Annals of the New York Academy of SciencesVolume 744, Issue 1 p. 289-298 Preclinical Exploration of the Potential Antiinflammatory Properties of the Peptide Leukotriene Antagonist ICI 204,219 (Accola™) ROBERT D. KRELL, Corresponding Author ROBERT D. KRELL ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Current address: Biofor, Inc., P.O. Box 629, Waverly, Pennsylvania 18471.Search for more papers by this authorCHRISTOPHER J. DEHAAS, CHRISTOPHER J. DEHAAS ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorDAVID J. LENGEL, DAVID J. LENGEL ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorEDWARD J. KUSNER, EDWARD J. KUSNER ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorJOSEPH C. WILLIAMS, JOSEPH C. WILLIAMS ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorCARL K. BUCKNER, CARL K. BUCKNER ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this author ROBERT D. KRELL, Corresponding Author ROBERT D. KRELL ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Current address: Biofor, Inc., P.O. Box 629, Waverly, Pennsylvania 18471.Search for more papers by this authorCHRISTOPHER J. DEHAAS, CHRISTOPHER J. DEHAAS ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorDAVID J. LENGEL, DAVID J. LENGEL ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorEDWARD J. KUSNER, EDWARD J. KUSNER ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorJOSEPH C. WILLIAMS, JOSEPH C. WILLIAMS ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this authorCARL K. BUCKNER, CARL K. BUCKNER ZENECA Pharmaceuticals Group, Department of Pharmacology, Wilmington, Delaware 19897Search for more papers by this author First published: November 1994 https://doi.org/10.1111/j.1749-6632.1994.tb52746.xCitations: 19AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES 1 Murphy, R. C., S. Hammarstrom & B. Samuelsson. 1979. Leukotriene C: A slow reacting substance from murine mastocytoma cells. Proc. Natl. Acad. Sci. USA 76: 4275– 4279. 2 Krell, R. D., D. Aharony, C. K. Buckner, R. A. Keith, E. J. Kusner, D. W. Snyder, P. R. Bernstein, V. G. Matassa, Y. K. Yee, F. J. Brown, B. Hesp & R. E. Giles. 1990. The preclinical pharmacology of ICI 204,219: A peptide leukotriene antagonist. Am. Rev. Respir. Dis. 141: 978– 987. 3 Weichman, B. M., M. A. Wasserman, D. A. Holden, R. R. Osborn, D. F. Woodward, T. W. Ku & J. G. Gleason. 1983. Antagonism of the pulmonary effects of peptidoleukotrienes by a leukotriene D4 analog. J. Pharmacol. Exp. Ther. 227: 700– 705. 4 Mong, S., H.-L. Wu, J. Miller, R. F. Hall, I. G. Gleason & S. T. Cooke. 1987. SKF 104353, a high affinity antagonist for human and guinea pig lung leukotriene D4 receptor, blocked phosphatidylinositol metabolism and thromboxane synthesis induced by leukotriene D4. Mol. Pharmacol. 32: 223– 229. 5 Jones, T. R., R. Zamboni, M. Belley et al. 1989. Pharmacology of L-660,711 (MK571): A novel, potent and selective leukotriene D4 receptor antagonist. Can. J. Physiol. Pharmacol. 67: 17– 28. 6 McMillan, R. M., K. E. Spruce, G. C. Crawley, E. R. H. Walker & S. J. Foster. 1992. Preclinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase. Br. J. Pharmacol. 107: 1042– 1047. 7 Gillard, J., A. W. Ford-Hutchinson, C. Chan, S. Charleson, D. Denis, A. Foster, R. Fartin, S. Leger, C. S. McFarlane, H. MArtin, H. Prechuta, D. Riendeau, C. A. Rouzer, R. Young, D. E. MacIntyre, L. Peterson, T. Bach, G. Eirman, S. Hopple, J. Humes, L. Hope, S. Luell, J. Metzger, R. Meuer, D. K. Miller, E. Opas, S. Pacholok. 1989. L-663,556 (MK-886), a novel orally active leukotriene biosynthesis inhibitor. Can. J. Physiol. Pharmacol. 67: 456– 464. 8 Manning, P. J., R. M. Watson, D. J. Margolskee, V. C. Williams, J. I. Schwartz & P. M. O'Bryne. 1990. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4 receptor antagonist. N. Engl. J. Med. 323: 1736– 1739. 9 Israel, E., R. Dermarkarian, M. Rosenberg, R. Sperling, G. Taylor, P. Rubin & J. M. Drazen. 1990. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N. Engl. J. Med. 323: 1740– 1744. 10 Taylor, I. K., K. M. O'Shaughnessy, R. W. Fuller & C. T. Dollery. 1991. Effect of cysteinyl-leukotriene receptor antagonist ICI 204,219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet 337: 690– 694. 11 Finnerty, J. P., R. Wood-Baker, H. Thomson & S. T. Holgate. 1992. Role of leukotrienes in exercise-induced asthma: Inhibitory effect of ICI 204,219, apotent leukotriene D4 receptor antagonist. Am. Rev. Respir. Dis. 145: 746– 749. 12 Findlay, S. R., J. M. Barden, C. B. Easley & M. Glass. 1992. Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma. J. Allergy Clin. Immmol. 89: 1040– 1045. 13 Makker, H. K., L. C. Lau, H. W. Thomson, S. M. Binks & S. T. Holgate. 1993. The protective effect of inhaled leukotriene D4 receptor antagonist ICI 204,219 against exercise-induced asthma. Am. Rev. Respir. Dis. 147: 1413– 1418. 14 O'Shaughnessy, K. M., I. K. Taylor, B. O'Connor, F. O'Connell, H. Thomson & C. T. Dollery. 1993. Potent leukotriene D4 receptor antagonist ICI 204,219 given by the inhaled route inhibits the early but not the late phase of allergen-induced bronchoconstriction. Am. Rev. Respir. Dis. 147: 1431– 1435. 15 Friedman, B. S., E. H. Bel, A. Buntinx, W. Tanaka, Y.-H. R. Han, S. Shingo, R. Spector & P. Sterk. 1993. Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am. Rev. Respir. Dis. 147: 839– 844. 16 Christie, P. E., B. W. Spur & T. H. Lee. 1991. The effect of inhalation of the leukotriene receptor antagonist, SK&F 104353, on leukotriene C4- and leukotriene E4-induced bronchoconstriction in subjects with asthma. J. Allergy Clin. Immunol. 88: 193– 198. 17 Chan, C.-C., K. McKee, P. Tagari, P. Chee & A. Ford-Hutchinson. 1990. Eosinophileicosanoid interactions: Inhibition of eosinophil chemotaxis in vivo by an LTD4 receptor antagonist. Eur. J. Pharmacol. 191: 273– 280. 18 Chan, C. C. & A. Foster. 1991. Peptide leukotriene involvement in pulmonary eosinophil migration upon antigen challenge in the actively sensitized guinea pig. Int. Arch. Allergy Appl. Immunol. 96: 279– 284. 19 Laitinen, L. A., A. Laitinen, T. Haahtela, V. Vilkka, B. W. Spur & T. H. Lee. 1993. Leukotriene E4 and granulocyctic infiltration into asthmatic airways. Lancet 341: 989– 990. Citing Literature Volume744, Issue1Cellular Generation, Transport, and Effects of Eicosanoids: Biological Roles and Pharmacological InterventionNovember 1994Pages 289-298 ReferencesRelatedInformation

The non-redox 5-lipoxygenase inhibitor Zeneca ZD2138 (6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy- methyl]-1-methyl-2-quinolone) was evaluated for its ability to inhibit antigen-induced leukotriene release from guinea-pig lung in vitro and antigen-induced increases in pulmonary resistance in guinea pigs in vivo. ZD2138 inhibited antigen-induced release of leukotriene D4 and leukotriene B4 with IC50 values of 0.3 +/- 0.06 microM and 0.4 +/- 0.09 microM, respectively. At about ten times higher concentrations, ZD2138 had no effect on antigen-induced release of thromboxane B2, indicating selectivity for inhibition of 5-lipoxygenase vs. phospholipase A2, cyclooxygenase, or thromboxane synthetase. Similarly, ZD2138 did not inhibit histamine release, indicating that the compound did not have a generalized effect on the mediator release processes. Zeneca ZM230487-(6-[(3-fluoro-5-[4-methoxy- 3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-ethyl-2-quinolone), the N-ethyl analog of ZD2138, was approximately equipotent toward inhibition of antigen-induced leukotriene D4 release, with an IC50 of 0.2 +/- 0.08 microM. The so-called 5-lipoxygenase activating protein (FLAP) inhibitor, MK-886 (3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2 ,2- dimethylpropanoic acid), and the iron ligand 5-lipoxygenase inhibitor zileuton (N-(1-benzo[b]thien-2-ylethyl)-N-hydroxy-urea) were also active, but less potent than ZD2138 with IC50 values for inhibition of antigen-induced leukotriene release in vitro of 9.3 +/- 3.2 microM and 14.8 +/- 1.8 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosol administration of neurokinin A (NKA) or substance P (SP) to conscious guinea pigs produced labored abdominal breathing (dydpnea). Time to onset of dyspnea was inversely related to tachykinin concentration. Aerosol administration of the neutral endopeptidase inhibitor thiorphan significantly potentiated tachykinin-induced without affecting responses to leukotriene D4 (LTD4), carbachol, histamine, platelet activating factor or serotonin (5-HT), indicating selectivity for tachykinins rather than a nonspecific effect on agonist reactivity. The rank order of potency for producing dyspnea was LTD⩾ NKA (with thiorphan) ⪢ SP (with thiorphan) > 5-HT = carbachol > histamine > platelet-activating factor. Pretreatment with propranol, phentolamine, methysergide, pyrilamine or the peptide leukotriene antagonist, ICI 198,165, did not alter dyspnea induced by NKA or SP. The dose-response curves for NKA and SP were shifted to small degrees (< 3-fold) to the right by atropine and to the left by indomethacin. Also, pretreatment with capsaicin did not affect responses to NKA or SP, indicating that they do not cause dyspnea by activating capsaicin sensitive C-fibers. These results suggest primarily direct effects of NKA and SP. This model may be useful for in vivo evaluation of tachykinin antagonists.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Annals of the New York Academy of SciencesVolume 629, Issue 1 p. 176-192 Pharmacologic Analysis of Platelet Activating Factor16- and 18-Induced Bronchoconstriction in the Guinea Pig ROBERT D. KRELL, ROBERT D. KRELL ICI Pharmaceuticals Group Department of Pharmacology Pulmonary Section Wilmington, Delaware 19897Search for more papers by this authorMICHELLE McCARTHY, MICHELLE McCARTHY ICI Pharmaceuticals Group Department of Pharmacology Pulmonary Section Wilmington, Delaware 19897Search for more papers by this author ROBERT D. KRELL, ROBERT D. KRELL ICI Pharmaceuticals Group Department of Pharmacology Pulmonary Section Wilmington, Delaware 19897Search for more papers by this authorMICHELLE McCARTHY, MICHELLE McCARTHY ICI Pharmaceuticals Group Department of Pharmacology Pulmonary Section Wilmington, Delaware 19897Search for more papers by this author First published: July 1991 https://doi.org/10.1111/j.1749-6632.1991.tb37975.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1 Braquet, P., L. Touqui, T. Y. Shen & B. B. Vargaftig. 1987. Perspectives in platelet-activating factor research. Pharmacol. Rev. 39: 97–145. CASPubMedWeb of Science®Google Scholar 2 Robertson, D. N. & C. P. Page. 1987. Effect of platelet agonists on airway reactivity and intrathoracic platelet accumulation. Br. J. Pharmacol. 92: 105–111. 10.1111/j.1476-5381.1987.tb11301.x CASPubMedWeb of Science®Google Scholar 3 Dixon, E. J. A., P. Wilsoncroft, D. N. Robertson & C. P. Page. 1989. The effect of PAF antagonists on bronchial hyperresponsiveness induced by PAF, propranolol or indomethacin. Br. J. Pharmacol. 97: 717–722. 10.1111/j.1476-5381.1989.tb12008.x PubMedWeb of Science®Google Scholar 4 Chung, K. F., H. Aizawa, G. D. Leikauf, I. F. Ueki, T. W. Evans & J. A. Nadel. 1985. Airway hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation. J. Pharmacol. Exp. Ther. 236: 580–584. PubMedWeb of Science®Google Scholar 5 Cuss, F. M., C. M. S. Dixon & P. J. Barnes. 1986. Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet 189–192. Google Scholar 6 Rubin, A-H. E., L. J. Smith & R. Patterson. 1987. The bronchoconstrictor properties of platelet-activating factor in humans. Am. Rev. Resp. Dis. 136: 1145–1151. 10.1164/ajrccm/136.5.1145 CASPubMedWeb of Science®Google Scholar 7 Townley, R. G., R. J. Hopp, D. K. Agrawal & A.K. Bewtra. 1989. Platelet-activating factor and airway reactivity. J. Allergy Clin. Immunol. 83: 997–1010. 10.1016/0091-6749(89)90437-5 CASPubMedWeb of Science®Google Scholar 8 Vargaftig, B. B., J. Lefort, M. Chignard & J. Benveniste. 1980. Platelet-activating factor induces a platelet-dependent bronchoconstriction unrelated to the formation of prostaglandin derivatives. Eur. J. Pharmacol. 65: 185–192. 10.1016/0014-2999(80)90391-X CASPubMedWeb of Science®Google Scholar 9 Vargaftig, B. B., J. Lefort, F. Wal, M. Chignard & M. C. Medeiros. 1982. Non-steroidal anti-inflammatory drugs if combined with anti-histamine and anti-serotonin agents interfere with the bronchial and platelet effects of “platelet-activating factor” (PAF-ACETHER). Eur. J. Pharmacol. 82: 121–130. PubMedWeb of Science®Google Scholar 10 Iwana, T., K-I. Shikada & S. Tanaka. 1988. Pharmacological modulation of platelet activating factor (PAF)-induced bronchoconstriction and hypertension in anaesthetized guinea-pigs. J. Pharm. Pharmacol. 40: 544–547. 10.1111/j.2042-7158.1988.tb05299.x PubMedWeb of Science®Google Scholar 11 Christman, B. W., P. L. Lefferts, G. A. King & J. R. Snapper. 1988. Role of circulating platelets and granulocytes in PAF-induced pulmonary dysfunction in awake sheep. J. Appl. Physiol. 64: 2033–2041. CASPubMedWeb of Science®Google Scholar 12 Evans, T. W., K. F. Chung, D. F. Rogers & P. J. Barnes. 1987. Effect of platelet-activating factor on airway vascular permeability: possible mechanisms. J. Appl. Physiol. 63: 479–484. CASPubMedWeb of Science®Google Scholar 13 Gamse, R., A. Wax, R. E. Zigmond & S. E. Leeman. 1981. Immunoreactive substance P in sympathetic ganglia: distribution and sensitivity towards capsaicin. Neuroscience 6: 437–441. 10.1016/0306-4522(81)90136-6 CASPubMedWeb of Science®Google Scholar 14 Pretolani, M., J. Lefort, E. Malanchére & B. B. Vargaftig. 1987. Interference by the novel PAF-acether antagonist WEB 2086 with the bronchopulmonary responses to PAF-acether and to active and passive anaphylactic shock in guinea-pigs. Eur. J. Pharmacol. 140: 311–321. PubMedWeb of Science®Google Scholar 15 Terashita, Z-I., Y. Imura, M. Takatani, S. Tsushima & K. Nishikawa. 1987. CV-6209, a highly potent antagonist of platelet activating factor in vitro and in vivo. J. Pharmacol. Exp. Ther. 242: 263–268. CASPubMedWeb of Science®Google Scholar 16 Handley, D. A., R. G. Van Valen, J. C. Tomesch, M. K. Melden, J. M. Jaffe, F. H. Ballard & R. N. Saunders. 1987. Biological properties of the antagonist SRI 63–441 in the PAF and endotoxin models of hypotension in the rat and dog. Immunopharmacology 13: 125–132. 10.1016/0162-3109(87)90049-X CASPubMedWeb of Science®Google Scholar 17 Krell, R. D., R. E. Giles, Y. K. Yee & D. W. Synder. 1987. In vivo pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist. J. Pharmacol. Exp. Ther. 243: 557–564. CASPubMedWeb of Science®Google Scholar 18 Snyder, D. W., R. E. Giles, R. A. Keith, Y. K. Yee & R. D. Krell. 1987. In vitro pharmacology of ICI 198,615: a novel, potent and selective peptide leukotriene antagonist. J. Pharmacol. Exp. Ther. 243: 548–556. CASPubMedWeb of Science®Google Scholar 19 Skidgel, R. A., S. Engelbrecht, A. R. Johnson & E. G. Erdös. 1984. Hydrolysis of substance P and neurotensin by converting enzyme and neutral endopeptidase. Peptides 5: 769–776. 10.1016/0196-9781(84)90020-2 CASPubMedWeb of Science®Google Scholar 20 Stimler-Gerard, N. 1987. Neutral endopeptidase-like enzyme controls the contractile activity of substance P in guinea pig lung. J. Clin. Invest. 79: 1819–1825. 10.1172/JCI113023 CASPubMedWeb of Science®Google Scholar 21 Hooper, N. M., A. J. Kenney & A. J. Turner. 1985. The metabolism of neuropeptides: neurokinin A (substance K) is a substrate for endopeptidase-24.11 but not for peptidyl dipeptidase A (angiotensin-converting enzyme). Biochem. J. 231: 357–361. 10.1042/bj2310357 CASPubMedWeb of Science®Google Scholar 22 Roques, B. P. M. C. Fournié-Zaluski, E. Saroca, J. M, Lecomte, B. Malfroy, C. Liorens & J. C. Schwartz. 1980. The enkephalinase inhibitor thiorphan shows antinociceptive in mice. Nature 20: 286–288. 10.1038/288286a0 Web of Science®Google Scholar 23 Chand, N., J. Pillar, K. Nolan, W. Diamantis & R. D. Sofia. 1990. Inhibition of PAF-induced histamine secretion and bronchoconstriction by WEB 2086. Res. Commun. Chem. Pathol. Pharmacol. 67: 155–158. PubMedWeb of Science®Google Scholar 24 Bonnet, J., D. Thibaudeau & P. Bessin. 1983. Dependency on the PAF-acether induced bronchospasm on the lipoxygenase pathway in the guinea pig. Prostaglandins 26: 457–466. 10.1016/0090-6980(83)90180-6 CASPubMedWeb of Science®Google Scholar 25 Buckner, C. K., D. Dea, N. Liberati & R. D. Krell. A pharmacologic examination of receptors mediating serotonin-induced bronchoconstriction in the anesthesized guinea pig. J. Pharmacol. Exp. Ther. In press. PubMedGoogle Scholar 26 Baumgartner, R. A., M. Wills-Karp, M. J. Kaufman, M. Munakata & C. Hirshman. 1990. Serotonin induces constriction and relaxation of guinea pig airway. J. Pharmacol. Exp. Ther. 255: 165–173. CASPubMedWeb of Science®Google Scholar Citing Literature Volume629, Issue1Advances in the Understanding andTreatment of AsthmaJuly 1991Pages 176-192 ReferencesRelatedInformation

1-0-Alkyl-2-Acetyl-sn-Glycero-3-Phosphocholine (AGEPC) produced dose-dependent (75–500 ng/site) increases in cutaneous vascular permeability (CVP) in rats as measured by extravasation of Evans blue dye. In contrast, lyso-AGEPC, at 1000 ng/site, was without effect. Pyrilamine, methysergide, and phenoxybenzamine, antagonists of mast-cell derived mediators, did not affect the AGEPC-induced increase in CVP. Likewise, agents capable of inhibiting mast cell mediator release, such as disodium cromoglycate, PRD-92-EA, theophylline, or nifedipine, had no effect. The cyclooxygenase inhibitor indomethacin produced significant inhibition of the response to AGEPC, whereas the lipoxygenase inhibitor nordihydroguiaretic acid (NDGA) and the peptide leukotriene antagonist FPL 55712 were without effect. The response to AGEPC was enhanced by the vasodilator PGE2 and inhibited by the vasoconstrictor phenylephrine. The selective AGEPC antagonist CV-3988 provided marked inhibition of the response. Unaccountably, the combination of indomethacin and CV-3988 provided no greater inhibition of the responses than either agent alone. These observations indicate that the AGEPC-induced increase in CVP in rats is mediated in part by products of the cyclooxygenase pathway and in part by activation of an AGEPC receptor.

Annals of the New York Academy of SciencesVolume 435, Issue 1 p. 113-115 Measurement of Leukotriene Release from Rat Peritoneal Cells with a Specific Radioimmunoassay DAVID AHARONY, DAVID AHARONY Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorPAUL DOBSON, PAUL DOBSON Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorPETER BERNSTEIN, PETER BERNSTEIN Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorROBERT D. KRELL, ROBERT D. KRELL Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorJ. BRYAN SMITH, J. BRYAN SMITH Center for Thrombosis Research Temple Medical School Temple University Philadelphia, Pennsylvania 19140Search for more papers by this author DAVID AHARONY, DAVID AHARONY Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorPAUL DOBSON, PAUL DOBSON Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorPETER BERNSTEIN, PETER BERNSTEIN Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorROBERT D. KRELL, ROBERT D. KRELL Biomedical Research Department Stuart Pharmaceuticals Wilmington, Delaware 19897Search for more papers by this authorJ. BRYAN SMITH, J. BRYAN SMITH Center for Thrombosis Research Temple Medical School Temple University Philadelphia, Pennsylvania 19140Search for more papers by this author First published: December 1984 https://doi.org/10.1111/j.1749-6632.1984.tb13744.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Samuelsson, B. 1983. Science 220: 568–575. 10.1126/science.6301011 CASPubMedWeb of Science®Google Scholar 2 Krell, R. D., R. Osborn. L. Vickery, K. Falcone, M. O'donnell. J. Gleason, C. Kinzig & D. Bryan. 1981. Prostaglandins 22: 387–409. 10.1016/0090-6980(81)90101-5 CASPubMedWeb of Science®Google Scholar 3 Aharony, D., P. Dobson, P. R. Bernstein, E. J. Kusner, R. D. Krell & J. B. Smith. 1983. Biochem. Biophys. Res. Commun. 117: 574–579. 10.1016/0006-291X(83)91239-1 CASPubMedWeb of Science®Google Scholar 4 Young, R. M., M. Kakushima & J. Rokach. 1982. Prostaglandins 23: 603–613. 10.1016/0090-6980(82)90120-4 CASPubMedWeb of Science®Google Scholar 5 Dobson, P., D. Aharony & R. D. Krell. 1983. Res. Commun. Chem. Pathol. Pharmacol. 42: 3–23. CASPubMedWeb of Science®Google Scholar Volume435, Issue1First Colloquium in Biological SciencesDecember 1984Pages 113-115 ReferencesRelatedInformation

The pharmacology of leukotrienes (LT) C4 and D4 in isolated airway smooth muscle was investigated. In rat trachea, neither LTC4 or D4 elicited a response. In contrast, LTC4 was a potent contractile agonist in guinea-pig trachea, bronchus and parenchymal lung strip. Similar effects were obtained with LTD4 in trachea and parenchyma. In trachea and bronchus, the concentration-response curve to LTC4 was biphasic: indomethacin converted the biphasic response curve to a simple sigmoidal shape and enhanced the maximum contractile response. The SRS-A antagonist FPL 55712 antagonized the effect of LTD4 in both trachea and parenchyma. As regards LTC4-induced contraction of trachea and bronchus, FPL 55712, depending on concentration, either antagonized, or antagonized and enhanced the maximum contractile response. The enhancement of the maximum contractile response by FPL 55712 was not apparent when indomethacin was present. FPL 55712 failed to antagonize the effect of LTC4 in parenchyma.

Cimetidine, an H2 receptor antagonist, moderately enhanced immunologically-induced histamine release from rhesus monkey, but not rat, lung. This effect was presumed to be due to H2 receptor blockade, i.e. interference with a negative feedback on histamine release. SK&F 91581, a burimamide analog with weak H2 antagonist activity also moderately enhanced immunologically-induced histamine release, at similar concentrations. The H2 agonist, dimaprit, failed to inhibit histamine release from rhesus monkey lung at concentrations ranging from 10−5 to 10−3 M, and impromidine, a potent H2 agonist, produced only modest inhibition of amine release from primate lung at low concentrations, but this effect was lost at 4 × 10−4 M.

The pathophysiology of allergic and “nonallergic” asthma is presented, and several classes of antiallergic agents are discussed.