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Biomedical subjects

B A Peskar

Publications and source records attributed to B A Peskar.

At least 19 recordsLinked to original sources
PubMed1992

13,14-Dihydro-prostaglandin E1 decreases low-density lipoprotein influx into rabbit aorta.

The effect of 4-week daily administration of 13,14-dihydro-prostaglandin E1 (13,14-DH-PGE1; 2 micrograms/kg) on LDL influx into the rabbit aortic wall was examined versus the effect of the same dose of PGE1 and sham-treatment in 108 male animals fed an 1% cholesterol supplemented diet. Treatment was started after de-endothelialization of the abdominal aorta with a Fogarty catheter. After the 1-month treatment period the animals were injected with 10 microCi 125I-low-density lipoprotein (LDL; 0.5 mg protein/ml). Uptake of the radiolabelled LDL was measured in morphologically verified endothelialized, re-endothelialized and de-endothelialized abdominal aortic segments. The LDL influx into the aorta was significantly (P less than 0.001) lower in 13,14-DH-PGE1- and PGE1-treated rabbits than in the controls. This reduction was most pronounced in re- and de-endothelialized segments. No significant difference between effect of PGE1 and of its biologically active derivative, 13,14-DH-PGE1, on arterial LDL entry was found. These data demonstrate a comparable beneficial effect of 13,14-DH-PGE1 and PGE1 on vascular wall lipid metabolism by decreasing LDL entry into the aortic wall in vivo.

Alprostadil↗
PubMed1992

Release of endothelin in the oleic acid-induced respiratory distress syndrome in rats.

Rats injected intravenously with oleic acid developed pulmonary edema leading to hypoxia and hypercarbia. These changes were accompanied by an increase in immunoreactive endothelin (ir-ET) in plasma as early as 15 min after injection. At 45 min after injection plasma levels peaked at 114 +/- 19 pg/ml plasma (n = 8) and reached basal levels again after 240 min. In contrast, much larger amounts of ir-ET were found in the bronchoalveolar lavage fluid, with a peak at 120 min (2878 +/- 258 pg/lung, n = 7) preceding the maximum hypoxia observed at 180 min. In both plasma and bronchoalveolar lavage fluid samples ir-ET was characterized by reverse-phase HPLC as a mixture consisting mainly of ET-1 and smaller amounts of big ET-1, ET-2 and ET-3. In light of the biological effects of ET, the data suggest that these peptides might be of pathophysiological significance in this model of adult respiratory distress syndrome.

Animals↗
PubMed1992

Effect of 3-morpholinosydnonimine (SIN-1), NG-nitro-L-arginine (NNA) and NG-monomethyl-L-arginine (NMMA) on isolated anaphylactic guinea-pig hearts.

In isolated perfused ovalbumin-sensitized guinea-pig hearts modulating effects of nitric oxide (NO) on cardiac function and eicosanoid release were investigated. While the NO-donor SIN-1 exhibited a protective effect during cardiac anaphylaxis, inhibition of NO biosynthesis by NNA or NMMA aggravated anaphylactic changes of cardiac functions. Exogenous and endogenous NO seems to functionally antagonize the effects of vasoconstrictor mediators released during the anaphylactic reaction. In addition, inhibition of cysteinyl-leukotriene (cys-LT) release could contribute to the protective effect of SIN-1 observed.

Anaphylaxis↗
PubMed1992

Release of eicosanoids and endothelin in an experimental model of adult respiratory distress syndrome.

In an experimental model of adult respiratory distress syndrome (ARDS) we have investigated the release of several vasoactive mediators since the rapid and severe increase in pulmonary arterial pressure is known to be a key feature in this condition. Intravenous injection of oleic acid (OA) into rats resulted in the development of a syndrome similar to ARDS characterized by severe hypoxia. As early as 15 min after OA injection elevated levels of 11-deoxy-15-keto-13,14-dihydro-11,16-cyclo-prostaglandin (PG) E2 (DKH2-cyclo-PGE2) as an indicator of endogenous PGE2 formation could be observed. Similarly, elevated levels of cysteinyl-leukotrienes (LT), determined as immunoreactive (ir) LTE4, and ir-endothelin (ET) could be detected. These mediators were found to be elevated in plasma samples for at least 3 h. In addition, rather large amounts of ir-ET could be detected in bronchoalveolar lavage (BAL) fluid samples between 1 h and 3 h. Thus, it seems possible that cysteinyl-LT and peptides of the ET family, both known for their vasoactivity, might be involved in the pathophysiological process of ARDS.

Animals↗
PubMed1992

Effect of 3-morpholinosydnonimine (SIN-1) and NG-nitro-L-arginine (NNA) on isolated perfused anaphylactic guinea-pig hearts.

The modulating effects of exogenous and endogenous nitric oxide (NO) on the cardiac anaphylactic reaction and eicosanoid release were investigated in isolated perfused sensitized guinea-pig hearts using 3-morpholinosydnonimine (SIN-1), the active metabolite of molsidomine, as NO-donor and NG-nitro-L-arginine (NNA) as an inhibitor of NO biosynthesis. Infusion of SIN-1 (final concentrations in the perfusates 0.3 or 1.0 mmol/l) elevated coronary flow under basal conditions as well as during cardiac anaphylaxis, while NNA (0.1 mmol/l) decreased basal coronary flow and aggravated the anaphylactic coronary constriction. Both drugs did not modify the characteristic biphasic profile of the coronary constriction after antigen challenge with an initial more severe phase followed by a less pronounced long-lasting flow reduction. Neither SIN-1 nor NNA affected spontaneous heart rate. However, while NNA tended to prolong the duration of antigen-induced arrhythmias, SIN-1 (1 mmol/l) had an inhibitory effect. This protection might be related to the increased coronary flow in the presence of SIN-1. SIN-1 inhibited anaphylactic release of cysteinyl-leukotrienes (LT) and 6-keto-prostaglandin (PG) F1 alpha, but did not influence thromboxane (TX) B2 release. On the other hand, NNA (0.1 mmol/l) inhibited anaphylactic release of TXB2, but had only marginal effects on the release of cysteinyl-LT and 6-keto-PGF1 alpha. The results suggest that exogenous and endogenous NO functionally antagonize the effects of vasoconstrictor mediators released after antigen challenge. Additional effects of high concentrations of SIN-1 and NNA on antigen-induced eicosanoid release could modulate the vascular actions of these drugs during cardiac anaphylaxis.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Effect of prostaglandin E2 and 3-morpholinosydnonimine (SIN-1) on arachidonic acid metabolism in fMLP-stimulated rat neutrophils and on thrombin-induced human platelet aggregation.

The effects of prostaglandin (PG) E2 and the nitric oxide (NO) donor SIN-1 on leukotriene (LT) release from formyl-methionyl-leucyl-phenylalanine (fMLP) (100 nM)-stimulated rat peritoneal neutrophils (RPN) and on thrombin-induced aggregation of washed human platelets were investigated. Both PGE2 (1-100 nM) and SIN-1 (30-300 microM) inhibited release of LTB4 and cysteinyl-LT from RPN in a concentration-dependent manner. The combined effects of PGE2 and SIN-1 were not greater than expected by summation. On the other hand, the inhibitory effect of SIN-1 (0.5 or 1.0 microM) on platelet aggregation was potentiated by PGE2 (0.3-5 microM) in a concentration-dependent manner, while PGE2 alone in the concentrations used had only marginal effects. The results suggest differential regulation of platelet and leukocyte functions by the mediators PGE2 and NO, which could be relevant for various physiological and pathophysiological conditions.

Animals↗
PubMed1992

Synergism between PGE1-metabolites(13,14-dihydro-prostaglandin E1, 15-keto prostaglandin E1, 15-keto-13,14-dihydro-prostaglandin E1) and nitric oxide (NO) on platelet aggregation.

A synergistic antiplatelet effect between prostaglandins (PG), cAMP-stimulators and nitric oxide (NO), a cGMP-stimulator, has already been described. Data on a synergism between NO and the metabolites of PGE1, however, are lacking so far. We therefore tested the antiplatelet activity of the metabolites of PGE1 alone and their synergism with NO on human platelets of 8 healthy volunteers in vitro. 13,14-DH-PGE1 (ID 50 = 10.8 ng/ml platelet rich plasma (PRP)) was the only PGE1 metabolite inhibiting the ADP-induced platelet aggregation, its efficacy being 76.4% of the parent compound PGE1 (ID 50 = 8.25 ng/ml PRP). NO (ID 50 = 0.52 microM) also inhibited platelet aggregation. The combined addition of 13,14-dihydro-prostaglandin E1 (13,14-DH-PGE1) and NO caused an additive effect. The other PGE1-metabolites tested, 15-keto prostaglandin (15-K-PGE1) (ID 50 = 16.2. micrograms/ml PRP) and 15-keto-13,14-dihydro-prostaglandin(15-K-13,14-DH-PGE1) (ID 50 = 14.8 micrograms/ml PRP), neither had any relevant antiaggregatory capacity themselves nor a synergistic effect with NO. These findings could be of clinical relevance as a NO-synergism may occur not only with therapeutically administered PGE1 but also with its biologically active metabolite 13,14-DH-PGE1.

Adult↗
PubMed1991

Aspirin-like drugs, ethanol-induced rat gastric injury and mucosal eicosanoid release.

The effect of oral administration of various non-steroidal antiinflammatory drugs on ethanol-induced rat gastric injury and mucosal release of leukotriene C4, 6-keto-prostaglandin F1 alpha and 15-hydroxy-5,8,11,13-eicosatetraenoic acid was investigated. It was found that besides sodium salicylate and high doses of aspirin, other salicylate-type drugs, such as diflunisal, 4-aminosalicylic acid, 2,4-dihydroxybenzoic acid and methyl salicylate, and several non-acidic compounds, such as proquazone, benzydamine and paracetamol, were gastroprotective. All these drugs inhibited ex vivo leukotriene C4 formation by ethanol-stimulated gastric mucosa. However, naproxen, lonazolac, ibuprofen, gentisic acid and 5-aminosalicylic acid also inhibited leukotriene C4 formation, but were not protective. Gastroprotection was independent of 6-keto-prostaglandin F1 alpha formation. Both protective and non-protective drugs inhibited the ethanol-stimulated, but not the basal, release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid. The results indicate that the differential effects of various non-steroidal antiinflammatory drugs on gastroprotection against ethanol are not correlated with specific effects on mucosal cyclooxygenase, 5-lipoxygenase or 15-lipoxygenase activity.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition.

Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.

Animals↗
PubMed1991

Effect of platelet-activating factor on porcine pulmonary blood vessels in vitro.

Platelet-activating factor (PAF) induced contractions of porcine pulmonary vein strips in a concentration-dependent manner, while porcine pulmonary artery strips were unresponsive. Exposure to the specific PAF-antagonists WEB 2086 or BN 52021 antagonized the contractile responses of pulmonary vein strips. Cysteinyl-leukotrienes (LT) and thromboxane (TX) B2 were not detected in the bath fluid after stimulation with PAF suggesting that these eicosanoids as well as their precursors are not mediators of PAF-induced contractions of porcine pulmonary vein strips. Furthermore, PAF had no significant effect on 6-keto-prostaglandin (PG) F1a release and flurbiprofen did not affect the PAF response, while it inhibited the release of 6-keto-PGF1a. This indicates that PGI2 or any other cyclooxygenase product is unlikely to modulate or mediate the PAF response. Incubation experiments with fragments of pulmonary vascular tissues demonstrated spontaneous release of small amounts of cysteinyl-LT, TXB2 and 6-keto-PGF1a, which was significantly increased during incubation in the presence of ionophore A23187. While these results demonstrate the synthesizing capacity of the porcine pulmonary vascular tissues for various eicosanoids, PAF failed to stimulate eicosanoid release under these experimental conditions. We conclude that PAF causes contractions of porcine pulmonary vein strips, which are not mediated by cysteinyl-LT or cyclooxygenase products of arachidonate metabolism. The specific contractile effect of PAF on pulmonary veins, but not arteries, could contribute to the disturbances of the pulmonary circulation observed after injection of PAF or release of endogenous PAF, e.g. after administration of endotoxin.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid and cysteinyl-leukotrienes in carrageenin-induced inflammation: effect of non-steroidal anti-inflammatory drugs.

Inflammatory exudates obtained in rats after subcutaneous implantation of carrageenin-soaked sponges were found to contain relatively large amounts of 15-hydroxy-5,8,11, 13-eicosatetraenoic acid (15-HETE) and smaller amounts of cysteinyl-leukotrienes (LT) in addition to LTB4, thromboxane (TX) B2 and prostaglandin (PG)E2. Concentrations of 15-HETE and cysteinyl-LT were high 5 hours after sponge implantation and decreased significantly within 24 hours. This time-course, which is similar to that of TXB2, but differs from that of PGE2, suggests migrating leukocytes as a major source of 15-HETE and cysteinyl-LT. Aspirin, sodium salicylate, dipyrone (100 mg/kg each) and indomethacin (2 and 20 mg/kg) decrease the concentrations of cyclooxygenase products of arachidonate metabolism, but did not significantly affect levels of 15-HETE. Cysteinyl-LT were increased by 20 mg/kg indomethacin, but remained unaffected by 2 mg/kg indomethacin and by the other non-steroidal anti-inflammatory drugs (NSAID) tested. 15-HETE and cysteinyl-LT could play a mediator role in inflammation. In addition, they could modulate the release and effects of other inflammatory mediators.

Animals↗
PubMed1991

Effects of pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on eicosanoid release from various rat organs ex vivo.

The effects of oral treatment of rats with pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on ex vivo release of eicosanoids from gastric mucosa, jejunum, lung, brain and clotting whole blood were investigated. With the S(+) enantiomer and the racemate dose-dependent inhibition of release of cyclooxygenase products of arachidonate metabolism in all tissues tested was observed, while release of leukotriene (LT) C4 was inhibited in gastric mucosa, but not in jejunum and lung. On the other hand, the R(-) enantiomer inhibited cyclooxygenase in the various tissues less potently and to a variable degree with no significant effect in the jejunum. The R(-) enantiomer had no effect on LTC4 release from any of the tissues investigated. Furthermore, the effect of a high dose of 25 mg/kg of the S(+) enantiomer on release of cyclooxygenase products from the various tissues was much longer lasting than that of an identical dose of the R(-) enantiomer. Stereoselective pharmacokinetics of the flurbiprofen enantiomers and/or organ specific cyclooxygenase activities could underly these results. The more potent cyclooxygenase inhibition by the S(+) enantiomer correlates with its higher anti-inflammatory activity and gastrointestinal toxicity. On the other hand, both enantiomers have been shown previously to be almost equally effective analgesics. Inhibition of brain cyclooxygenase might contribute to this effect.

Animals↗
PubMed1991

Formation of 13,14-dihydro-prostaglandin E1 during intravenous infusions of prostaglandin E1 in patients with peripheral arterial occlusive disease.

Formation of 13,14-dihydro-prostaglandin (PG) E1 during intravenous infusions of PGE1 in patients with peripheral arterial occlusive disease was investigated. Using both high performance liquid chromatography (h.p.l.c.) combined with radioimmunoassay and gas chromatography/triple stage quadrupole mass spectrometry (GC/MS/MS) basal levels of 13,14-dihydro-PGE1 were found to be close to or below the detection limits of the assay methods. Levels of the PGE1 metabolite increased significantly during the infusion periods and decreased after their end. Since 13,14-dihydro-PGE1, in contrast to its precursors 15-keto-PGE1 and 15-keto-13,14-dihydro-PGE1, is biologically active, its formation could contribute to the beneficial effects of PGE1 administered intravenously in patients with peripheral arterial occlusive disease.

Alprostadil↗
PubMed1991

Thiopental and ether anaesthesia decrease the prostaglandin receptor density of the rat liver.

Male Sprague-Dawley rats were killed either by decapitation or during anaesthesia with thiopental or diethylether by aortectomy. Livers were removed and liver plasma membranes were prepared using standard techniques. Direct binding experiments with 3H-PGE1 and 3H-iloprost revealed heterogeneity of the binding sites (high and low affinity binding sites), whereas 3H-PGE2 demonstrated only high affinity binding to the liver. The highest binding capacity for all radioligands was found for livers after decapitation. Livers obtained during anaesthesia showed a significantly (p less than 0.05 to p less than 0.001) lower binding capacity and binding affinity for 3H-PGE1, 3H-PGE2 and 3H-iloprost. The reduction in binding activity was more pronounced in livers obtained during inhalation than thiopental anaesthesia. Specific binding amounted to 82.1 +/- 7% for 3H-PGE2, 75.3 +/- 9% for 3H-PGE1 and 78.9 +/- 8% for iloprost in livers obtained after decapitation. In livers obtained during anaesthesia specific prostaglandin binding was significantly (p less than 0.01) decreased, again being more pronounced during inhalation than thiopental anaesthesia. These results suggest that some anaesthetics interfere with prostaglandin receptors of the liver.

Alprostadil↗
PubMed1991

Effect of carbenoxolone on the biological activity of nitric oxide: relation to gastroprotection.

1. The interactions between carbenoxolone and nitric oxide (NO) were examined by investigating their effects on human platelet aggregation, on rat aortic strips precontracted by phenylephrine and on protection of rat gastric mucosa against ethanol-induced injury. 2. Carbenoxolone (100-300 microM) caused a significant and concentration-dependent potentiation of rat peritoneal neutrophil (RPN)- 3-morpholino-syndnonimine (SIN-1)- or iloprost-induced inhibition of platelet aggregation. Higher concentrations (500 microM) of carbenoxolone alone markedly inhibited platelet aggregation. Pretreatment with carbenoxolone (100-300 microM) antagonized the reversal of the RPN- or SIN-1-induced antiaggregatory effect by oxyhaemoglobin (10 microM). 3. Rat aortic strips with intact endothelium precontracted by phenylephrine (0.1-0.3 microM) were relaxed by carbenoxolone (100-300 microM) in a concentration-dependent manner. Relaxations were abolished by mechanical removal of the endothelium or by incubation with methylene blue (10 microM) or NG-nitro-L-arginine (L-NNA, 100 microM). Sodium nitroprusside (10 nM)-induced relaxations of endothelium-denuded rat aortic strips were potentiated by carbenoxolone (100 microM). . The carbenoxolone (200 mg kg-1, p.o.)-induced gastroprotection against ethanol was antagonized by L-NNA (5-40 mg kg-1) in a dose-dependent manner. Pretreatment of rats with indomethacin (10 mg kg-1, s.c.) increased the effect of L-NNA. 5. The results suggest that the activity of carbenoxolone in the experimental systems tested is due to phosphodiesterase inhibition, although radical scavenging properties of the drug could contribute to some of the effects observed. In the rat gastric mucosa both increased prostaglandin levels and effects on the NO system could contribute to the protective action of carbenoxolone.

Animals↗
PubMed1991

Role of peptidergic sensory neurons in gastric mucosal blood flow and protection.

The present findings have revealed a new aspect of how mechanisms of gastric mucosal resistance to injury are called into effect and are coordinated by the nervous system. Capsaicin-sensitive sensory neurons in the stomach play a physiological role in monitoring acid influx into the superficial mucosa. Once activated, they strengthen gastric mucosal defense against deep injury, with a key process in this respect being an increase in blood flow through the gastric mucosa. This concept opens up completely new perspectives in the physiology and pathophysiology of the gastric mucosa if we consider that the long-term integrity of the gastric mucosa may be under the subtle control of acid-sensitive sensory neurons and that, vice versa, improper functioning of these neutral control mechanisms may predispose to gastric ulcer disease. The present observations also indicate that some of the peptides contained in gastric sensory nerve endings might fulfill a transmitter or mediator role in controlling gastric mucosal blood flow and integrity. Whereas substance P and neurokinin A are unlikely to play a role in the regulation of gastric mucosal blood flow, there is severalfold evidence that CGRP is very important in this respect. This peptide, which in the rat gastric mucosa originates exclusively from spinal sensory neurons, is released upon stimulation of sensory nerve endings and is extremely potent in facilitating gastric mucosal blood flow and in protecting the mucosa from injurious factors. Selective ablation of spinal sensory neurons containing CGRP weakens the resistance of the gastric mucosa against acid injury, which is most likely due to inhibition of protective vasodilator reflexes. We now aim at providing direct pharmacological evidence that antagonism of endogenously released CGRP results in similar pathophysiological consequences as ablation of capsaicin-sensitive sensory neurons.

Animals↗