Abstract
Neurotransmitters are thought to influence cell development in their target tissues. In the current study, neonatal rats were given 6-hydroxydopamine to produce permanent sympathetic denervation, and the effects on cardiac and hepatic DNA and protein synthesis were assessed. Lesioned animals showed deficits in cardiac DNA synthesis over the first 8 d postpartum, a period in which sympathetic innervation is sparse and synaptic norepinephrine concentrations are low; the effect of lesioning was also evident for protein synthesis. Subsequently, DNA synthesis in control animals declined precipitously during the second to third postnatal week, the phase associated with ingrowth of the majority of sympathetic terminals and sympathetic hyperactivity. Neonatal lesioning delayed the ontogenetic decline in DNA synthesis; this effect was not shared by protein synthesis. In the liver, a tissue whose cells, unlike the heart, maintain the ability to divide into adulthood, there was no effect of 6-hydroxydopamine on DNA synthesis and only minor changes in protein synthesis. These results suggest that neural input provides two distinct trophic signals to the developing heart: an early promotion of cell replication associated with low levels of stimulation, and a subsequent promotion of the switchover from cell replication, to cell differentiation and enlargement, associated with high levels of stimulation. In light of the precipitous rise in circulating catecholamines at parturition, and of the subsequent development of sympathetic innervation, catecholamines are likely to play a trophic role in the establishment of the proper pattern of cardiac cell development.
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Abbreviations
- ANCOVA:
-
analysis of covariance
- ANOVA:
-
analysis of variance
- 6-OHDA:
-
6-hydroxydopamine
References
Buznikov GA, Chudakova IV, Zvedina ND 1964 The role of neurohumors in early embryogenesis. I. Serotonin content of developing embryos of sea urchin and loach. J Embryol Exp Morphol 12: 563–573
Buznikov GA, Kost AN, Berdysheva LV 1970 The role of neurohumours in early embryogenesis. 3. Pharmacological analysis of the role of neurohumours in cleavage divisions. J Embryol Exp Morphol 23: 549–569
Vernadakis A, Gibson DA 1974 Role of neurotransmitter substances in neural growth. In: Dancis J, Hwang JC (eds) Perinatal Pharmacology: Problems and Priorities. Raven Press, New York, pp 65–76
Lovell J 1982 Effects of 6-hydroxydopamine-induced norepinephrine depletion on cerebellar development. Dev Neurosci 5: 359–368
Lauder JM 1985 Roles for neurotransmitters in development: possible interaction with drugs during the fetal and neonatal periods. In: Marois M (ed) Prevention of Physical and Mental Congenital Defects. Alan R. Liss, New York, pp 375: 380
Whitaker-Azmitia PM 1991 Role of serotonin and other neurotransmitter receptors in brain development: basis for developmental pharmacology. Pharmacol Rev 43: 553–561
Hohmann CF, Brooks AR, Coyle JT 1988 Neonatal lesions of the basal forebrain cholinergic neurons result in abnormal cortical development. Dev Brain Res 42: 253–264
Claycomb WC 1976 Biochemical aspects of cardiac muscle differentiation. J Biol Chem 251: 6082–6089
Slotkin TA, Whitmore WL, Orband-Miller L, Queen KL, Haim K 1987 Beta adrenergic control of macromolecule synthesis in neonatal rat heart, kidney and lung: relationship to sympathetic neuronal development. J Pharmacol Exp Ther 243: 101–109
Slotkin TA, Windh R, Whitmore WL, Seidler FJ 1988 Adrenergic control of DNA synthesis in developing rat brain regions: effects of intracisternal administration of isoproterenol. Brain Res Bull 21: 737–740
Slotkin TA, Levant B, Orband-Miller L, Queen KL, Stasheff S 1988 Do sympathetic neurons coordinate cellular development in the heart and kidney? Effects of neonatal central and peripheral catecholaminergic lesions on cardiac and renal nucleic acids and proteins. J Pharmacol Exp Ther 244: 166–172
Slotkin TA 1986 Endocrine control of synaptic development in the sympathetic nervous system: the cardiac-sympathetic axis. In: Gootman PM (ed) Developmental Neurobiology of the Autonomic Nervous System. Humana Press, Clifton, NJ, pp 97–133
Friedhoff AJ, Miller JC 1983 Prenatal psychotropic drug exposure and the development of central dopaminergic and cholinergic neurotransmitter systems. Monogr Neural Sci 9: 91–98
Slotkin TA, Seidler FJ, Haim K, Cameron AM, Antolick L, Lau C 1988 Neonatal central catecholaminergic lesions with intracisternal 6-hydroxydopamine: effects on developmental of presynaptic and postsynaptic components of peripheral sympathetic pathways and on the ornithine decarboxylase/polyamine system in heart, lung and kidney. J Pharmacol Exp Ther 247: 975–982
Hou Q-C, Eylers JP, Lappi SE, Kavlock RJ, Slotkin TA 1989 Neonatal sympathectomy compromises development of responses of ornithine decarboxylase to hormonal stimulation in peripheral tissues. J Dev Physiol 12: 189–192
Slotkin TA, Lorber BA, McCook EC, Barnes GA, Seidler FJ 1995 Neural input and the development of adrenergic intracellular signaling: neonatal denervation evokes neither receptor upregulation nor persistent supersensitivity of adenylate cyclase. Dev Brain Res 88: 17–29
Seidler FJ, Slotkin TA 1979 Presynaptic and postsynaptic contributions to ontogeny of sympathetic control of heart rate in the preweanling rat. Br J Pharmacol 65: 431–434
Seidler FJ, Slotkin TA 1981 Development of central control of norepinephrine turnover and release in the rat heart: responses to tyramine, 2-deoxyglucose and hydralazine. Neuroscience 6: 2081–2086
Bareis DL, Slotkin TA 1980 Maturation of sympathetic neurotransmission in the rat heart. I. Ontogeny of the synaptic vesicle uptake mechanism and correlation with development of synaptic function. Effects of neonatal methadone administration on development of synaptic vesicles. J Pharmacol Exp Ther 212: 120–125
Smith PG, Slotkin TA, Mills E 1982 Development of sympathetic ganglionic neurotransmission in the neonatal rat. Pre- and postganglionic nerve response to asphyxia and 2-deoxyglucose. Neuroscience 7: 501–507
Kugler JD, Gillette PC, Graham SP, Garson A, Goldstein MA, Thompson HK 1980 Effect of chemical sympathectomy on myocardial cell division in the newborn rat. Pediatr Res 14: 881–884
Slotkin TA, Persons D, Slepetis RJ, Taylor D, Bartolome J 1984 Control of nucleic acid and protein synthesis in developing brain, kidney, and heart of the neonatal rat: effects of α-difluoromethylornithine, a specific, irreversible inhibitor of ornithine decarboxylase. Teratology 30: 211–224
McMillian MK, Schanberg SM, Kuhn CM 1983 Ontogeny of rat hepatic adrenoceptors. J Pharmacol Exp Ther 227: 181–186
Rao GS, Seidler FJ, Slotkin TA 1995 Modulation of hepatic adrenergic receptor ontogeny by thyroid hormone. Res Commun Mol Pathol Pharmacol 87: 27–42
Bell JM, Whitmore WL, Queen KL, Orband-Miller L, Slotkin TA 1987 Biochemical determinants of growth sparing during neonatal nutritional deprivation or enhancement: ornithine decarboxylase, polyamines, and macromolecules in brain regions and heart. Pediatr Res 22: 599–604
Bell JM, Whitmore WL, Slotkin TA 1986 Effects of-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase, on nucleic acids and proteins in developing rat brain: critical perinatal periods for regional selectivity. Neuroscience 17: 399–407
Deskin R, Mills E, Whitmore WL, Seidler FJ, Slotkin TA 1980 Maturation of sympathetic neurotransmission in the rat heart. VI. The effect of neonatal central catecholaminergic lesions. J Pharmacol Exp Ther 215: 342–347
Deskin R, Slotkin TA 1981 Central catecholaminergic lesions in the developing rat: effects on cardiac noradrenaline levels, turnover and release. J Auton Pharmacol 1: 205–210
Duncan CP, Seidler FJ, Lappi SE, Slotkin TA 1990 Dual control of DNA synthesis by α- and β-adrenergic mechanisms in normoxic and hypoxic neonatal rat brain. Dev Brain Res 55: 29–33
Lidow MS, Rakic P 1994 Unique profiles of theα1-, α2-, and β-adrenergic receptors in the developing cortical plate and transient embryonic zones of the rhesus monkey. J Neurosci 14: 4064–4078
Rokosh DG, Stewart AFR, Chang KC, Bailey BA, Karliner JS, Camacho SA, Long CS, Simpson PC 1996 α1-Adrenergic receptor subtype mRNAs are differentially regulated by α1-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo: repression of α1B and α1D but induction ofα1C . J Biol Chem 271: 5839–5843
Thomas SA, Matsumoto AM, Palmiter RD 1995 Noradrenaline is essential for mouse fetal development. Nature 374: 643–646
Kudlacz EM, Navarro HA, Eylers JP, Slotkin TA 1990 Prenatal exposure to propranolol via continuous maternal infusion: effects on physiological and biochemical processes mediated by β-adrenergic receptors in fetal and neonatal rat lung. J Pharmacol Exp Ther 252: 42–50
Kudlacz EM, Navarro HA, Eylers JP, Slotkin TA 1990 Adrenergic modulation of cardiac development in the rat: effects of prenatal exposure to propranolol via continuous maternal infusion. J Dev Physiol 13: 243–249
Hou Q-C, Baker FE, Seidler FJ, Bartolome M, Bartolome J, Slotkin TA 1989 Role of sympathetic neurons in development of β-adrenergic control of ornithine decarboxylase activity in peripheral tissues: effects of neonatal 6-hydroxydopamine treatment. J Dev Physiol 11: 139–146
Hou Q-C, Seidler FJ, Slotkin TA 1989 Development of the linkage of β-adrenergic receptors to cardiac hypertrophy and heart rate control: neonatal sympathectomy with 6-hydroxydopamine. J Dev Physiol 11: 305–311
Wagner JP, Seidler FJ, Lappi SE, McCook EC, Slotkin TA 1995 Role of presynaptic input in the ontogeny of adrenergic cell signaling in rat brain: β receptors, adenylate cyclase, and c-fos protooncogene expression. J Pharmacol Exp Ther 273: 415–426
Metz LD, Seidler FJ, McCook EC, Slotkin TA 1996 Cardiac α-adrenergic receptor expression is regulated by thyroid hormone during a critical developmental period. J Mol Cell Cardiol 28: 1033–1044
Lagercrantz H, Slotkin TA 1986 The “stress” of being born. Sci Am 254: 100–107
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Supported by U.S. Public Health Service Grant HD-09713.
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Renick, S., Seidler, F., McCook, E. et al. Neuronal Control of Cardiac and Hepatic Macromolecule Synthesis in the Neonatal Rat: Effects of Sympathectomy. Pediatr Res 41, 359–363 (1997). https://doi.org/10.1203/00006450-199703000-00009
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DOI: https://doi.org/10.1203/00006450-199703000-00009
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