Diabetes, dietary protein and glomerular hyperfiltration.
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These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs Homer A. Boushey, Professor of Medicine, and David G. Warnock, Associate Professor of Medicine, under the direction of Dr Lloyd H. Smith, Jr, Professor of Medicine and Associate Dean in the School of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA 94143. (+info)
Pharmacology of Schultz-Dale reaction in canine lung strip in vitro: possible model for allergic asthma.
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1 Isolated lung parenchymal strips of the dog contracted in response to histamine > carbachol > prostaglandin F(2alpha) (PGF(2alpha)) > bradykinin (Bk) > 5-hydroxytryptamine (5-HT). The order of the relative activity of these agents on the tracheobronchial smooth muscles (TBSM) was carbachol > 5-HT > histamine; PGF(2alpha) and Bk were inactive. Thus there are marked differences in the responsiveness of the smooth muscle of central (trachea and bronchus) and peripheral (lung strip) airways to autonomic and autacoid agents.2 Lung strips and TBSM partially contracted by carbachol, histamine or horse plasma, were relaxed by isoprenaline, PGE(1) and PGE(2).3 Lung strips from dogs sensitized to horse-plasma contracted in response to antigen (Schultz-Dale anaphylactic reaction). Tachyphylaxis or desensitization to subsequent antigen challenge was invariably observed; it was followed after 1 to 2 h of rest by partial recovery of the anaphylactic response.4 Mepyramine selectively antagonized responses to histamine without altering responses to carbachol and antigen.5 Metiamide, an H(2)-receptor antagonist, did not influence responses to histamine, carbachol or horse plasma.6 Indomethacin was found to be ineffective as an inhibitor of the Schultz-Dale anaphylactic reaction.7 The results showed the presence of H(1)-histamine receptors mediating constriction in the peripheral airways of the dog. Histamine and PGF(2alpha) appear to have no important role in the anaphylactic reaction in this tissue. The involvement of slow reacting substance of anaphylaxis (SRS-A) and endoperoxides (thromboxanes) in allergic reactions of canine lung is strongly suggested. (+info)
Comparative studies on immunologically and non-immunologically produced slow-reacting substances from man, guinea-pig and rat.
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1 Slow-reacting substance of anaphylaxis (SRS-A) was produced by antigen challenge of passively sensitized human lung and actively sensitized guinea-pig lung. 2 A slow-reacting substance (SRS) was prepared from the peritoneal fluid of rats treated with calcium ionophore A23187. 3 These substances were extensively purified by charcoal adsorption, Sephadex G-15 gel filtration, ether extraction and reverse phase high pressure liquid chromatography. 4 The three substances are pharmacologically, chemically and chromatographically indistinguishable. 5 Our data suggest that the same SRS entities are released from a variety of tissues and that these acidic lipids may have a wider physiological significance than just anaphylaxis. (+info)
Immunological release of histamine and slow reacting substance of anaphylaxis from human lung.
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The immunologic release of histamine and slow reacting substance of anaphylaxis (SRS-A) from human lung tissue can be enhanced by stimulation with either alpha adrenergic agents (phenylephrine or norepinephrine in the presence of propranolol) or cholinergic agents (acetylcholine or Carbachol). The finding that atropine prevents cholinergic but not comparable alpha adrenergic enhancement is consistent with the view that cholinergic and alpha adrenergic agonists interact with separate receptor sites on the target cells involved in the immunologic release of chemical mediators. The consistent qualitative relationship between the antigen-induced release of mediators and the level of cyclic adenosine monophosphate (cyclic AMP) as measured by the isolation of (14)C-labeled cyclic AMP after incorporation of adenine-(14)C into the tissues or by the cyclic AMP binding protein assay suggests that changes in the level of this cyclic nucleotide mediate adrenergic modulation of the release of histamine and SRS-A. The addition of 8-bromo-cyclic guanosine monophosphate (cyclic GMP) produces an enhancement of the immunologic release of mediators while dibutyryl cyclic AMP is inhibitory. As cholinergic-induced enhancement was not associated with a measurable change in the levels of cyclic AMP, the possibility is suggested that cyclic GMP may be the intracellular mediator of cholinergic-induced enhancement of the immunologic release of histamine and SRS-A. (+info)
Leukotriene C: a slow-reacting substance from murine mastocytoma cells.
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Murine mastocytoma cells treated with calcium ionophore A23187 produced a slow-reacting substance (SRS) that caused guinea pig ileum to contract. The response was reversed by the SRS antagonist FPL 55712. On the basis of isotope incorporation experiments, spectroscopy, and chemical degradations, the SRS was identified as a cysteine-containing derivative of 5-hydroxy-7,9,11,14-icosatetraenoic acid. This amino acid was attached in thioether linkage at C-6. The SRS is structurally related to previously identified epoxy and dihydroxy metabolites of arachidonic acid in leukocytes. A common feature is the presence of a conjugated triene, and the name "leukotriene" has been introduced to designate these compounds. Leukotriene A (5,6-epoxy-7,9,11,14-icosatetraenoic acid) is an intermediate in the formation of leukotriene B (5,12-dihydroxy-6,8,10,14-icosatetraenoic acid) and is proposed to be a precursor also of leukotriene C, which is the SRS identified here. (+info)
Inhibition by non-steroid anti-inflammatory agents of rabbit aorta contracting activity generated in blood by slow reacting substance C.
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1 A crude and a partially purified preparation of slow reacting substance C (SRS-C) as well as arachidonic acid decreased resistance to perfusion of the dog hind paw. This effect was suppressed by treatment with non-steroid anti-inflammatory drugs.2 Injections of SRS-C or of arachidonic acid induced marked and reproducible contractions of strips of rabbit aorta and a rat stomach which were bathed in blood from an anaesthetized dog. The effect on the rabbit aorta is attributed to formation of a rabbit aorta contracting substance (RCS). The contractions were suppressed when the dog was treated with a non-steroid anti-inflammatory drug.3 Incubation of blood or of platelet-rich plasma with SRS-C or arachidonic acid resulted in the formation of similar materials. This formation was suppressed by anti-inflammatory drugs.4 SRS-C, linoleic, linolenic, and arachidonic acids are suitable substrates for soybean lipoxidase for the generation of RCS.5 It is suggested that RCS and prostaglandin are formed within platelets, when SRS-C or arachidonic acid are injected into animals or added in vitro. Non-steroid anti-inflammatory drugs suppress these effects, possibly by inhibiting prostaglandin synthetase. (+info)
Antigen-induced release of slow reacting substance of anaphylaxis (SRS-A rat) in rats prepared with homologous antibody.
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The polymorphonuclear leukocyte appears to be an essential cellular prerequisite for the antigen-induced release of SRS-A(rat) in the peritoneal cavity of rats prepared with homologous, hyperimmune antisera. Depletion of PMN leukocytes is associated with a marked suppression of SRS-A(rat) release, whereas depletion of circulating lymphocytes or peritoneal mast cells does not influence the antigen-induced release of SRS-A(rat). A local increase in the number of PMN leukocytes produced by the induction of a peritoneal exudate was associated with an enhanced release of SRS-A(rat). A distinct difference in the cellular requirements for the antigen-induced release of histamine and SRS-A(rat) in the rat was observed. Homocytotropic antibody-mediated histamine release could be achieved in leukopenic rats but not in mast cell-depleted animals. Conversely, SRS-A(rat) release was suppressed in leukopenic rats but was unaffected by mast cell depletion. Diethylcarbamazine inhibited the antigen-induced release of SRS-A(rat) following preparation with homologous, hyperimmune antisera but did not interfere with homocytotropic antibody-mediated histamine release. In preventing SRS-A(rat) release, diethylcarbamazine did not interfere with antigen-antibody interaction since desensitization of tissues was possible in the presence of this inhibitor. This observation is consistent with the view that diethylcarbamazine inhibits the reaction sequence leading to the formation and release of SRS-A(rat) at some step subsequent to antigen-antibody interaction. These studies support the view that the immunologic pathways leading to the release of SRS-A(rat) and histamine in the rat are distinctly different in terms of the immunoglobulins involved, the cellular prerequisites, and the effective pharmacologic inhibitors. (+info)
Leukotriene D: a slow reacting substance from rat basophilic leukemia cells.
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A slow reacting substance produced by rat basophilic leukemia cells, treated with ionophore A23187, was characterized by spectroscopic methods, enzymatic conversions, and chemical degradations as 5-hydroxy-6-S-cysteinylglycyl 7,9,11,14-eicosatetraenoic acid (leukotriene D). gamma-Glutamyltranspeptidase [gamma-glutamyltransferase; (5-glutamyl)-peptide: amino-acid 5-glutamyltransferase, EC 2.3.2.2] converted leukotriene C to a product identical to leukotriene D. This suggests that the stereochemistry of the arachidonyl moiety of leukotrienes C and D is the same [5(S)-6(R)-7,9-trans-11,14-cis]. Leukotriene D induces a faster contraction and, on a molar basis, is more potent than leukotriene C in the isolated guinea pig ileum bioassay. (+info)