Malfatto G, Rosen T S, Steinberg S F, Ursell P C, Sun L S, Daniel S, Danilo P, Rosen M R
Department of Pharmacology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Circ Res. 1990 Feb;66(2):427-37. doi: 10.1161/01.res.66.2.427.
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.
在新生大鼠出生后的前10天，我们给它们注射了神经生长因子、神经生长因子抗血清或安慰剂。我们的目标是确定发育中心脏的交感神经支配、心脏节律的心电图表现以及心脏对苯肾上腺素α-肾上腺素能刺激的反应之间的关系。由于之前在分离细胞系统中已证明交感神经对41 kDa GTP调节蛋白和α-肾上腺素能反应性有调节作用，所以我们对后一个领域特别感兴趣。与安慰剂组相比，接受神经生长因子治疗的10至11日龄大鼠具有更完整的交感神经支配、更快的心率以及更高水平的41 kDa蛋白。在37.0℃至37.5℃用台氏液灌流的离体室间隔上进行电生理研究。来自10至11日龄神经生长因子组的室间隔对10(-9)和10(-8) M苯肾上腺素的电生理反应与3周龄对照动物相当。相比之下，与安慰剂组相比，接受抗血清治疗的10至11日龄大鼠的神经支配模式异常、41 kDa蛋白水平较低，并且对α-肾上腺素能刺激的电生理反应更不成熟。此外，接受抗血清治疗的大鼠心电图QT间期异常延长。我们的结果首次在完整动物中证明了交感神经支配与α-肾上腺素能受体-效应器偶联之间的直接联系，以及α-激动剂对冲动起始调节的神经支配依赖性。这一发育事件序列可能不仅在正常心脏节律的调节中很重要，而且在某些病理实体如先天性长QT综合征和婴儿猝死综合征的表现中也很重要。
