The proposed studies will investigate regulation of growth, differentiation, and intrinsic beating rate of fetal rat heart by autonomic nerves, circulating factors and mechanisms intrinsic to the heart. Neural, hormonal and cardiac controls of cardiac development will be isolated by studying hearts maturing in an in vivo culture system, the anterior chamber of the eye of a host rat (i.e., in oculo). The following hypotheses will be tested: 1. Sympathetic innervation of heart tissue maturing in oculo causes myocyte hypertrophy and promotes differentiation into adult-like heart tissue. 2. Circulating catecholamines contribute to the growth, differentiation and determination of intrinsic beating rat of heart tissue maturing in oculo. 3. Growth, differentiation, and intrinsic beating rate of heart tissue developing in oculo are regulated by both sympathetic and parasympathetic innervation. 4. Autonomic innervation ceases to influence cardiac growth, differentiation, and intrinsic beating rate by 2 months in oculo. 5. Thyroid hormone promotes growth, differentiation and intrinsic beating rate of fetal heart cultured in oculo both by direct action and by increasing sensitivity to sympathetic stimulation. Cardiac growth will be measured by increases in size of transplanted atria and ventricles. The sizes of myocytes from implanted heart tissue will be measured to identify growth by hypertrophy. Differentiation from fetal to adult-like heart tissue will be examined by ultrastructural and biochemical criteria (i.e. electron microscopy and myosin isoenzyme composition). Intrinsic heart rate will be measured from in oculo atria after combined beta-adrenergic and muscarinic receptor blockade. With the in oculo culture system, heart development can be studied under conditions where neural and hormonal influences can be selectively controlled without changing hemodynamic load. This model provides a method for studying interactions among developing cardiovascular target organs, their autonomic innervation and their hormonal milieu. Early developmental influences may modulate genetically programmed maturation and contribute to subsequent individual differences in cardiovascular regulation and in the predisposition to cardiovascular diseases such as hypertension.
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