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Biomedical subjects

B A Peskar

Publications and source records attributed to B A Peskar.

At least 109 records · Page 6Linked to original sources
PubMed1988

Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance.

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacological activities. Actively sensitized guinea pigs were used to examine the broncholytic effect of azelastine in vivo. Furthermore, the influence of azelastine on the production of arachidonic acid (AA) metabolites was investigated in vitro and compared to the effects of nordihydroguaiaretic acid (NDGA), indomethacin and ketotifen. In vivo, azelastine protected actively sensitized guinea-pigs against ovalbumin-induced bronchospasm with an ID50 of 0.08 mg/kg orally. Ketotifen was similarly active (ID50 = 0.05 mg/kg). Antigen-induced contraction of isolated tracheal rings of sensitized guinea-pigs was concentration-dependently inhibited by azelastine and NDGA with IC50-values of 94.1 and 34.2 mumol/l, respectively. Ketotifen exerted only weak inhibitory activity (18% at 100 mumol/l). The arachidonic acid-induced contraction of isolated guinea-pig tracheal rings was also inhibited both by azelastine (IC50 = 92.6 mumol/l) and NDGA (IC50 = 20.4 mumol/l). Ketotifen was inactive on this model. Antigen challenge of chopped lung tissue from sensitized guinea-pigs resulted in the release of cysteinyl-leukotrienes (LT) which were identified by reversed phase high pressure liquid chromatography (HPLC) as LTD4 and LTE4. The release of cysteinyl-LT from sensitized guinea-pig lung tissue induced by antigen challenge was concentration-dependently inhibited by azelastine (IC50 = 35.2 mumol/l) and NDGA (IC50 = 8.4 mumol/l) but not by ketotifen and indomethacin. By contrast, indomethacin caused a pronounced augmentation of cysteinyl-LT release. The concentration of indomethacin, which augmented cysteinyl-LT release by 50% was 0.19 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Acid infusion elicits thromboxane A2-mediated effects on respiration and pulmonary hemodynamics in the cat.

We have recently reported that infusion of stoichiometrically equal quantities of acid and base (neutral acid-base infusion) in the cat resulted in rapid, shallow breathing and in pulmonary hypertension (Orr et al., 1987). To investigate the mechanisms involved in these effects, we have measured in the anesthetized cat thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha, the stable metabolites of TXA2 and PGI2, in blood as well as cardiorespiratory parameters in response to neutral acid-base infusion. The first acid-base infusion prompted right ventricular blood pressure (Prv) to rise from 30 to a peak of about 55 mm Hg, with a concomitant rise in the right ventricular TXB2 level from below detection level to over 500 pg/ml. The second or third infusion evoked no (or small) rises in Prv and TXB2, individual values of Prv and TXB2 being tightly correlated. After blockade of TX synthesis by Dazmegrel, no changes were observed even at the first acid-base infusion in either Prv or TXB2. The TXA2 mimetic, U 46,619, caused Prv to rise with no change in TXB2, and this effect was repeatable. Increases were also observed in ventilation, particularly in respiratory rate. We conclude that acid exposure of blood stimulates TX synthesis and release from platelets, which in turn leads to pulmonary hypertension and to hyperventilation. The fact that these effects cannot be repeated within the same animal is due to a lack in TX release but not to a loss of responsiveness of the TX receptors in the lung.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Effects of non-steroidal anti-inflammatory drugs on rat gastric mucosal leukotriene C4 and prostanoid release: relation to ethanol-induced injury.

1. The effects of oral and subcutaneous administration of the non-steroidal anti-inflammatory drugs sodium salicylate, aspirin and indomethacin on ex vivo gastric mucosal release of leukotriene C4 (LTC4) prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2) were investigated in rats under basal conditions as well as after challenge with ethanol. 2. Basal release of PGE2, 6-oxo-PGF1 alpha and TXB2 was inhibited by oral administration of aspirin (0.6-400 mgkg-1) and indomethacin (4 or 20 mgkg-1), but not by sodium salicylate (up to 400 mgkg-1), in a dose-dependent manner. Oral administration of aspirin in the dose range 3.2-400 mgkg-1 and of indomethacin (20 mgkg-1) additionally inhibited release of LTC4, while sodium salicylate (up to 400 mgkg-1) had no effect. Indomethacin (20 mgkg-1) and aspirin (400 mgkg-1) administered subcutaneously inhibited generation of cyclo-oxygenase products of arachidonate metabolism, but did not significantly affect LTC4 synthesis. 3. Oral instillation of ethanol caused gastric mucosal damage and simultaneously induced a selective increase in the ex vivo release of LTC4 from rat gastric mucosa, while release of cyclo-oxygenase products of arachidonate metabolism was not significantly affected. Oral pretreatment of rats with sodium salicylate protected the gastric mucosa and simultaneously inhibited the ethanol-stimulated gastric mucosal LTC4 release in a dose-dependent manner. Sodium salicylate had no effects on the release of PGE2 and TXB2, while that of 6-oxo-PGF1 alpha was slightly increased. 4. Pretreatment with indomethacin (4 or 20mg kg- p.o.) or aspirin in doses up to 25mg kg-1 p.o. prior to oral instillation of ethanol did not inhibit gastric mucosal damage and had no effect on the stimulatory action of ethanol on LTC4 release. Higher doses of aspirin (100mgkg-1 or 400mgkg-1 p.o.) reduced the mucosal damaging effect of ethanol and simultaneously inhibited LTC4 release. 5. The results suggest that aspirin and indomethacin in concentrations higher than those necessary to inhibit the cyclo-oxygenase pathway of arachidonate metabolism additionally inhibit gastric mucosal LTC4 synthesis under basal conditions, while sodium salicylate has no such effect. On the other hand, sodium salicylate, but not indomethacin or low doses of aspirin (up to 25mg kg 1), by an unknown mechanism inhibits stimulation of LTC4 biosynthesis by ethanol and simultaneously protects the gastric mucosa against ethanol-induced damage. Similar effects of high oral doses (> 100mgkg- 1) of aspirin might be due to significant formation of salicylate. These results suggest that there is a causal relationship between enhanced LTC4 biosynthesis and the development of ethanol-induced gastric injury.

Animals↗
PubMed1988

Quantitative determination of eicosanoids in biological material.

Radioimmunoassay is the most widely used method for determination of eicosanoids in biological material. Although this technique is, in principle, simple, radioimmunological data generally require extensive validation procedures. Here some examples for such methods are presented with special emphasis on the determination of cysteinyl-leukotrienes.

Animals↗
PubMed1988

Release of cysteinyl-leukotrienes is of minor importance in PAF induced reduction of perfusion rate in the gastric vascular bed.

In the isolated rat gastric vascular bed, PAF dosedependently decreased the perfusion rate and increased the formation of cysteinyl-leukotrienes, TXB2 and 6-keto F1 alpha (measured by radioimmunoassay). Inhibition of cysteinyl-leukotrienes biosynthesis by NDGA or antagonism of cysteinyl-leukotrienes receptors by FPL 55712 did not prevent the PAF induced reduction of gastric flow. Inhibition of cyclooxygenase by indomethacin aggravated the PFA-induced reduction of flow, however in the later period of experiment. BN 552021 - the PAF receptor antagonist, completely prevented the release of cysteinyl-leukotrienes, TXB2 and 6-keto F1 alpha into perfusate, however was not able to prevent completely the PAF induced reduction of gastric flow. We conclude that the reduction of flow observed after PAF administration seems to be related rather to the vasocongestion induced by PAF itself.

Animals↗
PubMed1987

Modulation of the contractile activity of the guinea-pig lung parenchymal strip by exogenous 5,8,11,14,17-eicosapentaenoic acid.

Exogenous eicosapentaenoic acid (EPA, 16.5 mumol/l or 33 mumol/l) inhibited dose-dependently the anaphylactic contractile response of guinea-pig lung parenchymal strips suspended in an organ bath. As determined by radioimmunoassay, EPA inhibited in a dose-dependent manner the anaphylactic release of the cyclooxygenase products thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha but simultaneously enhanced the release of sulfidopeptide (SP)-leukotrienes (LT). Indomethacin (2.8 mumol/l) abolished the release of cyclooxygenase products but potentiated the release of SP-LT. However, indomethacin treatment did not affect the inhibitory action of EPA on the contractile response of the anaphylactic lung strips. The lipoxygenase inhibitor, esculetin (50 mumol/l), inhibited the release of SP-LT and also that of cyclooxygenase products of polyunsaturated fatty acid metabolism. The combination of esculetin and EPA resulted in enhanced inhibition of the anaphylactic contractile response as compared to EPA alone. By reversed phase high pressure liquid chromatography (HPLC), SP-LT from anaphylactic lung parenchymal strips was shown to consist of LTD4 and LTE4. EPA-pretreated lung strips released upon immunologic challenge additional immunoreactivity comigrating with authentic LTC4, LTC5, LTD5 and LTE5. While anaphylactic control strips also released LTB4, in the bath fluid of EPA-treated strips, an additional immunoreactive compound migrating with the retention time of LTB5 was observed. In non-sensitized guinea-pig lung parenchymal strips EPA inhibited the myotropic activity of exogenous mediators such as histamine (9 mumol/l), LTC4 (16 nmol/l) and the TX mimetic U 46619 (28.4 nmol/l), an effect which was neither affected by indomethacin (2.8 mumol/l) nor by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 10 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

Formation of cysteinyl-containing leukotrienes by human arterial tissues.

Human arterial rings incubated in modified Tyrode solution released small amounts of leukotriene (LT) C4-like material spontaneously and larger amounts upon stimulation with the ionophore A23187 as determined by radioimmunoassay. By reversed phase high pressure liquid chromatography (HPLC) LTC4-like material was found to comigrate with authentic LTC4, LTD4 and LTE4. Nordihydroguaiaretic acid (NDGA) significantly inhibited the ionophore A23187-induced release of LTC4-like material, while indomethacin was without effect. Simultaneously the arterial rings released much larger amounts of 6-keto-prostaglandin (PG) F1 alpha, which were significantly decreased by indomethacin. The results demonstrate that human arterial tissue has the capacity to synthesize cysteinyl-containing LT from endogenous arachidonic acid.

Adult↗
PubMed1987

Prostacyclin synthesis stimulating plasma factor in patients with peripheral vascular disease.

Human plasma contains a factor capable of stimulating vascular prostacyclin generation even in atherosclerotic vessels with minimal in-vitro capacity for PGI2-synthesis. The activity of this prostacyclin stimulating plasma factor (PSPF) has been reported to be elevated in renal failure and hepatic coma. We are not aware of any data as to whether this PSPF plays a role in maintaining hemostatic balance in patients with peripheral vascular lesions. Therefore, we examined 62 patients with peripheral vascular disease (PVD). This study group was subdivided into normo- and hyperlipemic subjects, patients with and without maturity onset diabetes, and plasma beta-thromboglobulin levels higher and lower than 50 ng/ml. 10 healthy sex and age matched persons served as controls. Vascular prostacyclin formation was studied in vitro after incubation of the patients' plasma and a buffer control with various tissue samples (human femoral artery, rat abdominal and thoracic aorta of healthy and of streptozotocin induced diabetic animals, swine endothelial layer and remaining tissue (media and adventitia) and cultured endothelial (EC) and smooth muscle cells (SMC) of minipig arota. In addition, 6-oxo-PFG1 alpha formation by cultured EC and SMC (minipig aorta source) after incubation with tris HCl-buffer or plasma were estimated by means of specific radioimmunoassays. In general, tissue samples and cells incubated in plasma exhibit a marked increase of in-vitro PGI2-formation as compared to buffer. No difference could be found between PSPF of CHD-patients and healthy controls. Similar findings were obtained using incubated vascular tissue and cultured cells by means of the bioassay and specific RIA, respectively. These findings indicate that the PSPF does not seem to be of any clinical relevance in hemostatic regulation in patients with advanced atherosclerosis.

Adult↗
PubMed1987

Effect of exogenous 5,8,11,14,17-eicosapentaenoic acid on cardiac anaphylaxis.

The effects of infusions of eicosapentaenoic acid (EPA) (6 X 10(-8) mol min-1 and 15 X 10(-8) mol min-1) on the coronary constriction and the release of immunoreactive sulphidopeptide-leukotrienes (SP-LT), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) from perfused anaphylactic guinea-pig hearts were investigated. EPA dose-dependently inhibited the profound early coronary flow reduction after antigen injection. The less pronounced late phase of anaphylactic coronary flow reduction was, however, not significantly affected. EPA (15 X 10(-8) mol min-1) significantly shortened the average duration of antigen-induced arrhythmias. EPA dose-dependently decreased release of immunoreactive TXB2 and 6-keto-PGF1 alpha from anaphylactic guinea-pig hearts. Release of immunoreactive SP-LT was dose-dependently increased after antigen challenge in the presence of EPA. Inhibiton of the release of SP-LT by the lipoxygenase inhibitor esculetin (1 X 10(-7) mol min-1) was accompanied by a significant attenuation of flow reduction during the late phase of anaphylactic vasoconstriction. Reversed phase h.p.l.c. of perfusates from anaphylactic guinea-pig hearts revealed immunoreactivity comigrating with authentic leukotriene C4 (LTC4), LTD4, and LTE4. In perfusates from hearts treated with EPA infusions, additional immunoreactivity was detected comigrating with LTC5, LTD5 and LTE5. In addition to immunoreactivity migrating with LTB4, as observed in control heart perfusates, in perfusates from EPA-treated hearts, a second peak was observed, which coincides with the retention time described for LTB5. Exogenous LTC5 (1 X 10(-12) mol min-1 and 20 X 10(-12) mol min-1) induced dose-dependent reductions of coronary flow and was found to be a slightly weaker constrictor than LTC4, but no significant differences were observed. Coronary vasoconstriction elicited by infusion of exogenous LTC4 (20 X 10(-12) mol min-1) was dose-dependently inhibited by infusions of EPA. However, the negative inotropic effect of LTC4 remained unaffected. Thus, in the isolated anaphylactic heart of the guinea-pig exogenous EPA was effectively metabolized via the 5-lipoxygenase pathway whereas the cyclo-oxygenase pathway of polyunsaturated fatty acid metabolism was found to be inhibited. The results are in agreement with the suggestion that cyclo-oxygenase products are mediators of the early phase of the anaphylactic coronary constriction, while vasoconstrictor SP-LT are involved in the later phase. However, in spite of enhanced release of SP-LT, EPA infusion did not result in increased coronary constriction. Considering the fact that EPA antagonizes LTC4-induced coronary constriction, it seems possible, that EPA might act as a functional antagonist of vasoconstrictor eicosanoids including EPA-derived SP-LT.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Profiles of endogenous prostaglandin F2 alpha, thromboxane A2 and prostacyclin with regard to cardiovascular and organ functions in early septic shock in man.

15 out of 68 patients with severe sepsis were examined in an early stage of shock and analyzed for objective hemodynamic and functional shock criteria. These data were correlated to endogenous plasma concentrations of the vasoactive arachidonate derivatives: prostaglandin F2 alpha (PGF2 alpha), thromboxane A2 (TXA2) and prostacyclin (PGI2). Marked differences in invasively measured data of cardiac, pulmonary and renal functions divided clinically otherwise comparable patients into group I and II. Group I was characterized by a hypodynamic response as compared to group II which was hyperdynamic. In spite of similar levels of PGF2 alpha (570 +/- 80 vs. 560 +/- 103 pg/ml) in both groups indicating a comparable state of arachidonate turnover, opposing profiles with regard to the TXA2/PGI2 ratio as measured from their stable degradation products were found (TXB2 [I]: a 740 +/- 184; TXB2 [II]: 280 +/- 75; 6-k-PGF1 alpha [I]: 260 +/- 117; 6-k-PGF1 alpha [II]: 940 +/- 190 pg/ml). It is concluded that early sepsis in man leads to variable profiles of endogenously released prostaglandins and thromboxane in which the predominance of PGI2 over TXA2 is associated with better cardiovascular performance and organ functions, and vice versa.

Adolescent↗