The objectives of this proposal are to define the specific contributions of insulin and the thyroid hormones to myocardial and coronary regulatory systems in the developing neonate. A lamb model for juvenile (Type I) diabetes which is now well characterized will be used to study the insulin-deficient state. Variables to be tested will include neonatal age, duration of diabetes, and the effects of chronic and acute insulin replacement. Relationships to altered concentrations of thyroid hormone will be examined in animals rendered thyrotoxic by thyroxin administration. These will be compared with neonates in which thyroid hormone levels are sharply reduced by surgical thyroidectomy. Reversibility of changes will be sought by interruption of thyroxin or replacement therapy in hypothyroid animals. Cardiac performance, myocardial 02 and substrate metabolism and myosin ATPase activity will be determined. Inotropic responses will be quantified to assess myocardial receptor sensitivity using specific beta and alpha agonists and antagonists. Physiological significance of altered receptor function will be evaluated by comparing responses to autonomic nerve stimulation and by measuring changes induced by the carotid sinus and cephalic ischemia reflexes. Coronary vascular reactivity will be determined in each model. Vasomotor responses induced by administration of adrenergic agonists and antagonists, autonomic nerve stimulation and reflex activation will be compared. Changes in sensitivity to adenosine and results of blockade of the nucleoside will be assessed. Distribution of coronary flow will be measured with the radiolabelled microsphere method. Tolerance of each of the preparations to hypoxemia and hypercapnia will be determined to evaluate metabolic responses and to assess cardiac autonomic compensatory mechanisms and coronary vascular reactivity in the presence of these common clinical abnormalities. These studies will define alterations in the heart and coronary system in each of the three neonatal models. They will determine the contributions of altered thyroid function to changes associated with the diabetic state, and delineate pathogenetic mechanisms. They will also provide important information regarding the extent and time course of reversibility of the observed changes.
