticlopidine at a single dose of 500 mg. In cats ticlopidine produced instantaneous anti-thrombotic and thrombolytic effects at doses of 0.3-1 mg/kg and 10-15 mg/kg i.v., respectively. Thrombolysis by ticlopidine (10 mg/kg i.v.) was comparable to that by prostacyclin at a dose of 0.3 microgram/kg i.v. Ticlopidine at a concentration of 100 microM increased endothelial thromboresistance in vitro. The drug did not inhibit the activity of cyclooxygenase-1 or 12-lipoxygenase while it inhibited lipid autooxidation (IC50 = 18 microM) in rat liver microsomes. Our data point to a possibility that the therapeutic efficacy of ticlopidine might be associated not only with its delayed anti-platelet effects but also with its immediate thrombolytic action which is likely to be mediated by endothelial prostacyclin and tissue plasminogen activator rather than by platelet mechanisms.

Aged↗
PubMed1996

A paradox of thrombogenesis by streptokinase and its prevention by iloprost and camonagrel.

Here we report that streptokinase is responsible for forming thrombi both in vitro on blood-superfused endothelial cells of rabbit aorta and in vivo on blood-superfused collagen strips in extracorporal circulation of anesthetized cats. This short-lasting paradoxical thrombogenic phase is followed by the expected long-lasting thrombolysis. The biphasic action of streptokinase occurred in vitro at concentrations of 100-2000 U/ml and in vivo at doses of 1000-3000 U/kg i.v. Both phases are mediated by endogenous plasmin as evidenced by deleting the streptokinase-induced thrombogenesis and thrombolysis following pretreatment with epsilon-aminocaproic acid or aprotinin. On the other hand, selective block of the paradoxical thrombogenesis was achieved after pretreatment with camonagrel, a thromboxane synthase inhibitor which raises plasma levels of endogenous prostacyclin, or with iloprost, a stable analog of prostacyclin. It is suggested that endogenous or exogenous prostacyclin inhibits activation of platelets by plasmin, and hence the thrombogenesis by streptokinase is abolished, while the beneficial thrombolytic action of streptokinase is augmented.

Animals↗
PubMed1996

Treatment with L-arginine is likely to stimulate generation of nitric oxide in patients with peripheral arterial obstructive disease.

The impairment of endothelial function in hypercholesterolaemic animals and humans is known to be reversed by intravenous infusions of L-arginine (L-ARG), the precursor of NO. 22 patients with peripheral arterial obstructive disease (PAOD) received L-ARG (60 mmol) as intravenous infusions, each lasting three hours, daily for seven consecutive days. This treatment resulted in elongation of the painfree and maximum walking distances, as well as shortening of the period of time required for pain relief after walking the maximum distance. A rise in the ankle/arm pressure ratio (AAPR) was associated with an increase of arterial blood flow in both calves. The transcutaneous oxygen tension (tcpO2) in the ischaemic foot was also increased. After the 1st and the 7th infusion of L-ARG the spontaneous (PAR) as well as the ADP- and collagen-induced platelet aggregation were suppressed, the euglobulin clot lysis time (ECLT) shortened, plasma levels of platelet activator inhibitor (PAI) decreased, and cGMP levels increased. These data indicate beneficial effects of L-ARG as a therapeutic agent in patients with PAOD. We presume that in these patients high doses of exogenous L-ARG can be partially converted to NO.

Adult↗
PubMed1996

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

Six hours after administration of E. Coli endotoxin (LPS) into rats (10 mg kg-1, i.p.) a significant (P < 0.001) decline in the red blood cell deformability index (RBC Dj) was observed. The control Di value of untreated animals it was 300 +/- 39 RBC x 10(6)/min (means +/- S.D.; n = 12) while in LPS treated animals was 140 +/- 50 RBC x 10(6)/min; n = 12. Pretreatment of the animals with the stable analogue of prostacyclin, iloprost (30 micrograms/kg, i.p.) or with the inhibitor of thromboxane A2-synthase, camonagrel (10 mg/kg, i.p.), but not with nitric oxide donor, such as GEA 5285 (10 mg/kg, i.p.), significantly increased deformability of red blood cells in the group of non-septicaemic animals, and antagonized the LPS-induced decline in red blood cell deformability of septicaemic rats. Administration of NG-nitro-L-arginine (L-NNA, 30 mg/kg, i.p.), as that of aspirin (50 mg/kg, i.p.), did not affect red blood cell deformability in non-septicaemic rats, however, in contrast with aspirin, it significantly improved deformability of red blood cells in LPS-treated animals. It is concluded that prostacyclin, camonagrel and L-NNA can act as protective agents against LPS-induced loss of red blood cell deformability. The mechanisms of this protection are complex and, possibly, related to the specific effects of these agents on biochemical function of leukocytes present in RBC suspension. While the effect of exogenous prostacyclin (iloprost) may be explained on the basis of its direct cytoprotective potency on leukocytes, the effect of camonagrel is indirect and can be attributed both to the release of endogenous prostacyclin and to the inhibition of thromboxane A2-synthase. The protection induced by NO-synthase inhibitor seems to depend upon inhibition of an increase of the generation of nitric oxide which follows administration of LPS.

Animals↗
PubMed1995

The effect of nitric oxide donors on the release of plasminogen activator inhibitor (PAI) from rabbit platelets in vitro.

Here we describe effects of four nitric oxide (NO) donors, 4-arylsubstituted oxatriazol derivatives and 3-morpholino-sydnonimine (SIN-1) at concentrations of 30-1000 microM on the release of plasminogen activator inhibitor (PAI) from rabbit platelets in vitro. At 37 degrees C, pH of 7.4 and a concentration of 30 microM, all compounds released NO as measured by the Werringloer's technique. The NO-generating potency of the compounds correlated with their capacity to inhibit the release of PAI from platelets and both phenomena were concentration-dependent. We conclude that various types of NO-donors activate plasma fibrinolytic system through inhibition of the release of PAI from platelets.

Animals↗
PubMed1995

The mechanism of anti-thrombotic, thrombolytic and fibrinolytic actions of camonagrel--a new thromboxane synthase inhibitor.

So far pharmacological consequences of inhibition of thromboxane A2 (TXA2) synthase by imidazole derivatives (e.g., camonagrel or dazoxiben) were linked to suppression of platelet activity. Here we report that in patients with peripheral atherosclerosis or in cats with extracorporeal thrombogenesis treatment with camonagrel is associated with activation of fibrinolysis or thrombolysis. These phenomena seem to be related to the camonagrel-induced shift in metabolism of prostaglandin endoperoxides from TXA2 to prostacyclin (PGI2), although in an in vitro model the involvement of the L-arginine/nitric oxide pathway cannot be excluded. In cats camonagrel (10 mg/kg i.v.) produced not only a fall in TXB2 but also a rise in 6-keto-PGF1 alpha and no change in cyclic-GMP plasma levels. This points to PGI2 rather than to nitric oxide as an in vivo mediator of camonagrel-induced thrombolysis. The crucial role of endogenous PGI2 in the thrombolytic response to camonagrel in cats was evidenced by its blockade following pretreatment of animals with a megadose of aspirin (50 mg/kg i.v.) and lack of any effect on pretreatment with L-NAME (100 micrograms/kg/min, i.v.). Obviously TXA2 synthase inhibitors (e.g., camonagrel) and cyclo-oxygenase inhibitors (e.g., aspirin) antagonize each other in their anti-thrombotic actions and must not be administered at the same time. Furthermore, in patients camonagrel (800 mg orally) suppressed TXA2 generation by 99.5% and doubled the plasma level of 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Platelets in fibrinolytic system.

Platelets play a vital role in mediating the activity of plasma fibrinolytic system. They have both the potential to inhibit as well as to activate fibrinolysis. Just as platelet can affect thrombolysis, thrombolytic agents can have reciprocal effects on platelet function. Accumulating evidence indicates that thrombolysis induced both by streptokinase and t-PA results in rapid activation of platelets, the phenomenon being possibly responsible for reocclusion of arteries after successful thrombolysis. However, caution is required in comparing the results of the various studies because of differences in the thrombotic models employed, with the major variables being the mechanism of thrombus formation (in vivo or in vitro), the platelet concentrations and the doses of investigated agent. Various studies indicate that adjunctive therapy with anti-platelet agents, such as inhibitors of cyclooxygenase, inhibitors of thromboxane A2-synthase and activators of platelet cyclic-AMP or -GMP may lower the dose of the thrombolytic agent required to attain reperfusion.

Animals↗
PubMed1994

The effect of nitric oxide synthase inhibition on the plasma fibrinolytic system in septic shock in rats.

1. We have investigated the effect of pretreatment of rats with nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) on the E. coli lipopolysaccharide (LPS)-induced changes in the plasma fibrinolytic system, platelet count, fibrinogen level, as well as in gross and microscopic pathophysiological changes indicative of disseminated intravascular coagulation (DIC) in rats. 2. E. coli LPS (6 mg kg-1, i.p.) produced a decrease in the levels of plasma fibrinogen and a drop in the blood platelet count 6 h after administration. The decrease in fibrinogen but not the drop in platelet count was reversed by pretreatment with L-NAME (30 mg kg-1, i.p., 24 h and 15 min before administration of LPS). 3. Pretreatment with L-NAME antagonized the LPS-induced activation of fibrinolysis as measured by changes in the euglobulin clot lysis time (ECLT) and enhanced the LPS-induced rise in the plasma level of plasminogen activator inhibitor (PAI). In animals pretreated with L-NAME there was also a marked reduction in the histological changes indicative of DIC. 4. We propose that L-NAME can act as a protective agent in LPS-induced DIC, and this protection is due to an increased generation of PAI following inhibition of NO synthase.

Amino Acid Oxidoreductases↗
PubMed1993

Nitric oxide from polymorphonuclear leukocytes modulates red blood cell deformability in vitro.

We confirmed that iloprost is very potent in preserving the deformability of rabbit red blood cells (RBC). Incubation of RBC with a small number (up to 1.2 x 10(6) cells/ml) of polymorphonuclear leukocytes (PMNs) caused a gradual decline in RBC deformability. The addition of PMNs up to 2.8 x 10(6) cells/ml increased RBC deformability but, at higher concentrations, both in the presence and absence of a neutrophil activating cytokine (interleukin-8; IL-8), PMNs reduced the deformability of RBCs. In the presence of a small number of PMNs, the deformability of RBC was increased by nitric oxide (NO) donors, such as sydnonimine (SIN-1) or sodium nitroprusside, and reduced by the NO synthase inhibitor, NG-monomethyl-L-arginine. We suggest that the deformability of RBC is modulated by PMNs via the release of NO and that the NO concentration is of critical importance in this modulatory mechanism. NO seems to preserve or enhance RBC deformability within a certain range of concentrations, but these effects are reversed or eliminated at both too low and too high concentrations.

Animals↗
PubMed1993

Nitric oxide complements prostacyclin in the regulation of endothelial thromboresistance under flow conditions.

Using a novel method of measuring thrombogenesis on the surface of rabbit aorta endothelium superfused with whole blood, it was demonstrated that the thrombogenic properties of endothelium are potentiated by pretreatment with inhibitors of nitric oxide (NO) synthase (NG-monomethyl-L-arginine, MeArg, 100 mcM) or cyclooxygenase (aspirin, ASA, 60 mcM). Since MeArg is less effective than aspirin and moreover does not influence thrombogenesis after previous inhibition of the synthesis of PGI2, it is concluded that the generation of NO by vascular endothelium complements PGI2 in its antithrombotic activity but NO may be ineffective when the generation of PGI2 has been impaired.

Animals↗
PubMed1990

Endothelins release tissue plasminogen activator and prostanoids.

Endothelin (ET)-1 (0.1-1 nmol/kg), ET-2 (0.1-1 nmol/kg) or ET-3 (0.3-3 nmol/kg) dose dependently inhibited platelet aggregation induced by adenosine di-phosphate (ADP) ex vivo in anaesthetised rabbits, while having no effect on aggregations induced by ADP, collagen or arachidonic acid in vitro. This anti-aggregatory effect of the peptides is most likely due to the release of prostacyclin into the circulation, for the inhibition was abolished by an injection of indomethacin (5 mg/ml). All three peptides produced a significant, bi-phasic reduction of the euglobulin clot lysis time. This ET-induced enhancement of plasma fibrinolytic activity was associated with a release of tissue plasminogen activator into the circulation. ET-1 or ET-2 caused a transient decrease in left ventricular systolic pressure (LVSP) followed by a prolonged pressor response. However, ET-3, while inducing a similar transient fall in LVSP caused a second, more prolonged, decrease in LVSP. The haemodynamic responses to all three peptides were modulated by the release of prostanoids, as evidenced by the elevation of the pressure responses by indomethacin.

Adenosine Diphosphate↗