Acetylcholinesterase (AChE), a secreted glycoprotein, is an important enzyme of the cholinergic system of the heart by virtue of its control of acetylcholine (ACh) turnover. This is illustrated by the fact that inhibition of cardiac AChE, resulting in higher ACh levels, causes changes in heart function. AChE exhibits a polymorphism which appears to be important for its subcellular deposition. The main classes of AChE are globular (soluble and membrane-bound) and asymmetric forms with collagen-tails that attach to the basal lamina. The proposed experiments will investigate the composition of the external (functionally-relevant) AChE pool in various regions of rat heart in order to determine if the extracellular pool of this enzyme varies as a function of the amount and type (pre- and post-ganglionic) of cholinergic innervation. Secondly, the contribution of cholinergic nerves and muscle cells to the cardiac AChE pool will be determined by studying cardiac AChE after vagotomy and in isolated adult rat cardiac myocytes. Since alterations in the expression of AChE could result in alterations in autonomic tone especially if not coupled with a change in choline acetyltransferase activity, the proposed experiments will investigate the regulation of the expression of AChE in mature rat heart. The regulation of the expression of AChE in intact rat heart will be investigated after manipulation of thyroid hormone levels and after excessive adrenergic stimulation. In addition, the synthesis and externalization of AChE molecular forms in isolated cardiac myocytes, cultured under various conditions (different substrata, thyroid hormone, and adrenergic and cholinergic stimulation) will be determined. The expression of AChE during heart hypertrophy will also be investigated using two models of hypertension: the Dahl-salt sensitive strain of rats and aortic-banded rats. This last group of experiments should also indicate if there are genetic differences in the expression of cardiac AChE.
