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Biomedical subjects

B A Peskar

Publications and source records attributed to B A Peskar.

At least 163 records · Page 9Linked to original sources
PubMed1984

Effects of exogenous prostaglandins on the release of leukotriene C4-like immunoreactivity and on coronary flow in indomethacin-treated anaphylactic guinea-pig hearts.

It is known that both vasoconstrictor cyclooxygenase products and sulfidopeptide-containing leukotrienes (LT) contribute to the biphasic coronary constriction observed in isolated perfused anaphylactic guinea-pig hearts. We have now investigated the effects of the cyclooxygenase inhibitor indomethacin and of several exogenous prostaglandins (PG) on the release of LTC4-like immunoreactivity and on various symptoms of cardiac anaphylaxis. Indomethacin decreased basal coronary flow and delayed the onset of coronary vasoconstriction after antigenic challenge. Furthermore, indomethacin inhibited cardiac release of 6-keto-PGF1 alpha and thromboxane (TX) B2 and simultaneously enhanced the antigen-induced release of LTC4-like immunoreactivity significantly. Neither the vasodilators PGE2 and PGI2 nor the vasoconstrictors PGF2 alpha, PGD2 and 11,9-epoxymethano-PGH2, a compound with biological properties similar to TXA2, affected the anaphylactic release of immunoreactive LTC4 in the presence of indomethacin. These results suggest that the indomethacin-induced increase in LT release is not due to inhibition of synthesis of a cyclooxygenase product, which normally curbs anaphylactic release of immunoreactive LTC4. The indomethacin effect may rather be explained by diversion of arachidonic acid metabolism away from fatty acid cyclooxygenase towards the synthesis of lipoxygenase products. Although the various PG did not significantly affect cardiac release of LTC4-like immunoreactivity, they antagonized the anaphylactic coronary constriction. This antagonism may be due to direct effects of the PG on vascular smooth muscle tone as well as to indirect effects on the release of anaphylactic mediators not related to LT like histamine and platelet-activating factor.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Effect of histamine, acetylcholine and compound 48/80 on bronchoconstriction and release of eicosanoids in the dog.

The effects of Hi and ACH aerosol and of intravenous infusion of compound 48/80 on bronchoconstriction and plasma levels of Hi, TXB2, KH2PGF2 alpha and KH2PGE2 were investigated in 11 bastard dogs. Administration of Hi and ACH aerosol induced bronchoconstriction accompanied by an increase in the plasma levels of Hi and TXB2. No effect on the plasma levels of KH2PGF2 alpha and KH2PGE2 was detected. Release of endogenous Hi by compound 48/80 induced bronchoconstriction and significant increases in the plasma levels of TXB2 as well as of KH2PGF2 alpha and KH2PGE2. The effects of a second administration of Hi and ACH aerosols after compound 48/80 did not differ qualitatively from the effects of the first aerosol administration. However, quantitatively, the second Hi aerosol induced significantly less bronchoconstriction and TXB2 release. Similarly, effects of the second ACH aerosol tended to be decreased as compared to the first ACH aerosol, although the difference was not significant. The diminished effect of the agonists could be due to receptor desensibilization and/or release of adrenaline, which in turn decreases bronchoconstriction and eicosanoid release.

Acetylcholine↗
PubMed1984

Pharmacological control of leukotriene and prostaglandin production from mouse peritoneal macrophages.

Leukotriene and prostaglandin production by mouse peritoneal macrophages was investigated. It could be shown that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate initiated the release of prostaglandin E2 but had little effect on the release of leukotriene C4-like immunoreactivity. The divalent cation ionophore A 23187 at concentrations between 10(-6) and 10(-8) mol/l initiated prostaglandin as well as leukotriene release. This prostaglandin and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs including benoxaprofen inhibited prostaglandin release but simultaneously enhanced leukotriene production. The analgesics paracetamol and 4-methylaminoantipyrine had similar effects at high concentrations. The experimental compound BW 755 c inhibited prostaglandin and leukotriene production while the antithrombotic compound nafazatrom inhibited the production of leukotriene C4-like immunoreactivity but enhanced prostaglandin E2 production. Nordihydroguaiaretic acid inhibited prostaglandin and leukotriene production. The results show that the metabolism of arachidonic acid in macrophages via the cyclooxygenase or the lipoxygenase pathway is dependent on the stimulus applied. Both pathways can be inhibited conjointly or selectively by drugs. Our results do not provide evidence that differences in anti-inflammatory activity claimed for some of the drugs tested can be explained by differential inhibition of either pathway. The experimental system described may be used for assessing the potency of drugs to inhibit the lipoxygenase and the cyclooxygenase pathway of arachidonic acid metabolism.

Analgesics↗
PubMed1984

Plasma levels of 15-keto-13,14-dihydro-prostaglandin E2 in patients with bronchogenic carcinoma.

Plasma levels of the circulating metabolite of prostaglandin (PG) E2, 15-keto-13,14-dihydro-PGE2 (KH2PGE2), were determined radioimmunologically after conversion to the stable degradation product 11-deoxy-15-keto-13,14-dihydro-11,16-cyclo-PGE2 (DKH2-cyclo-PGE2). In healthy volunteers a plasma level of 25 +/- 2 pg/ml (mean +/- S.E.M., n = 24) was found. The plasma level of KH2PGE2 was significantly decreased after administration of acetylsalicylic acid (4 x 1 g/24 hours). A significant elevation of the plasma levels of the circulating metabolite of PGE2 was observed in patients with bronchogenic carcinoma as compared to healthy controls, while no elevation was found in patients with chronic myeloid leukemia, lymphatic leukemia and non-Hodgkin lymphoma. The increased plasma levels of KH2PGE2 in the patients with bronchogenic carcinoma were independent of the clinical condition, histological type of tumor, tumor spread and therapeutic regimen. The results indicate that the elevated plasma level of the circulating PGE2 metabolite in patients with bronchogenic carcinoma is not an expression of malignant disease in general. On the other hand, the results do not suggest that the increase in the plasma level of KH2 PGE2 is a biochemical tumor marker closely related to a particular clinical feature of patients with bronchogenic carcinoma.

Adult↗
PubMed1984

Prostacyclin-synthesis-stimulating plasma factor in patients with different stages of hepatic coma.

In patients with acute hepatic coma the prostacyclin synthesis stimulating plasma factor is significantly enhanced. This increased activity has been verified by using various test systems. However, there is no correlation between the actual plasma factor activity and the coma stage, respectively. The increase of plasma factor activity in these patients might account at least in part for the increased bleeding tendency seen in these patients.

Adolescent↗
PubMed1984

[Influence of vagus nerve, histamine, prostaglandin and catecholamine on airway obstruction].

In three series of experiments, aerosols of acetylcholine, histamine, and Ascaris were administered in a maximal concentration before and after bilateral vagus transection. Vagotomy induced a clear reduction of the dynamic elastance increase by maintaining a constant breath volume. The persisting reaction of the dynamic elastance after vagotomy depends on the intensity of the reaction before vagus transection. Acetylcholine induced the largest reaction. Changes in epinephrine and norepinephrine were found to be variable, but an increase related to dynamic elastance increase could be assumed. Acetylcholine induced a maximal increase in thromboxane B2, and Ascaris induced preferentially a maximal increase in the prostaglandin F2 alpha metabolite 15-Keto-13, 14-dihydro-PGF2 alpha. Vagotomy showed no influence on changes of thromboxane B2, prostaglandin F2 alpha metabolite, or histamine in arterial plasma. The variability in changes of these metabolites may be the cause of the clinical differences in obstructive airway diseases.

Acetylcholine↗
PubMed1984

Formation of lipoxygenase and cyclooxygenase metabolites of arachidonic acid by brain tissue.

Rat brain slices released spontaneously and after challenge with A23187 LTC4-like radioimmunoactivity. Total cat brain ischemia followed by short postischemic reperfusion period resulted in the increased release of lipid peroxides and PGE2 but not in LTC4-like substance by brain slices. In lumbar cerebrospinal fluid of patients with completed stroke presence of LTC4-like material was observed.

Animals↗
PubMed1983

Release of slow-reacting substance of anaphylaxis and leukotriene C4-like immunoreactivity from guinea pig colonic tissue.

Colonic mucosa, muscularis propria and subserosa from ovalbumin-sensitized guinea pigs were incubated and challenged with antigen in vitro. Slow-reacting substance of anaphylaxis (SRS-A) was determined biologically as well as radioimmunologically in terms of leukotriene (LT) C4-like immunoreactivity. Before antigenic challenge release of immunoreactive LTC4 by all tissues was below or close to the detection limit of the radioimmunoassay. After addition of antigen colonic mucosa released considerable amounts of LTC4-like immunoreactivity, while muscularis propria and subserosa were less active. The biological activity of the SRS-A formed after challenge was antagonized by FPL 55712. Contrary to LTC4-like immunoreactivity release of 6-keto-prostaglandin (PG) F1 alpha was predominant in the subserosa and smaller amounts were released from the smooth muscular and mucosal layers. Synthesis of SRS-A and LTC4-like immunoreactivity, respectively, as well as synthesis of 6-keto-PGF1 alpha was inhibited by the dual inhibitor of lipoxygenase and cyclooxygenase BW755c. The results suggest a role for LTs as local mediators of inflammatory reactions in colonic disease states, particularly those with possible involvement of immunological processes.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1983

Release of slow-reacting substance of anaphylaxis from layers of guinea pig aorta.

Release of slow-reacting substance of anaphylaxis (SRS-A) from layers of ovalbumin-sensitized guinea pig aorta after antigenic challenge in vitro was investigated. SRS-A was determined by bioassay and in terms of leukotriene C4-like immunoreactivity using radioimmunoassay. While no SRS-A could be detected before challenge, the adventitia released considerable amounts of SRS-A after addition of antigen to the incubation medium. On the other hand, an inner layer of the aortic wall consisting of smooth muscle tissue with some adherent endothelium released only small amounts of SRS-A after challenge.

Animals↗
PubMed1983

Effect of inhibition of synthesis and receptor antagonism of SRS-A in cardiac anaphylaxis.

The effects of infusions of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 1.1 X 10(-7) mol min-1) and the antagonist of slow-reacting substance of anaphylaxis (SRS-A) FPL 55712 (1.2 X 10(-7) mol min-1) on the coronary constriction and the release of SRS-A, leukotreine C4-like immunoreactivity, thromboxane B2 and 6-keto-prostaglandin F1 alpha from perfused anaphylactic guinea-pig hearts were investigated. Both NDGA and FPL 55712 in the concentrations used induced an increase in basal coronary flow, but did not prevent the coronary flow reduction in the early phase (0-4 min) after antigen injection. On the other hand, NDGA and FPL 55712 inhibited the less pronounced long-lasting coronary flow reduction in the later phase of cardiac anaphylaxis. NDGA decreased the release of SRS-A from the anaphylactic guinea-pig hearts below or close to the detection limit of the bioassay and simultaneously diminished the release of leukotriene C4-like immunoreactivity. On the other hand, FPL 55712 did not influence the amounts of leukotriene C4-like immunoreactivity released in cardiac anaphylaxis. Neither NDGA nor FPL 55712 affected the release of immunoreactive thromboxane B2 (TXB2) from anaphylactic guinea-pig hearts. Release of 6-keto-prostaglandin F1 alpha after challenge, however, was decreased by NDGA, while FPL 55712 had no significant effect. These results suggest, that SRS-A may be a relatively more important mediator in the late phase of coronary constriction occurring during cardiac anaphylaxis, while the effects of other mediators, particularly vasoconstrictor cyclo-oxygenase products, seem to prevail in the early phase.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Release of leukotriene C4 from human polymorphonuclear leucocytes as determined by radioimmunoassay.

Rabbits were immunized with a conjugate of leukotriene (LT) C4 and bovine serum albumin prepared by coupling the single free amino group of the hapten to the protein using gluteraldehyde. Binding of [3H]LTC4 to the antibodies obtained is inhibited by 50% with 1.5 ng LTC4. The relative cross-reaction of LTD4 is 16% and of LTC4-methyl ester 3.6%. The validity of the radioimmunoassay was demonstrated by comparison with bioassay using the isolated guinea pig ileum. Using the radioimmunoassay it could be shown that endogenous LTC4 is released in a dose-dependent manner by human polymorphonuclear leucocytes stimulated with the divalent cation ionophore A23187.

Animals↗
PubMed1982

Evidence for a direct stimulatory effect of prostacyclin on renin release in man.

THE OBJECTIVES OF THIS INVESTIGATION WERE: (a) to characterize the time and dose dependence of the effects of prostacyclin (PGI(2)) on renin release in healthy men; (b) to define whether PGI(2)-induced renin release is secondary to hemodynamic changes; (c) to determine the plasma and urine concentrations of 6-keto-PGF(1alpha) (the stable breakdown product of PGI(2)) associated with renin release induced by exogenous or pharmacologically enhanced endogenous PGI(2). Intravenous PGI(2) or 6-keto-PGF(1alpha) infusions at nominal rates of 2.5, 5.0, 10.0, and 20.0 ng/kg per min were performed in each of six normal human subjects; in three of them, PGI(2) infusion was repeated after beta-adrenergic blockade and cyclooxygenase inhibition. PGI(2), but not 6-keto-PGF(1alpha), caused a time- and dose-dependent increase of plasma renin activity, which reached statistical significance at 5.0 ng/kg per min and was still significantly elevated 30 min after discontinuing the infusion. Although combined propranolol and indomethacin treatment significantly enhanced the hypotensive effects of infused PGI(2), it did not modify the dose-related pattern of PGI(2)-induced renin release. Plasma 6-keto-PGF(1alpha) levels rose from undetectable levels (<7.5 pg/ml) in a stepwise fashion during increasingly higher infusion rates of PGI(2) or 6-keto-PGF(1alpha). The threshold concentration of plasma 6-keto-PGF(1alpha) associated with a statistically significant stimulation of renin release was approximately 200 pg/ml. Upon discontinuing PGI(2) or 6-keto-PGF(1alpha) infusion, the disappearance of 6-keto-PGF(1alpha) from blood showed an identical biphasic behavior, the initial phase having an apparent t((1/2)) of 3.2 min. The intravenous infusion of furosemide, which is known to stimulate renin release via a cyclooxygenase-dependent mechanism, caused a three-to fourfold increase of urinary 6-keto-PGF(1alpha) excretion rate, concomitant with the elevation of plasma renin activity levels, in six healthy women. 6-Keto-PGF(1alpha) remained undetectable in peripheral venous plasma throughout the study. WE CONCLUDE THAT IN HUMAN SUBJECTS: (a) PGI(2)-induced renin release occurs with a dose and time dependence similar to its reported platelet effects; (b) PGI(2)-induced renin release is not mediated by adrenergic stimuli or cyclooxygenase-dependent mechanisms secondary to hemodynamic changes; (c) furosemide-induced renin release is associated with increased renal PGI(2) formation; and (d) PGI(2) appears to act as a local modulator rather than a circulating hormone in controlling juxtaglomerular function.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Control of arachidonic acid accumulation in bone marrow-derived macrophages by acyltransferases.

The turnover of phospholipid fatty acid moieties of bone marrow-derived macrophages was analyzed by separate determination of degrading and acylating activities. Acylating activities were followed in intact cells by incubation with excess arachidonic acid and degradation of phospholipids was followed in cells prelabeled with fatty acids. Significant phospholipase A2 activity was detectable only if the reutilization of liberated fatty acid was inhibited , e.g. by p-chloromercuribenzoate. It was of interest that the divalent cation ionophore A 23187 and various antiphlogistic drugs like indomethacin, diclofenac, and acetylsalicylic acid were found to inhibit the acylation reaction. These compounds led to increased levels of free arachidonic acid in stimulated, as well as in unstimulated cells. Increased activities of phospholipase A2 were achieved by treatment with the bivalent cation ionophore A 23187 and with zymosan. The effect of zymosan obtained from various sources was found to be exclusively due to contamination of tee zymosan particles with phospholipase A2 activity. Even when the cellular phospholipase activity was increased by the addition of exogenous phospholipase activity contained in the zymosan particles, degradation of cellular phospholipids was not measurable unless the reacylation was inhibited. These results suggest that in the cells studied, the level of free arachidonic acid is mainly controlled by the activity of the lysophosphatide acyltransferase.

Acyltransferases↗
PubMed1981

Inhibition of anti-inflammatory drugs of prostaglandin production in cultured macrophages.

1. A sensitive, simple, reproducible, and economical assay for structure-activity investigations of non-steroidal anti-inflammatory drugs (NSAID) is lacking. This has prompted us to investigate the advantages and limitations of defining for that purpose the potency of NSAID's as inhibitors of tumour promoter-induced prostaglandin (PG) release from mouse peritoneal macrophages in culture. 2. These cells release mainly PGE2 and PGI2 (measured as its stable hydrolysis product 6-keto-PGF1 alpha) upon stimulation with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). 3. The PG release was dose-dependently inhibited by a variety of NSAID's. Their inhibitory potency was dependent on the culture conditions employed. The widely used acidic NSAID's were more potent when assayed under serum free culture conditions at low pH. 4. Dose response curves for acidic NSAID tested under serum free conditions allowed for the definition of IC50 values being reproducible within their 95% confidence limits. 5. The IC50 values obtained for different standard acidic NSAID's varied within 4 orders of magnitude. They corresponded favourably to their clinical potency and their potency in a variety of standard tests for anti-inflammatory drugs. 6. IC50 values of five congeners of indomethacin differed up to 2 orders of magnitude in agreement with in vivo observations indicating the applicability of this assay for structure-activity investigations.

Animals↗
PubMed1981

Release of prostaglandins by small intestinal tissue of man and rat in vitro and the effect of endotoxin in the rat in vivo.

Rat jejunal tissue in vitro synthesizes large amounts of prostaglandin (PG) D2 and smaller amounts of 6-keto-PGF1 alpha and PGE2, whereas human small intestinal mucosa synthesizes much smaller amounts of the three PG determined with about equal amounts of PGE2 and PGD2. Intraperitoneal administration of bacterial endotoxin to rats induce fluid accumulation in the small intestine and increases significantly the release of PGD2, PGE2 and 6-keto-PGF1 alpha into the small intestinal lumen in vivo. Endotoxin-induced stimulation of PG release is particularly pronounced for PGD2. Fluid accumulation and PG output are inhibited by indomethacin. It seems possible that the different total amounts of PG synthesized by small intestinal tissue of man and rat as well as the different pattern of PG released might contribute to species-specific responses of the gastrointestinal tract to various pathophysiological stimuli.

Animals↗
PubMed1981

Increased plasma levels of 6-oxo-prostaglandin F1 alpha, a stable metabolite of prostacyclin, in acute kidney transplant rejection.

In 30 patients after kidney transplantation, 6-oxo-PGF1 alpha was examined in unextracted plasma by a specific radioimmunoassay. The material was divided into three groups. Patients with acute transplant rejection showing the highest 6-oxo-PGF1 alpha levels, patients with delayed transplant rejection having significantly lower plasma values and a third group of patients with stable transplant function. In these patients the plasma 6-oxo-PGF1 alpha-values were below the lower limit of detection (70 pg/ml). The enhanced 6-oxo-PGF1 alpha during rejection crisis could be interpreted as a self protection mechanism of vascular tissue which is, however, not sufficient in many cases, to prevent the irreversible rejection of the transplant.

6-Ketoprostaglandin F1 alpha↗