The sympathetic nervous system plays a major role in the cardiovascular adaptations to both acute and chronic hypoxemia. During acute hypoxemia, increased sympathetic tone is responsible for increasing heart rate and cardiac output, and thus maintaining systemic oxygenation. During chronic hypoxemia, additional compensatory mechanisms obviate the need for a sustained increase in cardiac output so that the benefits of increased sympathetic stimulation may be outweighed by its deleterious cellular, metabolic and circulatory effects The purpose of this study is to determine the role of the sympathetic nervous system in regulating the myocardial response to chronic hypoxemia in the newborn. Whereas previous studies have attempted to define this role in chronic alveolar hypoxemia, we will utilize a model more applicable to infants with cyanotic congenital heart disease, that of chronic hypoxemia associated with an intracardiac right-to-left shunt. The first specific aim of this study is to determine whether the increase in sympathetic tone which supports myocardial function during acute hypoxemia persists when hypoxemia is prolonged. Second, we will determine whether chronic hypoxemia alters the regulation of the myocardial beta-adrenergic receptor/adenylate cyclase system. These studies will include quantification of beta-adrenergic receptor density, receptor-agonist affinity states mediated via coupling to the guanyl nucleotide stimulatory binding protein, and distal effector activity mediated via adenylate cyclase. Third, to be physiologically relevant, alterations in the beta- receptor/adenylate cyclase system must be correlated with alterations in physiologic responsiveness to adrenergic stimulation. Thus, we will determine the myocardial and total circulatory responses to beta-adrenergic agonist administration . Fourth, we will investigate whether myocardial metabolism, also dependent on adrenergic control, is altered. The fifth specific aim is to determine the reflex mechanisms responsible for the increase in sympathetic stimulation during chronic hypoxemia, by examining the contributions of the peripheral chemoreceptor, circulating catecholamines, and parasympathetic withdrawal. Finally, to determine if the down-regulatory effects of chronic adrenergic stimulation can be attenuated pharmacologically, we will determine the cellular, metabolic and circulatory effects of chronic beta-antagonist administration. By better understanding the cellular and circulatory mechanisms of the sympathetic response to chronic hypoxemia, more effective medical therapies can be developed to attenuate the deleterious effects of chronic sympathetic stimulation in infants and children with cyanotic congenital heart disease.
