Sympathetic neural modulation of cardiac impulse initiation and repolarization in the newborn rat

We injected neonatal rats with nerve growth factor, the antiserum to nerve growth factor, or placebo for the first 10 days of life. Our goal was to determine the relation between sympathetic innervation of the developing heart, the electrocardiographic expression of cardiac rhythm, and the response of the heart to alpha-adrenergic stimulation with phenylephrine. We were especially interested in the latter area because of the prior demonstration in isolated cell systems of sympathetic neural modulation of a 41-kDa GTP regulatory protein and alpha-adrenergic responsiveness. Ten- to 11-day-old rats treated with nerve growth factor had more complete sympathetic innervation, faster heart rates, and higher levels of the 41-kDa protein than the placebo group. Electrophysiological studies were performed on isolated ventricular septa superfused with Tyrode's solution at 37.0 degrees-37.5 degrees C. The electrophysiological response of septa to 10(-9) and 10(-8) M phenylephrine from the 10-11-day-old nerve growth factor group was comparable with that of 3-week-old control animals. In contrast, 10-11-day-old antiserum-treated rats had an abnormal innervation pattern, lower levels of the 41-kDa protein, and a more immature electrophysiological response to alpha-adrenergic stimulation than the placebo group. In addition, antiserum-treated rats had an abnormally prolonged electrocardiographic QT interval. Our results demonstrate for the first time in intact animals a direct link between sympathetic innervation and alpha-adrenergic receptor-effector coupling as well as the dependence on innervation of the modulation of impulse initiation by alpha-agonists. This sequence of developmental events may be important not only in the regulation of normal cardiac rhythm but also in the expression of certain pathological entities such as the congenital long QT syndrome and the sudden infant death syndrome.