Cellular mechanisms of impaired adrenergic responsiveness in neonatal dogs.

Abstract

A B S T R A C T The myocardial responsiveness of conscious, instrumented dogs to exogenously administered isoproterenol and norepinephrine was investigated in neonatal, 6-wk-old, and adult animals. Comparable base-line values for peak left ventricular derivative of pressure with respect to time were observed in all age categories. However, when compared with adult responses, the sympathomimetic amine-induced increases in neonatal left ventricular dPldt were significantly blunted at each concentration of adrenergic agonist examined, whereas the 6-wk-old puppies displayed an intermediate inotropic response. To investigate the cellular mechanisms of this blunted neonatal response, we correlated physiologic and biochemical measurements of the myocardial responses to catecholamines in each age category. When compared with adult myocardial membrane preparations, neonatal cardiac membranes were characterized in vitro by an increased density of f3-adrenergic binding sites, comparable affinity for adrenergic agonists and antagonists, and an enhanced coupling of adenylate cyclase activation to receptor occupancy. Simultaneous changes in either the serum catecholamine concentration or the membrane content of other intrinsic proteins failed to account for the observed neonatal increase in 8-adrenergic receptor density. These findings are most consistent with a compensatory mechanism of the cardiac cell membrane, whereby an inherent depression in the adrenergic responsiveness of the immature myocardium appears to induce the increase in receptor density and activation of adenylate cyclase.

Differential regulation of inotropy and lusitropy in overexpressed Gsα myocytes through cAMP and Ca2+ channel pathways

“…Thus, the discrepancy between Ca 2+ channel activity in neonatal and adult myocytes appears consistent for both β 2 -AR overexpression and Gsα overexpression and points to an important limitation in extrapolating from neonatal or fetal to adult physiological regulation. This is particularly relevant to βAR-Gs-AC regulation, which is well recognized to be different in neonatal animals (15)(16)(17).…”

“…The isolated myocyte technique lends itself to examination of that aspect of myocardial function as well. Finally, it was important to conduct the present investigation in adult as opposed to neonatal (7) myocytes, because (a) it is possible to examine contractile and relaxation function as well as Ca 2+ channel activity in adult cells, and (b) it is well known that βAR-Gs-ΑC regulation differs markedly in neonatal animals (15)(16)(17).…”

A Differential Effect of Thyroxine and Glucocorticoids on Fetal Brain and Heart Insulin Receptor

“…Brain plasma membranes were prepared by the method of Havrankova and Roth (I 5) and cardiac plasma membranes by the method of Rockson et al (27). Briefly fetal brains from a litter were removed from the cranium and pooled prior to homogenization in a Dounce glass homogenizer containing 1 mM bicarbonate buffer (pH 8.0).…”

Differential regulation of right and left ventricular beta-adrenergic receptors in newborn lambs with experimental cyanotic heart disease.

“…Previous studies have also failed to examine the differential effects of hypoxemia and structural heart defects on 1-receptor regulation in both the left and right ventricles and have not correlated alterations in 13-receptor density with simultaneous measurements of sympathetic activity. Furthermore, all previous studies have used adult models, and thus have not accounted for developmental differences in cardiopulmonary and sympathetic nervous system function in the newborn which might alter the cellular response to hypoxemia (18)(19)(20) (4,21) or in thyroid hormone (22,23 After the lambs recovered for three days, hypoxemia was produced by gradually inflating the pulmonary arterial occluder balloon with saline, which partially obstructed the right ventricular outflow tract and induced atrial right-to-left shunting. The details of this gradual inflation procedure have been described previously (3).…”