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Pharmacological modulation of schultz-dale anaphylactic response of guinea-pig lung parenchymal strip
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EFFECTS OF SOME CALCIUM ANTAGONISTS ON PASSIVE CUTANEOUS ANAPHYLAXIS IN THE RAT F. Hertz, M. Ranson, F.V. DeFeudis and R. Deghenghi U.P.S.A., ]28 rue Danton, 92506 Rueil-Halmaison, France The effects of three Ca2+-antagonists (diltiazem, verapamil and D-600) were compared with those of several agents that are used in the treatment of asthma (disodium-cromoglycate, theophylline, clemastine, hydrocortisone, and isoproterenol). Using a type I (IgE-dependent) passive cutaneous anaphylactic reaction (PCA) in the rat, dose-dependent inhibition of the allergic response was evident with verapamil and diltiazem, as well as with theophylline, clemastine and hydrocortisone. In this test, isoproterenol and disodium-cromoglycate were active, and their respective EDs0s were 4.1 mg/kg (i.p.) and 2.4 mg/kg (i.v.) However, D-600 was too toxic for determination of its effect. Since results obtained with anti-H l agents and hydrocortisone were similar co those obtained with verapamil and diltiazem in this PCA test, evidence is provided for a possible usefulness of Ca2+-antagon ists in the treatment of asthma in man.
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PIIARMACOLOGICAL MODULATIONOF SCHULTZ-DALEANAPHYLACTICRESPONSEOF GUINEA-PIG LUNG PARENCHYMALSTRIP. Naresh Chand*, Departmente de'Anatomie et Physiologie Animals, Facult~ de M(dicine Vet~rnaire, Universit~ de Montreal, Saint-Hyacinthe, Quebec, Canada, J2S 7C6. Isolated guinea-pig lung parenchymal strips (LPS) react with concentration dependent contractile responses to histamine, carbachol, 5-HT, PGFpaand bradykinin. LPS obtained from ovalbumin (OA)-sensitized guinea-pigs also contracted~to antigen (OA) (Schultz-Dale p~eno~ enon). Pyrilamine, a selective Hi-receptor antagonist, strongly antagonized histamineinduced responses, and attenuated antigen-induced responses only in high concentrations. Metiamide, an H2-receptor antagonist, potentiated contractile responses to histamine as well as to antigen suggesting a n~dulatory role of H2-receptors in allergic responses in guinea-pig lung. Indo~thacin (a cyclo-oxygenase inh(bitor) enhanced responses to antigen as well as to histamine probably by diverting arachidonic acid metabolism via lipoxygen~e pathway(s). Anaphylactic responses, resistant to pyrilamine, atropine, ~thysergide and indomethacin were inhibited by compound FPL 55712, a SRS-A (Leukotriene) receptor antagonist. These findings strongly suggest that the products of lipoxygenase pathways, i.e. SRS-A (leukotrienes) play a major role in the mediation of allergic responses in the eripheral airways of guinea-pigs. "Current address: Wallace Laboratories, Div. of Carter-Wallace, Inc., Cranbury,NJ 08512)
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IgE RECEPTOR AND CYCLIC AMP (cAMP) IN MAST CELL ACTIVATION CoM. Winslow, Ph.D. and KoF. Austen, M.D. Harvard Medical School, Boston, MA 02115 USA Bridging of IgE-receptors by binding of divalent or multivalent antigen, or anti-lgE, to adjacent IgE molecules, or direct binding of anti-lgE-receptor antibody to the IgE receptor, results in membrane perturbation, cell activation and release of granule mediators. Within 15 sec. of coupled activation and secretion there occurs a transient monophaslc rise in cAMP (100-150% over baseline)° Pharmacologic manipulation of adenylate cyclase, using adenocine analogues which either inhibit or potentiate IgE receptor-agonlst-linked acclvatlon of adenylate cyclase, results in either an inhibition or an increase in secretion of mediators, which correlates with an attenuation or increase in the monophaslc rise in cAMP, and an attenuation or no change in the extent of acclvation (20-30%) of the two isoenzymes of cAMP-dependent protein kinase (cAPK)o Phosphodlesterase inhlbltors also inhibit mediator release and IgE-receptor perturbation in the presence of methylxanchines results in a rise in cAMP of 300-500% over baseline, as well as increased activation (50-100%) of both cAPK isoenzymes. Thus, prolonged elevatlon of cAMP and extensive activation of the protein kinases may have an antagonistic effect on mediator release, whereas transient elevation of cAMP and activation of cAPK in the range of 20-30% has an agonist function in mediator release. Possible sites of cAPK regulation of mast cell function will be discussed.
EFFECTS OF SOME CALCIUM ANTAGONISTS ON PASSIVE CUTANEOUS ANAPHYLAXIS IN THE RAT F. Hertz, M. Ranson, F.V. DeFeudis and R. Deghenghi U.P.S.A., ]28 rue Danton, 92506 Rueil-Halmaison, France The effects of three Ca2+-antagonists (diltiazem, verapamil and D-600) were compared with those of several agents that are used in the treatment of asthma (disodium-cromoglycate, theophylline, clemastine, hydrocortisone, and isoproterenol). Using a type I (IgE-dependent) passive cutaneous anaphylactic reaction (PCA) in the rat, dose-dependent inhibition of the allergic response was evident with verapamil and diltiazem, as well as with theophylline, clemastine and hydrocortisone. In this test, isoproterenol and disodium-cromoglycate were active, and their respective EDs0s were 4.1 mg/kg (i.p.) and 2.4 mg/kg (i.v.) However, D-600 was too toxic for determination of its effect. Since results obtained with anti-H l agents and hydrocortisone were similar co those obtained with verapamil and diltiazem in this PCA test, evidence is provided for a possible usefulness of Ca2+-antagon ists in the treatment of asthma in man.
41
PIIARMACOLOGICAL MODULATIONOF SCHULTZ-DALEANAPHYLACTICRESPONSEOF GUINEA-PIG LUNG PARENCHYMALSTRIP. Naresh Chand*, Departmente de'Anatomie et Physiologie Animals, Facult~ de M(dicine Vet~rnaire, Universit~ de Montreal, Saint-Hyacinthe, Quebec, Canada, J2S 7C6. Isolated guinea-pig lung parenchymal strips (LPS) react with concentration dependent contractile responses to histamine, carbachol, 5-HT, PGFpaand bradykinin. LPS obtained from ovalbumin (OA)-sensitized guinea-pigs also contracted~to antigen (OA) (Schultz-Dale p~eno~ enon). Pyrilamine, a selective Hi-receptor antagonist, strongly antagonized histamineinduced responses, and attenuated antigen-induced responses only in high concentrations. Metiamide, an H2-receptor antagonist, potentiated contractile responses to histamine as well as to antigen suggesting a n~dulatory role of H2-receptors in allergic responses in guinea-pig lung. Indo~thacin (a cyclo-oxygenase inh(bitor) enhanced responses to antigen as well as to histamine probably by diverting arachidonic acid metabolism via lipoxygen~e pathway(s). Anaphylactic responses, resistant to pyrilamine, atropine, ~thysergide and indomethacin were inhibited by compound FPL 55712, a SRS-A (Leukotriene) receptor antagonist. These findings strongly suggest that the products of lipoxygenase pathways, i.e. SRS-A (leukotrienes) play a major role in the mediation of allergic responses in the eripheral airways of guinea-pigs. "Current address: Wallace Laboratories, Div. of Carter-Wallace, Inc., Cranbury,NJ 08512)
~
42
IgE RECEPTOR AND CYCLIC AMP (cAMP) IN MAST CELL ACTIVATION CoM. Winslow, Ph.D. and KoF. Austen, M.D. Harvard Medical School, Boston, MA 02115 USA Bridging of IgE-receptors by binding of divalent or multivalent antigen, or anti-lgE, to adjacent IgE molecules, or direct binding of anti-lgE-receptor antibody to the IgE receptor, results in membrane perturbation, cell activation and release of granule mediators. Within 15 sec. of coupled activation and secretion there occurs a transient monophaslc rise in cAMP (100-150% over baseline)° Pharmacologic manipulation of adenylate cyclase, using adenocine analogues which either inhibit or potentiate IgE receptor-agonlst-linked acclvatlon of adenylate cyclase, results in either an inhibition or an increase in secretion of mediators, which correlates with an attenuation or increase in the monophaslc rise in cAMP, and an attenuation or no change in the extent of acclvation (20-30%) of the two isoenzymes of cAMP-dependent protein kinase (cAPK)o Phosphodlesterase inhlbltors also inhibit mediator release and IgE-receptor perturbation in the presence of methylxanchines results in a rise in cAMP of 300-500% over baseline, as well as increased activation (50-100%) of both cAPK isoenzymes. Thus, prolonged elevatlon of cAMP and extensive activation of the protein kinases may have an antagonistic effect on mediator release, whereas transient elevation of cAMP and activation of cAPK in the range of 20-30% has an agonist function in mediator release. Possible sites of cAPK regulation of mast cell function will be discussed.