Among the several mechanisms for modulation of histamine release, the autonomic nervous system is of special interest since drugs which can activate beta adrenergic receptors are of value in the treatment of allergic diseases like bronchial asthma. It is known that adrenergic substances can act to inhibit the allergic release of mediators and they have traditionally been effective by activation of beta type adrenergic receptors. Presumably, these receptors are located on the mast cells from which mediators are released by immunological means. Fewer studies have been conducted regarding the role of alpha receptors in modulation of mediator release from mast cells. This proposal is part of our long range goals of understanding how the autonomic nervous system can modulate mediator release from mast cells. To this end, this proposal describes techniques to be used in obtaining highly purified lung mast cells from guinea pigs and man. With the purified mast cells in hand, the pharmacological studies will focus on an examination of the properties of both alpha and beta adrenergic receptors using agonists and antagonists of these receptors. Additionally, this proposal outlines experiments to be conducted measuring changes in mast cell cyclic AMP and cyclic GMP in response to the adrenergic agonists. In all cases, attention will be focused on quantitation of drug parameters, affinity and efficacy in studies to subclassify and differentiate the receptors involved in producing responses in isolated mast cells. In addition to histamine, we will monitor release of leukotrienes and prostaglandins and examine the abilities of the adrenergic drugs to modify release of these substances. Results will be compared and contrasted with those obtained measuring histamine release. Information about different mechanisms for release modulation will also be sought. With information regarding receptor types and mechanisms involved in modulation of mediator release, a more rational approach to the design of better drugs to use in allergic disease can be made.
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