Expression of Phenylethanolamine N-methyltransferase in the Embryonic Rat Heart

Ebert, Steven N.; Baden, Jeffrey M.; Mathers, Lawrence H.; Siddall, Brenda; Wong, Dona L.

doi:10.1006/jmcc.1996.0155

Cited by 51 publications

(51 citation statements)

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“…Taken together, the survival pattern of these four types of mutant mice provides support for an essential role for norepinephrine in the fetus. Although low levels of epinephrine have been detected at midgestation and are synthesized in the embryonic heart (10,11), biosynthesis of epinephrine does not become substantial until after the peak window of death, suggesting that the essential catecholamine is norepinephrine (33). Because both norepinephrine and epinephrine act at the same receptors, these data show that activation of adrenergic receptors is essential for fetal viability.…”

mentioning

confidence: 81%

Catecholamines act via a β-adrenergic receptor to maintain fetal heart rate and survival

Portbury¹,

Chandra²,

Groelle³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Catecholamines act via a ␤-adrenergic receptor to maintain fetal heart rate and survival. Am J Physiol Heart Circ Physiol 284: H2069-H2077, 2003. First published February 6, 2003 10.1152/ajpheart.00588.2002Mice lacking catecholamines die before birth, some with cardiovascular abnormalities. To investigate the role of catecholamines in development, embryonic day 12.5 (E12.5) fetuses were cultured and heart rate monitored. Under optimal oxygenation, wild-type and catecholamine-deficient fetuses had the same initial heart rate (200-220 beats/min), which decreased by 15% in wild-type fetuses during 50 min of culture. During the same culture period, catecholamine-deficient fetuses dropped their heart rate by 35%. Hypoxia reduced heart rate of wild-type fetuses by 35-40% in culture and by 20% in utero, assessed by echocardiography. However, catecholamine-deficient fetuses exhibited greater hypoxia-induced bradycardia, reducing their heart rate by 70-75% in culture. Isoproterenol, a ␤-adrenergic receptor (␤-AR) agonist, reversed this extreme bradycardia, restoring the rate of catecholamine-deficient fetuses to that of nonmutant siblings. Moreover, isoproterenol rescued 100% of catecholamine-deficient pups to birth in a dose-dependent, stereospecific manner when administered in the dam's drinking water. An ␣-AR agonist was without effect. When wild-type fetuses were cultured with adrenoreceptor antagonists to create pharmacological nulls, blockade of ␣-ARs with 10 M phentolamine or ␤-ARs with 10 M bupranolol alone or in combination did not reduce heart rate under optimal oxygenation. However, when combined with hypoxia, ␤-AR blockade reduced heart rate by 35%. In contrast, the muscarinic blocker atropine and the ␣-AR antagonist phentolamine had no effect. These data suggest that ␤-ARs mediate survival in vivo and regulate heart rate in culture. We hypothesize that norepinephrine, acting through ␤-ARs, maintains fetal heart rate during periods of transient hypoxia that occur throughout gestation, and that catecholamine-deficient fetuses die because they cannot withstand hypoxia-induced bradycardia. tyrosine hydroxylase; dopamine ␤-hydroxylase; norepinephrine; hypoxia; adrenoreceptor DESPITE THE FACT THAT IN RODENTS catecholamines and their adrenergic receptors (AR) are present as early as embryonic day 8 and 9 (E8-9) (4, 33), pharmacological experiments suggested that ␤-AR activation by norepinephrine and epinephrine was not essential in the fetus. Pregnant rat dams treated with a nonselective

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mentioning

confidence: 81%

Catecholamines act via a β-adrenergic receptor to maintain fetal heart rate and survival

Portbury¹,

Chandra²,

Groelle³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…In some experiments, the serum was pretreated with charcoal before adding it to the media (10% volume as above) to remove possible trace amounts of catecholamines that may have been present. The cells were then "preplated" to remove fibroblasts as described previously (7), and the remaining cells counted and seeded onto multiwell culture plates at a density of 75,000 cells per cm 2 . The media was changed every 2-3 d beginning the day after seeding.…”

Section: Methodsmentioning

confidence: 99%

“…The catecholamines epinephrine and norepinephrine are neurotransmitter stress hormones that influence cardiac function profoundly. We and others have shown that the heart itself produces these catecholamines in specialized cells known as ICA cells (1)(2)(3). We have also shown that these cells are transiently and progressively associated with different regions of the embryonic rat heart that are important sites for pacemaking and conduction tissue development (e.g.…”

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confidence: 99%

Intrinsic Cardiac Catecholamines Help Maintain Beating Activity in Neonatal Rat Cardiomyocyte Cultures

Natarajan

Katchman

et al. 2004

Pediatr Res

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In the present study, we identify intrinsic cardiac adrenergic (ICA) cells in the neonatal rat heart using immunofluorescent histochemical staining techniques with antibodies that specifically recognize the major enzymes in the catecholamine biosynthetic pathway. ICA cells are most concentrated near the endocardial surface of ventricular myocardium, but are also found sporadically throughout the heart. In primary cultures of neonatal rat cardiomyocytes, ICA cells are closely associated with clusters of cardiomyocytes. To investigate a potential role for intrinsically produced catecholamines, we recorded beating rates in the presence and absence of the catecholamine-depleting agent reserpine or the adrenergic receptor blockers prazosin and timolol using videomicroscopy and photodiode sensors. Our results show that beating rates slow significantly when endogenous catecholamines are depleted or when their action is blocked with either a ␤-or an ␣ 1 -adrenergic receptor antagonist. These data indicate that intrinsic cardiac catecholamines help to maintain beating rates in neonatal rat cardiomyocyte cultures via stimulation of ␣ 1 -and ␤-adrenergic receptors. This information should help to increase our understanding of the physiologic mechanisms governing cardiovascular function in neonates. The catecholamines epinephrine and norepinephrine are neurotransmitter stress hormones that influence cardiac function profoundly. We and others have shown that the heart itself produces these catecholamines in specialized cells known as ICA cells (1-3). We have also shown that these cells are transiently and progressively associated with different regions of the embryonic rat heart that are important sites for pacemaking and conduction tissue development (e.g. sinoatrial node, atrioventricular canal, bundle of His, and ventricular septum) (3). ICA cells appear to persist in the heart postnatally as they have been found in neonatal (1, 4 -6) and adult (1, 7-11) hearts. In adult hearts, ICA cells are often found clustered around sites of innervation (6, 7, 10). In the neonate, sympathetic innervation of the heart is incomplete (12), and little is known about the specific distribution of ICA cells in the heart (13-15). Further, the functional significance of these ICA cells in the neonatal (or adult) heart is unknown.The neonatal period is characterized by dramatic cardiovascular adaptation to extrauterine life. Although peripheral catecholamines are synthesized by the adrenal medulla (16 -18) and organ of Zuckerkandl (19,20) in the perinatal period, functional sympathetic innervation of the heart is not completed until the second week after birth in rats (15, 21). The neonatal rat heart, nevertheless, expresses fully functional ␣-and ␤-adrenergic receptors, allowing for chronotropic responses to either ␣ 1 -or ␤-adrenergic agonists (22-24). Once functional sympathetic innervation of the heart is achieved, ␣ 1 -agonists lose their ability to stimulate heart rate (22), which comes increasingly under ␤-adrenergic control, as seen in...

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“…In both cases, cardiomyocyte cell size was decreased, and they were disorganized, resulting in atrophied hearts as early as E10.5 (47). Interestingly, the peak of PEX1 expression in the embryonic heart matches the transient burst of phenylethanolamine N-methyltransferase, the final enzyme in catecholamine synthesis which takes place between E9.5 and E13.5 (15). Together with its demonstrated function as a transcriptional regulator and an effector of ␣1-adrenergic signaling in cardiomyocytes, these data raise the intriguing possibility that PEX1 may have a role in the control of cardiomyocyte proliferation and/or the response of cardiac cells to catecholamines during development.…”

Section: Discussionmentioning

confidence: 98%

The Zinc Finger-Only Protein Zfp260 Is a Novel Cardiac Regulator and a Nuclear Effector of α1-Adrenergic Signaling

Debrus

Rahbani

Marttila

et al. 2005

Molecular and Cellular Biology

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␣1-Adrenergic receptors mediate several biological effects of catecholamines, including the regulation of myocyte growth and contractility and transcriptional regulation of the atrial natriuretic factor (ANF) gene whose promoter contains an ␣1-adrenergic response element. The nuclear pathways and effectors that link receptor activation to genetic changes remain poorly understood. Here, we describe the isolation by the yeast one-hybrid system of a cardiac cDNA encoding a novel nuclear zinc finger protein, Zfp260, belonging to the Krüppel family of transcriptional regulators. Zfp260 is highly expressed in the embryonic heart but is downregulated during postnatal development. Functional studies indicate that Zfp260 is a transcriptional activator of ANF and a cofactor for GATA-4, a key cardiac regulator. Knockdown of Zfp260 in cardiac cells decreases endogenous ANF gene expression and abrogates its response to ␣1-adrenergic stimulation. Interestingly, Zfp260 transcripts are induced by ␣1-adrenergic agonists and are elevated in genetic models of hypertension and cardiac hypertrophy. The data identify Zfp260 as a novel transcriptional regulator in normal and pathological heart development and a nuclear effector of ␣1-adrenergic signaling.The endogenous catecholamines epinephrine and norepinephrine are key regulators of numerous physiologic functions, including learning, memory, and cardiovascular and endocrine homeostasis. Their dysregulation has been implicated in human conditions such as depression and addiction and in cardiovascular and metabolic diseases. Their effects are mediated by three classes of adrenergic receptors (ARs), ␤, ␣1, and ␣2, each comprised of three distinct gene products. They all belong to the superfamily of seven transmembrane G-protein-coupled receptors. ␣1-ARs are critical for a variety of catecholamine actions such as the control of blood pressure, smooth muscle contraction, myocardial function, and glycogenolysis. The importance of ␣1-ARs in physiology and pathophysiology is evidenced by the wide clinical use of ␣1-AR agonists and antagonists for the treatment of cardiovascular disease, flu and allergy symptoms, and benign prostate hyperplasia (40, 43). Paradoxically, the molecular mechanisms underlying ␣1-AR action remain undefined.Historically, the role of ␣1-ARs in different biologic systems was largely inferred from pharmacologic studies, but the development of transgenic mice with targeted deletion or overexpression of specific ␣1-AR subtypes has further confirmed the essential role of specific ␣1-ARs in regulation of physiologic processes (reviewed in references 40 and 44). For example, ␣1-null mice rapidly develop hyperinsulinemia, insulin resistance, and obesity in response to high-fat feeding, confirming the important role of ␣1-AR in the regulation of glucose homeostasis (7). The use of genetically altered mice also confirmed the essential role of ␣1-ARs in mediating the effects of some psychostimulants and opiates and, more generally, their involvement in the regulation of vario...

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Expression of Phenylethanolamine N-methyltransferase in the Embryonic Rat Heart

Cited by 51 publications

References 0 publications

Catecholamines act via a β-adrenergic receptor to maintain fetal heart rate and survival

Catecholamines act via a β-adrenergic receptor to maintain fetal heart rate and survival

Intrinsic Cardiac Catecholamines Help Maintain Beating Activity in Neonatal Rat Cardiomyocyte Cultures

The Zinc Finger-Only Protein Zfp260 Is a Novel Cardiac Regulator and a Nuclear Effector of α1-Adrenergic Signaling

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