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Biomedical subjects

I Mucha

Publications and source records attributed to I Mucha.

At least 19 recordsLinked to original sources
PubMed1995

Endotoxin inhibits glucuronidation in the liver. An effect mediated by intercellular communication.

Endotoxin [lipopolysaccharide (LPS) 50 micrograms/mL] added to the perfusion medium increased glucose production and inhibited the glucuronidation of p-nitrophenol in perfused mouse liver both in recirculating and non-recirculating systems, while sulfation of p-nitrophenol was unchanged. The effects of endotoxin could be prevented by the addition of cyclooxygenase inhibitors, while PGD2 and PGE2 also caused a decrease in p-nitrophenol glucuronidation in perfused liver. In isolated hepatocytes endotoxin failed to affect p-nitrophenol conjugation, while PGD2 and PGE2 decreased the rate of it. Our results suggest that endotoxin inhibits glucuronidation through an intercellular communication presumably mediated by eicosanoids.

Animals↗
PubMed1995

Effects of NO-donors, SIN-1 and GEA 3175 on prostacyclin and cGMP synthesis in cultured rat endothelial cells.

The aim of the present study was to investigate, whether nitric oxide (NO) modifies prostacyclin synthesis in endothelial cells. Two different NO-donors: SIN-1 (3-morpholino sydnonimine) and GEA 3175 (4-aryl-substituted oxatriazol derivative), and the NO-synthesis inhibitor; L-NAME were used. Endothelial cells were incubated with the tested compounds with or without Ca ionophore A23187 stimulation. SIN-1 (> 33 microM) and GEA 3175 (> 1 microM) increased the endothelial cGMP levels independently of A23187 stimulation. SIN-1 did not influence prostacyclin synthesis. GEA 3175 (> 33 microM) increased prostacyclin synthesis up to 2-fold, when incubated without A23187. GEA 3175 with A23187 induced about 30% inhibition in prostacyclin synthesis. L-NAME decreased unstimulated prostacyclin synthesis and this inhibition was reversed by GEA 3175. Obviously NO is able to modulate prostacyclin synthesis, however, much higher concentrations are needed than those to increase cGMP synthesis.

Animals↗
PubMed1995

Smoking cessation and nicotine substitution modulate eicosanoid synthesis ex vivo in man.

The effects of smoking cessation with and without nicotine substitution on prostaglandin E2, leukotriene B4, leukotriene E4, and thromboxane B2 synthesis ex vivo in man were investigated. Blood samples were obtained from 20 healthy non-smoking controls and from 30 healthy smoking volunteers before and 3, 7 and 14 days after smoking cessation. Half of the smokers used nicotine chewing gum as a substitution therapy. Urinary cotinine and trans-3'-hydroxycotinine as well as thiocyanate excretions were used as indicators for the use of nicotine chewing gum and smoking, respectively. Prostaglandin E2, leukotriene E4, and thromboxane B2 were measured from whole blood after calcium ionophore A23187 stimulation by direct radioimmunoassay and leukotriene B4 by RP-HPLC. Prostaglandin E2 and thromboxane B2 syntheses were about three times and leukotriene B4 and E4 syntheses four times higher in smokers than in controls. Three days after smoking cessation without nicotine substitution, levels were lowered significantly to about 70%, 80%, 45% and 60% of the initial values; and after 14 days to 55%, 80%, 45% and 50%, respectively. In the nicotine substitution group no significant decreases were seen during the two-week follow-up. The increased level of eicosanoid synthesis detected in smokers in this ex vivo study may contribute to the harmful cardiovascular effects of smoking. Long-term nicotine substitution might diminish the beneficial effects of smoking cessation due to the possible stimulatory effects of nicotine and cotinine on eicosanoid synthesis even in vivo.

Adult↗
PubMed1995

Pregnancy enhances the pressor response to thromboxane analogues in rabbits.

In this study, we first tested the hypothesis that the previously demonstrated circulatory failure and thrombocytopenia induced by intracaval administration of thromboxane A2 (TxA2) analogues in nonpregnant (NP) rabbits [G. Losonczy, I. Mucha, J. DiPirro, J. Sweeney, G. Brown, J. Brentjens, and R. Venuto. Am. J. Physiol. 265 (Regulatory Integrative Comp. Physiol. 34): R772-R780, 1993] could be avoided if the compounds were given instead into the aortic arch. Conscious New Zealand White rabbits received bolus injections of U-46619 (5-20 micrograms) through a previously implanted catheter threaded into the aortic arch. Indeed, mean arterial pressure (MAP) rose modestly, and thrombocytopenia did not develop. Next, we compared the blood pressure responses of pregnant (P) rabbits with those of NP rabbits to intra-aortic U-46619 and I-BOP, because they had been found to be resistant to both the hypotensive and platelet aggregatory effects of intracaval U-46619. Resting blood pressure was lower in P than in NP rabbits (74 +/- 3 vs. 95 +/- 2 mmHg), but showed a greater increase in response to U-46619. For example, following a 20-micrograms dose blood pressure rose 20 +/- 0.3 mmHg in P vs. 12 +/- 2.1 mmHg in NP rabbits (P < 0.02). Similar results were obtained with the second TxA2 analogue I-BOP. Pregnancy-induced enhancement of blood pressure elevation may be the consequence of peripheral vasoconstriction, which was not seen in NP rabbits. Thus the actions of TxA2 analogues U-46619 and I-BOP are markedly influenced by the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Effects of Trolox C and SIN-1 on arachidonic acid metabolism and on cyclic GMP formation in leukocytes.

The effects of Trolox C (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a vitamin E analogue, (60-900 microM) and SIN-1 (3-morpholino sydnonimine), a nitric oxide donor, (30-3000 microM) on arachidonic acid metabolism and on cyclic GMP formation in calcium ionophore A23187 (calcimycin)-stimulated human polymorphonuclear leukocytes were investigated. Trolox C elicited a dose dependent decrease in leukotriene B4 levels and increase in prostaglandin E2 levels but did not affect cyclic GMP levels. SIN-1 dose dependently inhibited leukotriene B4 and stimulated prostaglandin E2 and cyclic GMP formation. Dibutyryl cyclic GMP did not affect the formation of leukotriene B4 and prostaglandin E2. Trolox C (180 microM), which itself had no effect on cyclic GMP levels, enhanced the effect of SIN-1 (100 microM) on cyclic GMP levels more than 5-fold. The effects of SIN-1 on arachidonic acid metabolism seem to be independent of cyclic GMP and are probably due to nitric oxide. In this experimental model both Trolox C and SIN-1 have similar actions on the prostaglandin/leukotriene ratio, and Trolox C potentiates the SIN-1-induced increase in cyclic GMP levels.

Antioxidants↗
PubMed1994

Selective solid-phase extraction of urinary 2,3-dinor-6-ketoprostaglandin F1 alpha for determination with radioimmunoassay.

This paper describes a method for selective two-step solid-phase extraction of urinary 2,3-dinor-6-ketoprostaglandin F1 alpha for reliable determination with radioimmunoassay. In the immunoreactivity profile of non-selectively extracted urine after HPLC separation, over 90% of the total 2,3-dinor-6-ketoprostaglandin F1 alpha immunoreactivity consisted of interfering material coeluting with 6-ketoprostaglandin F1 alpha and 2,3-dinor-6-ketoprostaglandin F1 alpha. Among the alkyl silica sorbents studied (methyl, butyl, octyl, and octadecyl), an efficient separation of 2,3-dinor-6-ketoprostaglandin F1 alpha from 6-ketoprostaglandin F1 alpha and the lowest immunoreactive concentration of analyte were achieved in extraction on the methyl silica sorbent by elution of 2,3-dinor-6-ketoprostaglandin F1 alpha with chloroform: hexane (85:15, v/v) from the cartridge. The proportion of specific immunoreactivity could be further increased by two-step extraction of sample on methyl silica cartridges, first at pH 3 and then at pH 10 using diethyl ether:hexane (85:15, v/v) and chloroform as eluent, respectively. After this, a high correlation was found with concentrations of samples determined by radioimmunoassay using three different antisera. A significant correlation of values was also observed between samples measured by radioimmunoassay and those measured by GC-MS. The values of 12-h excretion of 2,3-dinor-6-ketoprostaglandin F1 alpha in eight volunteers (268 +/- 204 ng/g creatinine, mean +/- SD) as well as the inhibitory effect of acetylsalicylic acid (74 +/- 12%) are in accordance with those reported in the literature. This selective extraction procedure provides a high validity in radioimmunoassay without requiring subsequent TLC or HPLC purification.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Nicotine and cotinine modulate eicosanoid production in human leukocytes and platelet rich plasma.

We investigated the effects of nicotine and cotinine (0.5 nM-0.5 mM) on prostaglandin E2 and leukotriene B4 production in human polymorphonuclear leukocytes and on thromboxane B2 formation in human platelet-rich plasma, stimulated by calcium ionophore A23187. Nicotine and cotinine dose-dependently increased prostaglandin E2 synthesis in polymorphonuclear leukocytes from 25% (0.5 nM) up to nearly four-fold (0.5 mM). In concentrations found in the plasma of smokers, nicotine and cotinine increased prostaglandin E2 production by 33% (50 nM) and 50% (500 nM), respectively. Nicotine and cotinine equipotentially reduced both leukotriene B4 production in polymorphonuclear leukocytes and thromboxane B2 production in platelet rich plasma, the inhibition increasing from 20% (0.5 nM) to 60% (0.5 mM). The stimulation of prostaglandin E2 and inhibition of leukotriene B4 and thromboxane B2 production by nicotine and cotinine may due to the pyridine moiety that these compounds have in common.

Blood Platelets↗
PubMed1993

Modulation of arachidonic acid metabolism by phenols: relation to positions of hydroxyl groups and peroxyl radical scavenging properties.

We have shown earlier that catecholamines have opposite regulative effects on prostaglandin (PG)E2 and leukotriene (LT)B4 formation with a receptor-independent mechanism in human polymorphonuclear leukocytes (PMNs) and whole blood. To shed further light on the mechanisms involved and structure-action relationship, we tested the effects of phenols (catechol, hydroquinone, phenol, and resorcinol) on the synthesis of PGE2 and LTB4 in human A23187-stimulated PMNs. To study the mechanism of how phenols influence PGE2 and LTB4 synthesis, their peroxyl radical-scavenging properties were analyzed. In general, low concentrations of phenols stimulated (catechol > hydroquinone >> phenol) and high concentrations inhibited (resorcinol > catechol > hydroquinone > phenol) PGE2 formation. Resorcinol was different from the other phenols: It did not stimulate PGE2 synthesis at all, but it was effective inhibitor at high concentrations. Phenols had only an inhibitory effect on LTB4 formation (catechol = hydroquinone >> phenol > resorcinol). The order of both stochiometric factors and reactivities of phenols for scavenging peroxyl radicals was catechol > hydroquinone > resorcinol >> phenol. According to these results, phenols having hydroxyl groups in ortho- or paraposition have the greatest stimulative effect on PGE2 synthesis, the highest inhibitory action on LTB4 synthesis, and are good antioxidants. Resorcinol, having hydroxyl groups in the metaposition, behaves differently. It neither stimulates PGE2 nor inhibits LTB4 formation, but it is the most potent inhibitor of PGE2 formation. In spite of resorcinol's two hydroxyl groups, it mimics as an antioxidant phenol more than catechol and hydroquinone.

Antioxidants↗
PubMed1993

The effect of pregnancy on the response to the TxA2/PGH2 analogue U-46619 in rabbits.

We compared the hemodynamic actions of U-46619, a stable thromboxane A2 (TxA2) prostaglandin H2 (PGH2) analogue, in nonpregnant (NP) rabbits with those observed in late pregnant (P) rabbits. An intravenous injection of U-46619 (10 micrograms) to each of eight NP chronically instrumented rabbits (mean body weight 3.4 kg) induced an immediate (1 min) and reversible fall of cardiac output (CO, 66%) and mean arterial pressure (MAP, 41%, both P < 0.01). P rabbits (n = 6, mean body weight 3.8 kg), however, responded with an elevation of MAP (5%, P < 0.02) upon intravenous injection of the drug (10 micrograms), while CO remained unchanged. The fall of CO in NP rabbits was associated with the temporary disappearance of a fraction of circulating platelets between the superior vena cava and the aortic arch. The number of platelets at 30 and 60 s after U-46619 was reduced (P < 0.05) by 14 and 20% respectively in the aortic blood, whereas caval platelet counts were unchanged until 90 s (-6%, P < 0.05). In contrast, intraaortic administration of this drug (10 micrograms) to NP rabbits resulted in neither thrombocytopenia nor hypotension. U-46619 (10-30 micrograms i.v.) caused no decrease in platelet count in the aorta of P rabbits. In vitro, U-46619-induced aggregation of platelets harvested from P rabbits was also blunted (P < 0.001). This could not be attributed to reduced affinity or number of platelet thromboxane receptors. The data indicate that U-46619 induces a fall of arterial pressure simultaneous with intravascular platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Solid-phase extraction of urinary 11-dehydrothromboxane B2 for reliable determination with radioimmunoassay.

In this paper we elaborate a one-step procedure for the selective extraction of urinary 11-dehydrothromboxane B2 on octylsilyl silica cartridges for reliable determination with radioimmunoassay. The immunoreactivity profile of nonselectively extracted urine after HPLC separation showed that as much as 70% of the total 11-dehydrothromboxane B2 immunoreactivity comigrates with polar interfering material. Its amount could be considerably decreased using acetonitrile:water (18:82, v/v) as wash solvent before elution of 11-dehydrothromboxane B2 from the cartridge. Alternatively, very high immunoreactive purity was achieved without the preceding wash step by selective elution of the analyte with dichloromethane:hexane (70:30). After both optimized steps in the extraction procedure were combined, immunoreactivity was found only in HPLC fractions corresponding to the retention volume of authentic 11-dehydrothromboxane B2. The homogeneity of this immunoreactivity was confirmed by two-step HPLC separation. A significant correlation of values was observed between samples measured after extraction and those measured after subsequent HPLC purification. A high correlation was also found with concentrations determined by radioimmunoassay using four different antisera. The values of 24 h excretion of 11-dehydrothromboxane B2 in 10 male volunteers (595 +/- 114 ng/g creatinine, mean +/- SD) as well as the inhibitory effect of acetylsalicylic acid (80 +/- 13%) closely correspond with those reported in the literature. This selective extraction procedure provides a high validity in radioimmunoassay without requiring any further purification step.

Chromatography, High Pressure Liquid↗
PubMed1992

Adrenaline stimulates thromboxane and inhibits leukotriene synthesis in man.

Catecholamines and other catecholic compounds have opposite effects on the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism in human polymorphonuclear leukocytes and whole blood in vitro. The hypothesis that high levels of adrenaline, found e.g. in myocardial infarction, are involved in the regulation of arachidonic acid metabolism was tested. Adrenaline (0.1 micrograms/kg per min for 45 min and thereafter 0.2 micrograms/kg per min for 15 min) was infused to healthy male volunteers to mimic relationships between high levels of adrenaline and arachidonic acid metabolism in myocardial infarction. Adrenaline infusion increased Ca ionophore A23187-induced TXB2 formation in whole blood. The effect was smaller when spontaneous clotting was used as a stimulus. Urinary 11-dehydro-TXB2 excretion, an indicator of total in vivo thromboxane synthesis, increased twofold. Adrenaline infusion decreased both LTB4 and LTE4 synthesis in A23187-stimulated whole blood. These results demonstrate that high levels of adrenaline influence the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism differentially in man.

Adult↗
PubMed1991

Catecholamines decrease leukotriene B4 and increase thromboxane B2 synthesis in A23187-stimulated human whole blood.

Catecholamines (adrenaline, dopamine, isoprenaline, noradrenaline) and caffeic acid (catecholic compound without adrenergic receptor activity) decreased leukotriene (LT)B4 synthesis in A23187-stimulated human whole blood. Salbutamol, a non-catecholic beta 2-adrenergic agonist, did not influence LTB4 synthesis. Catecholamines stimulated thromboxane (TX)B2 synthesis with a concomitant inhibition of LTB4 synthesis; caffeic acid and salbutamol did not stimulate TXB2 synthesis. These results, obtained in A23187-stimulated whole blood, which also takes into account the complex interaction between different cell types, are similar to our previous results with polymorphonuclear leukocytes. Catecholamines show an opposite effect on lipoxygenase and cyclooxygenase pathways, which may give rise to a marked change in LT/TX ratio in physiological or pathological conditions where sufficient concentrations of catecholamines are present.

Calcimycin↗
PubMed1991

Factors affecting the reliability of direct radioimmunoassay for urinary 11-dehydrothromboxane B2 with 125I-labelled ligand: albumin and heterogeneous immunoreactivity.

The determination of 11-dehydrothromboxane B2 (11-dehydro-TXB2) from unextracted human urine was studied by means of a specific radioimmunoassay based on the use of the 125I-labelled tyrosine methyl ester derivative of 11-dehydro-TXB2 as radioligand. The assay was evaluated in various incubation media by either dextran-coated charcoal (DCC) or polyethylene glycol (PEG) separation. Both the non-specific and the specific binding showed high variation in different assay media with DCC separation but with the use of PEG separation, however, the non-specific binding was constant. The verification tests carried out in both separation systems revealed a high variation of equilibrium with the individual samples. The albumin content of urine is proposed to be one important factor underlying poor reliability of direct radioimmunoassay. Both the immunoreactivity profiles observed after HPLC separation and the apparent 11-dehydro-TXB2-like immunoreactivity values determined by direct radioimmunoassay demonstrated that the unextracted urine contained a high ratio of interfering materials. It is concluded that efficient purification of human urine before determination is essential when this type of 125I-labelled radioligand is employed in radioimmunoassay.

Albumins↗
PubMed1990

Prostaglandin E2 and gestational hypotension in rabbits.

Arterial levels of 13,14-dihydro-15-keto-PGE2 (PGE2-M), a stable metabolite of prostaglandin E2 (PGE2) were compared between unanesthetized pregnant (n = 12) and nonpregnant (n = 8) rabbits with the aim of elucidating the role PGE2 in the development of physiological hypotension associated with pregnancy. On the 20th and 22nd days of the 30 day gestation period the mean arterial concentrations of PGE2-M were about 10-times higher (p less than 0.05) and largely variable as compared to that of nonpregnant rabbits. Mean arterial pressure was not lower on either the 20th (69 +/- 4 mmHg, mean +/- SD) or the 22nd (70 +/- 3 mmHg) days of gestation (dg) than in nonpregnant rabbits (69 +/- 4 and 73 +/- 6 mmHg, respectively). On the 23rd dg hypotension was invariably present (61 +/- 5 mmHg vs 72 +/- 4 in nonpregnants, p less than 0.001), but arterial levels of PGE2-M (31.0 +/- 31.6 ng/ml) did not overcome those measured on earlier, normotensive days of gestation. Hypotension was also evident in a subgroup of pregnant rabbits (n = 4) with low PGE2-M concentrations in the nonpregnant range (3.2 +/- 1.5 ng/ml vs 1.9 +/- 1.2 in nonpregnant rabbits, ns). Since the arterial level of PGE2-M proved to correlate (p less than 0.001) with both the uteroplacental venous and renal venous PGE2 concentrations, we suggest that a key role of uteroplacental and renal PGE2 played in the development of gestational hypotension is not probable in rabbits.

Animals↗
PubMed1990

Changes of arterial prostaglandin E2 during haemodialysis.

The absence of a reduction in peripheral vascular resistance secondary to hypervolaemia leads to so-called volume hypertension. In order to study whether a deficient formation of the vasodilator autacoid prostaglandin E2 (PGE2) contributes to the preservation of inadequate vascular tone during extracellular volume expansion, arterial plasma PGE2 and the stable PGE2 metabolite 13,14-dihydro-15-keto-PGE2 (PGE2-M) were determined in 13 oligoanuric women on chronic haemodialysis. Prior to treatment eight of them had hypervolaemia and hypertension (mean arterial pressure (MAP) 128 +/- 3 mmHg (mean +/- SE] and five patients had hypervolaemia of a similar degree but were not hypertensive (MAP: 99 +/- 4 mmHg P less than 0.005). Before haemodialysis the arterial PGE2 and PGE2-M concentrations were less (P less than 0.05) in hypertensive (11 observations in eight patients) than in normotensive patients (ten observations in five patients). As blood pressure decreased during the course of haemodialysis of volume hypertensive patients, the concentration of PGE2 and PGE2-M increased (P less than 0.02) by 104 +/- 43% and 89 +/- 32%, respectively. In normotensive patients neither blood pressure nor the concentration of PGE2 and PGE2-M were found to change during treatment. Since volume hypertension was associated with reduced values and dialysis induced normalisation of blood pressure with increased arterial values of PGE2 and PGE2-M, we hypothesise that the development of hypertension associated with fluid overload of haemodialysed patients may be related to a decreased release of prostaglandin E2.

Adolescent↗
PubMed1989

Changes of prostacyclin and thromboxane synthesis in the course of mouse liver perfusion. Stimulated thromboxane A2 synthesis of freshly prepared isolated mouse hepatocytes.

The formation of prostacyclin and thromboxane A2 (measured as 6-keto PGF1 alpha and TXB2 by radioimmunoassay) was investigated during a 30 min perfusion of mouse liver in a recirculation system. After cannulation of the portal vein an immediate increase of de novo synthesis and secretion of PGI2 occurred followed by a sharp decrease. Increased PGI2 synthesis was also followed by a continuous increase of TXA2 synthesis and secretion reaching a maximum at the end of the 30 min perfusion. Elevated TXA2 synthesis was also shown in freshly isolated hepatocytes investigated in the course of a 20 min incubation period immediately after the perfusion. However, the elevated TXA2 formation was not observed when it was measured after a 120 min preincubation of the cells. Both PGI2 and TXA2 production could be provoked to a similar extent by the addition of arachidonate and A 23187 immediately after the perfusion or after a 120 min preincubation.

6-Ketoprostaglandin F1 alpha↗