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M Hamberg

Publications and source records attributed to M Hamberg.

At least 163 records · Page 9Linked to original sources
PubMed1975

Prostaglandin d2 as a potential antithrombotic agent.

Prostaglandin D2 was found to be a potent inhibitor of platelet aggregation. Aggregation of human platelets by ADP, collagen and prostaglandin G2 was inhibited more strongly by PGD2 than by PGE1. Although ADP-induced aggregation of rabbit platelets was inhibited more strongly by PGE1 than by PGD2 the latter prostaglandin gave a more long-lasting inhibitory effect on platelet aggregation following intravenous or oral administration. These results coupled with the finding that PGD2 has less hypotensive effects on the cardiovascular system than PGE1 suggest the possible use of PGD2 as an antithrombotic agent.

Adenosine Diphosphate↗
PubMed1975

Increased concentrations of nonesterified arachidonic acid, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E2, and prostaglandin F2alpha in epidermis of psoriasis.

Lesional epidermis of psoriasis has a probable reduction in the cyclic AMP/cyclic GMP ratio. This altered ratio may in part be responsible for the characteristic glycogen storage, rapid cell proliferation, and reduced differentiation in lesional epidermis. The concentrations of prostaglandins E2 and F2alpha, free arachidonic acid, and 12L-hydroxy-5,8,10,14-eicosatetrawnoic acid in specimens of uninvolved and involved epidermis of psoriasis were measured with deuterium-labeled carriers and multiple ion analysis. Snap frozen specimens contained: 1.4 +/- 0.4 mug/g (wet weight) of arachidonic acid in uninvolved in contrast to 36.3 +/- 16.7 mug/g in involved epidermis (P = 0.015); less than 0.05 +/- 0.01 mug/g of hydroxyeicosatetraenoic acid in uninvolved in contrast to 4.1 +/- 1.9 mug/g in involved epidermis (P = 0.015); 23.6 +/- 5.0 ng/g of prostaglandin E2 in uninvolved in contrast to 33.1 +/- 5.7 ng/g in involved epidermis (P less than 0.01); and 21.0 +/- 4.4 ng/g of prostaglandin F2alpha in uninvolved in contrast to 39.0 +/- 5.9 ng/g in involved epidermis (P less than 0.01). The arachidonic acid and hydroxyeicosatetraenoic acid levels in involved epidermis were strongly correlated (r = 0.97). The increased levels of arachidonic acid and 12L-hydroxy-5,8,10,14-eicosatetraenoic acid in involved epidermis may have diagnostic and pathophysiological importance.

Arachidonic Acids↗
PubMed1975

Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclo-oxygenase deficiency.

The endoperoxide prostaglandin G2 (PGG2) induced platelet aggregation as well as the platelet release reaction (release of ADP and serotonin) when added to human platelet-rich plasma. Formation of a metabolite of PGG2 [8-(l-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid] and a lipoxygenase product [12L-hydroxy-5,8,10,14-eicosatetraenoic acid] accompanied the release reaction caused by aggregating agents such as collagen, ADP, epinephrine, and thrombin. Indomethacin inhibited the release reaction and PGG2 formation induced by these agents but had no effect on PGG2-induced release reaction. The aggregating effect of PGG2 was abolished by furosemide, which is a competitive inhibitor of ADP-induced primary aggregation. These data indicate that the aggregating effect of PGG2 is due to release of ADP and that PGG2 synthesis is required for induction of the release reaction by various aggregating agents. A subject with a hemostatic defect due to abnormal release mechanism [decreased aggregation with epinephrine (second wave) and collagen and normal platelet ADP] had a deficiency of the cyclo-oxygenase that catalyzes formation of PGG2. Normal aggregation and release reaction were obtained with added PGG2. Ii is concluded that the endoperoxide (PGG2) is essential in normal hemostasis because of its role in initiating the release reaction required for aggregation by collagen and the second wave of aggregation caused by, e.g., ADP.

Adenosine Diphosphate↗
PubMed1975

Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides.

An unstable [t1/2 at 37 degrees = 32 +/- 2 (SD) sec] intermediate, thromboxane A2, was detected in the conversion of prostaglandin G2 into 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid (thromboxane B2) in platelets. The intermediate was trapped by addition of methanol, ethanol, or sodium azide to suspensions of washed human platelets incubated for 30 sec with arachidonic acid or prostaglandin G2. The structures of the resulting derivatives demonstrated that the intermediate possessed an oxane ring as in thromboxane B2 but lacked its hemiacetal hydroxyl group. Additional experiments using 18O2 or [2H8]arachidonic acid in the formation of thromboxane B2 and CH3O2H for the trapping of thromboxane A2, together with information on the t1/2 of the intermediate, indicated the presence of an oxetane structure in thromboxane A2. Incubation of arachidonic acid or prostaglandin G2 with washed platelets led to formation of an unstable factor that induced irreversible platelet aggregation and caused release of [14C]serotonin from platelets that had been incubated with [14C]serotonin. The properties and the mode of formation of this factor indicated that it was identical with thromboxane A2. Furthermore, evidence is presented that the more unstable and major component of rabbit aorta contracting substance (RCS) formed in platelets and guinea pig lung is also thromboxane A2.

Arachidonic Acids↗
PubMed1975

Prostaglandin endoperoxides IX. Characterization of rabbit aorta contracting substance (RCS) from guinea pig lung and human platelets.

Material causing contraction of the isolated rabbit aorta (rabbit aorta contracting substance, RCS) was released from guinea pig lung following perfusion with arachidonic acid and from human blood platelets after addition of thrombin to induce aggregation. Prostaglandin endoperoxides (prostaglandins G2 and/or H2) were found both in the perfusate of guinea pig lung (1-3 ng/ml) and in the medium collected after platelet aggregation (13-37 ng/ml). The contractile response of the isolated rabbit aorta to the pure prostaglandins G2 and H2 was also determined. These data combined with the quantitative analyses of the endoperoxides released from the lungs and platelets showed that only a minor part of the rabbit aorta contracting activity was due to the prostaglandin endoperoxides. The major part of the activity consisted of very unstable material. The half life of this material was about 30 s at 37 degrees whereas at this temperature the prostaglandin endoperoxides had a half life of about 5 min.

Animals↗
PubMed1975

Prostaglandins.

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Adipose Tissue↗
PubMed1974

Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins.

Methods were developed for quantitative determination of the three major metabolites of arachidonic acid in human platelets, i.e., 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE), 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid (PHD). Aggregation of washed platelets by thrombin was accompanied by release of 1163-2175 ng/ml of HETE, 1129-2430 ng/ml of HHT, and 998-2299 ng/ml of PHD. The amount of PGG(2) (prostaglandin G(2)) produced as calculated from the sum of the amounts of its metabolites (HHT and PHD) was 2477-5480 ng/ml. In contrast, the amounts of PGE(2) (prostaglandin E(2)) and PGF(2alpha) (prostaglandin F(2alpha)) released were approximately two orders of magnitude lower. In this system, the prostaglandins thus exert their biological action through the endoperoxides, which are almost exclusively metabolized to nonprostanoate structures and only to a small extent to the classical prostaglandins. Platelets from subjects given aspirin produced less than 5% of the above mentioned amounts of HHT and PHD, whereas the production of HETE was stimulated about 3-fold. This provides additional evidence for our earlier proposal [Hamberg, M., Svensson, J., Wakabayashi, T. & Samuelsson, B. (1974) Proc. Nat. Acad. Sci. USA 71, 345-349] that the anti-aggregating effect of aspirin is through inhibition of PGG(2) formation.

Arachidonic Acids↗
PubMed1974

Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation.

Incubation for a short time of arachidonic acid with the microsomal fraction of a homogenate of the vesicular gland of sheep in the presence of 1 mM p-mercuribenzoate followed by extraction and silicic acid chromatography yielded two prostaglandin endoperoxides. The structures of these compounds, i.e., 15-hydroperoxy-9alpha,11alpha-peroxidoprosta-5,13-dienoic acid (prostaglandin G(2)) and 15-hydroxy-9alpha,11alpha-peroxidoprosta-5,13-dienoic acid (prostaglandin H(2)), were assigned mainly by a number of chemical transformations into previously known prostaglandins. The new prostaglandins were 50-200 times (prostaglandin G(2)) and 100-450 times (prostaglandin H(2)) more active than prostaglandin E(2) on the superfused aorta strip. The half-life of the prostaglandin endoperoxides in aqueous medium (about 5 min) was significantly longer than that of "rabbit aorta-contracting substance" released from guinea pig lung, indicating that none of the prostaglandin endoperoxides is identical with this factor. Addition of 10-300 ng/ml of the endoperoxides to suspensions of washed human platelets resulted in rapid aggregation. Furthermore, platelet aggregation induced by thrombin was accompanied by release of material reducible by stannous chloride into prostaglandin F(2alpha), thus indicating the involvement of endogenous prostaglandin endoperoxides in platelet aggregation.

Animals↗
PubMed1974

Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets.

Arachidonic acid incubated with human platelets was converted into three compounds, 12L-hydroxy-5,8,10,14-eicosatetraenoic acid, 12L-hydroxy-5,8,10-heptadecatrienoic acid, and the hemiacetal derivative of 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid. The formation of the two latter compounds from arachidonic acid proceeded by pathways involving the enzyme, fatty acid cyclo-oxygenase, in the initial step and with the prostaglandin endoperoxide, PGG(2), as an intermediate. The first mentioned compound was formed from 12L-hydroperoxy-5,8,10,14-eicosatetraenoic acid, which in turn was formed from arachidonic acid by the action of a novel lipoxygenase. Aspirin and indomethacin inhibited the fatty acid cyclo-oxygenase but not the lipoxygenase, whereas 5,8,11,14-eicosatetraynoic acid inhibited both enzymes. The almost exclusive transformation of the endoperoxide structure into non-prostaglandin derivatives supports the hypothesis that the endoperoxides can participate directly and not by way of the classical prostaglandins in regulation of cell functions. The observed transformations of arachidonic acid in platelets also explain the aggregating effect of this acid.

Arachidonic Acids↗
PubMed1973

Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis.

An earlier proposed endoperoxide intermediate in the biosynthesis of prostaglandins was detected in short-time incubations of arachidonic acid with the microsomal fraction of homogenates of sheep vesicular glands. Conversion of the endoperoxide into prostaglandin E(2) was stimulated by reduced glutathione but suppressed by p-mercuribenzoate and N-ethylmaleimide. The methyl ester of an unknown compound was isolated by solvent extraction and thin-layer chromatography after short-time incubation of arachidonic acid with the microsomal fraction and p-mercuribenzoate. This derivative was identical to the methylester of the endoperoxide, as shown by its conversion into the methyl esters of 11-dehydroprostaglandin F(2alpha) and prostaglandin E(2) by spontaneous rearrangement and its conversion into the methyl ester of prostaglandin F(2alpha) by mild chemical reduction. The smooth muscle-stimulating activity of the endoperoxide ester on the isolated rabbit aortas trip was 4- to 8-times higher than that of the methyl ester of prostaglandin E(2).

Animals↗