MUSCARINIC RECEPTOR DEVELOPMENT IN ANEURAL HEARTS

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The aim of the proposed research is to obtain a better understanding of the development and regulation of muscarinic acetylcholine receptor complexes (mAChR) in cardiac tissues, and in particular the influences of parasympathetic innervation on receptor development. Normal developmental patterns of mAChR will be studied in chick hearts to take advantage of the natural temporal separation of neural and myocardial elements. The influence of innervation on the development of mAChR will be assessed following cauterization of the areas of neural crest which give rise to the cardiac ganglia. Similarly, the influence of preganglionic parasympathectomy on cholinergic receptor systems will be studied after removal of the area of the rhombencephalon which gives rise to preganglionic cell bodies. Combined lesions will remove both pre- and postganglionic branches of parasympathetic innervation of the heart. The effectiveness of these procedures will be assessed through measures of ACh content and high affinity choline uptake in cardiac tissues. Histological examination will reveal the number of ganglion cells in the conotruncus during normal development and in the various experimental conditions. Receptor complex properties will be assessed using radiolabelled probes: The number of receptors, their agonist and antagonist binding affinities, their regulation by guanine nucleotides, and their ability to down regulate in response to exposure to muscarinic agonists will be measured. These experiments will provide a plethora of basic information concerning the relationship of the heart and its nerves, as well as the biochemical organization and regulation of cholinergic receptors in cardiac tissue.