Autonomic Receptors of the Early Rat Embryo Heart: Growth and Development

Robkin, Maurice A.; Shepard, Thomas H.; Dyer, Donald C.

doi:10.3181/00379727-151-39310

Cited by 42 publications

(19 citation statements)

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“…Cardiac development provides a particularly prominent example. Physiological responses to ␤AR stimulation are demonstrable as early as the 16-somite embryo (Robkin et al, 1976). Knockouts of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, result in embryolethality because of cardiac malformations, and the catecholamine-deficient animals can be rescued by supplying norepinephrine precursors or ␤AR agonists (Thomas et al, 1995;Portbury et al, 2003).…”

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confidence: 99%

Ontogenesis of β-Adrenoceptor Signaling: Implications for Perinatal Physiology and for Fetal Effects of Tocolytic Drugs

Slotkin

Auman²,

Seidler

2003

J Pharmacol Exp Ther

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G-Protein-coupled receptors play an instrumental role in cellular development and function. In the mature organism, receptor signaling is controlled through the processes of desensitization and down-regulation. Recent evidence suggests that these regulatory mechanisms are not inherent properties, however, but rather are acquired during ontogenesis. This review focuses on ␤-adrenoceptors (␤ARs), which are found in fetal and neonatal tissues and are effectively linked through adenylyl cyclase (AC) to the production of cAMP. Agonist-induced stimulation of ␤ARs in the immature organism fails to produce desensitization, and instead, responsiveness increases. The unique mechanisms underlying this anomalous response involve induction of AC, a switch to more catalytically efficient AC isoforms, an increase in the ratio of stimulatory to inhibitory G-proteins, and interference with the expression and/or function of other Gprotein-linked receptors that provide offsetting, inhibitory inputs. These adjustments are thus heterologous, influencing signaling mediated by a host of other G-protein-coupled neurotransmitter and hormone receptors. The net effect is to maintain and augment ␤AR signaling in the face of continued stimulation, properties that disappear with maturation. The unique regulatory mechanisms for ␤AR signaling in the fetus and neonate provide the necessary physiological adjustments required for the perinatal transition from intrauterine to extrauterine life. At the same time, however, the inability to restrict ␤AR function may underlie adverse effects of ␤AR-agonist tocolytics that are used in the treatment of preterm labor. Regulation of ␤-Adrenoceptor Signaling in the Mature OrganismG-Protein-coupled receptors, one of the largest families of transmembrane signaling systems, are among the most studied mediators of cell-to-cell communication, pervading areas as diverse as central nervous system and peripheral autonomic function, cardiovascular and respiratory function, hormone actions, and carcinogenesis. This review will focus on the unusual features of receptor regulation during fetal and neonatal development, work that has largely involved the ␤-adrenoceptor (␤AR). In the adult, signaling through adenylyl cyclase (AC) via ␤-adrenoceptors has been particularly well characterized, representing a controlled, homeostatic system (Kohout and Lefkowitz, 2003). Ordinarily, excessive receptor stimulation is attenuated through two classes of mechanisms: uncoupling of ␤ARs from their response elements (desensitization) and reductions in the concentration of receptors at the cell membrane (down-regulation). Desensitization can be of two types, homologous and heterologous. With homologous desensitization, effects are restricted to ␤AR signaling, entailing phosphorylation of the agonistbound receptor on its carboxyl terminus, an effect mediated by the G-protein receptor kinases. Next, arrestins bind to the phosphorylated receptors, impairing receptor-G-protein interactions and thus terminating receptor signaling....

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confidence: 99%

Ontogenesis of β-Adrenoceptor Signaling: Implications for Perinatal Physiology and for Fetal Effects of Tocolytic Drugs

Slotkin

Auman²,

Seidler

2003

J Pharmacol Exp Ther

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“…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 the adult (25,26). Well before such innervation-dependent changes happen, however, chronotropic responses to exogenously administered catecholamines occur (27)(28)(29)(30)(31). The source(s) of endogenous catecholamines that regulate heart rate during perinatal development remain undefined.…”

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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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“…However, the apparently exaggerated responsiveness to AcH noted in the least mature hearts in the present investigation is more difficult to explain. Indeed, other investigators using the mouse (37,45) as well as other species (12,32,36) suggest that AcH response becomes progressively greater with increasing GA and increasing parasympathetic innervation. Variability in species, developmental age, specific methodology of preparation and preservation of fetal hearts, AcH dose, and experimental design make comparisons of AcH dose response relationships difticult.…”

Section: Discussionmentioning

confidence: 99%

“…must imply functional muscurinic acetylcholine receptors and an operative, chronotropic receptor-response coupling. Investigations of chronotropic responsiveness in hearts from fetal rats, (12,36) chicks, (6,14) mice (45) and humans (42) have demonstrated AcH induced heart rate slowing before morphologic parasympathetic innervation. Furthermore, Roeske and Yamanura (37) and Sastre et al (39) have detected AcH receptors before innkrvation by labeled competitive antagonist binding.…”

Section: Discussionmentioning

confidence: 99%

Developmental Factors Contributing to the Susceptibility to Bradycardia in Isolated, Cultured Fetal Mouse Hearts

Maurer

1979

Pediatr Res

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Summarvtle and attention behavioral responses (3,21,34,35,42). 2) The A propensity for bradycardia in preterm human infants suggested that the heart rate response to cholinergic stimulation may ;ary during development. Isolated, intact fetal mouse hearts (FMH) in organ culture were used as a model to explore developmental differences in chronotropic response to cholinergic stimulation. FMH's of gestational ages (GA) from 13-22 days, maintained for 36 hr in culture, were exposed to acetylcholine (AcH) with and without prior addition of physostigmine. Heart rate decreased markedly with lo-' and lo-' M AcH (84 & 3 and 48 4 %) in 13-14 day hearts, but the decrease was progressively blunted with increasing age and was only 7 + 3 and 3 f 2 % at 21-22 days GA. Physostigmine markedly enhanced the cholinergic response in older hearts with 54 f 4 and 32 + 5 % decreases in heart rate with the two doses of AcH at 21-22 days. However, it did not alter the response i n younger hearts.The data suggest that the chronotropic response to AcH progressively diminishes with advancing GA and the extent of intrinsic cholinesterase activity at different GA's is, in part, responsible for the decrease. SpeculationIncreasing cholinesterase activity during gestation may, in part, protect more mature fetal hearts from severe bradycardia. Likekise, "unprotected" AcH receptors may account for the pronounced bradvcardia in less mature hearts. If unprotected AcH receptors are important to the bradycardic response, does this play any role in vivo? One possibility is that the fetal heart's capacity to synthesize AcH and acetylcholinesterase may not develop synchronously. Such nonparallel enzyme system develop ment might occur as a normal developmental sequence, exposed abnormally by premature birth or conversely, may be induced by abnormalities during gestation ( e.g., chronic hypoxemia, intrauterine malnutrition). This general scheme is not unprecedented in that asynchronous development of interrelated enzymes systems deleterious to the prematurely born have already been well documented in the liver and lung. This hypothesis is currently being investigated.The widespread use of heart rate monitoring in fetal and neonatal intensive care has revealed a rather high incidence of bradyarrhythmias in the newborn infant (8,21,25,38,41,42). In fact, detection of bradycardia has become a major factor in determining the therapeutic threshold of certain fetal and neonatal afflictions (13,17).Clinical and laboratory investigations as well as simple clinical observations have suggested: 1) Bradycardia (usually sinus) occurs spontaneously and.in response to a wide variety of stimuli such as increased CNS pressure, umbilical cord compression, hypoxemia, apnea, nasopharyngeal and laryngeal stimulation, defecation, star-incidence and/or the severity ofbradycardia may be increased in the premature infant (18,26,27,34).As a group, immature fetuses and neonates are certainly subject to more bradycardia-evoking stimuli. However, the occurrence and severity of this ...

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Autonomic Receptors of the Early Rat Embryo Heart: Growth and Development

Cited by 42 publications

References 0 publications

Ontogenesis of β-Adrenoceptor Signaling: Implications for Perinatal Physiology and for Fetal Effects of Tocolytic Drugs

Ontogenesis of β-Adrenoceptor Signaling: Implications for Perinatal Physiology and for Fetal Effects of Tocolytic Drugs

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

Developmental Factors Contributing to the Susceptibility to Bradycardia in Isolated, Cultured Fetal Mouse Hearts

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