Development of Anti-Asthma Drugs by Derek R. Buckle

By Derek R. Buckle

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Shifting the p H to a lower level increases the proportion of stimulated histamine secretion which is indep e n d e n t of extracellular calcium, possibly by increasing mobilization from internal stores of c a l c i u m . It has already b e e n pointed out that there are theoretical reasons for anticipating a certain level of spontaneous secretion from mast cells and basophils in the absence of any m e m b r a n e activation by a ligand-receptor interaction. S p o n t a n e o u s histamine release from mast cells increases very little over a period of u p to 2 hours incubation at 37°C and extracellular calcium has no a p p a r e n t effect on this spontaneous release.

Methyltransferase I, located on the inner surface of the m e m b r a n e , transfers a methyl group from 5-adenosylmethionine to phosphatidylethanolamine. 6 The membrane events of mast cell activation. Receptor cross-linking initiates changes in membrane phospholipid composition, arachidonate is released by a phospholipase A and calcium channels open. Cyclic AMP levels, which may be controlled by the receptor aggregation (adenylate cyclase not shown), activate a protein kinase which may interact with calcium channels or stores to control the secretory process.

Passive sensitization of the smooth muscle tissue with antibody was d e m o n s t r a t e d and it was n o t e d that the antigen-antibody reaction p r o d u c e d , in the muscle, a response similar to and as rapid as that produced directly by histamine. Not long after this pioneering work of D a l e and others. Feldberg and colleagues d e m o n s t r a t e d that challenge of the lung from a sensitized animal with the a p p r o p r i a t e antigen caused the release of histamine from the lung tissue.

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