Postnatal development of the pattern of respiratory and cardiovascular response to systemic hypoxia in the piglet: the roles of adenosine.

Elnazir, Basil; Marshall, Janice M.; Kumar, Prem

doi:10.1113/jphysiol.1996.sp021330

Cited by 55 publications

(36 citation statements)

References 39 publications

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“…This is of particular interest because there are reports in the literature indicating that the respiratory and cardiovascular responses evoked by systemic hypoxia in neonates are very similar to those we have seen in the rat: characteristically, ventilation increases and then falls and generally arterial pressure decreases (see 64,65). We have suggested this may arise because small mammals in general, whether the neonates of large mammalian species or the adults of small mammalian species, have a higher rate of O 2 consumption per gram body weight than larger mammals: they may therefore be more susceptible to the local metabolic effects of hypoxia when O 2 supply is reduced (55).…”

Section: The Gradual Effects Of Hypoxiasupporting

confidence: 54%

“…Our experiments on newborn piglets indicate that this positive feedback loop is particularly likely to develop in individuals in whom the stimulatory effect of hypoxia on respiration is weak (64). Furthermore, our studies on rats that have been kept chronically hypoxic from birth in a hypoxic chamber, have shown that the bradycardia fall in arterial pressure and fall in cerebral blood flow induced by acute hypoxia is greatly exaggerated in these animals relative to those seen in controls (67).…”

Section: A Positive Feedback Loop?mentioning

confidence: 62%

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Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

Jm¹

1998

Braz J Med Biol Res

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This review describes the ways in which the primary bradycardia and peripheral vasoconstriction evoked by selective stimulation of peripheral chemoreceptors can be modified by the secondary effects of a chemoreceptor-induced increase in ventilation. The evidence that strong stimulation of peripheral chemoreceptors can evoke the behavioural and cardiovascular components of the alerting or defence response which is characteristically evoked by novel or noxious stimuli is considered. The functional significance of all these influences in systemic hypoxia is then discussed with emphasis on the fact that these reflex changes can be overcome by the local effects of hypoxia: central neural hypoxia depresses ventilation, hypoxia acting on the heart causes bradycardia and local hypoxia of skeletal muscle and brain induces vasodilatation. Further, it is proposed that these local influences can become interdependent, so generating a positive feedback loop that may explain sudden infant death syndrome (SIDS). It is also argued that a major contributor to these local influences is adenosine. The role of adenosine in determining the distribution of O 2 in skeletal muscle microcirculation in hypoxia is discussed, together with its possible cellular mechanisms of action. Finally, evidence is presented that in chronic systemic hypoxia, the reflex vasoconstrictor influences of the sympathetic nervous system are reduced and/or the local dilator influences of hypoxia are enhanced. In vitro and in vivo findings suggest this is partly explained by upregulation of nitric oxide (NO) synthesis by the vascular endothelium which facilitates vasodilatation induced by adenosine and other NO-dependent dilators and attenuates noradrenaline-evoked vasoconstriction. Correspondence

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Section: The Gradual Effects Of Hypoxiasupporting

confidence: 54%

Section: A Positive Feedback Loop?mentioning

confidence: 62%

Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

Jm¹

1998

Braz J Med Biol Res

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“…This new finding narrows the window when a switch in adenosine's ability to depress breathing occurs. Previous studies in rats (5, 9), rabbits (4), and piglets (33), have reported a similar reduction of adenosinergic effect to occur within the first days or weeks after birth. Immediately after birth, as the partial pressure for oxygen increases, circulating levels of adenosine decrease (3,34), correlating with decreased extracellular levels in the brain (10), and thus the adenosinergic inhibition of breathing is reduced.…”

Section: Adenosinergic Respiratory Depression Decrease After Birthsupporting

confidence: 54%

Perinatal Respiratory Control and Its Modulation by Adenosine and Caffeine in the Rat

et al. 2002

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The perinatal development of respiratory rhythm generation and its modulation by adenosinergic drugs have been examined in rats from embryonic d 18 (E18) to postnatal d 3 using an in vitro brain stem-spinal cord preparation. Generation of rhythmic respiratory activity in the medulla oblongata and inhibition of this activity by pontine structures were evident on E18. The adenosine A 1 -receptor agonist, N 6 -(2-phenylisopropyl) adenosine, R (Ϫ) isomer (R-PIA) (1 M), induced an age-dependent reduction of respiratory frequency that could be reversed by the adenosine antagonist theophylline (55 M). The effect of R-PIA was reduced 24 h after birth compared with E21 and 2 h postnatal age. In preparations from pups that had been exposed to a low dose of caffeine (0.3 g/L in drinking water to dams), pontine inhibition of respiratory rhythm generation in the medulla was more pronounced. When the pons was removed, the respiratory frequency was higher than in the control group. Adenosine A 1 -mRNA and A 1 -receptor development in pons and medulla were studied, and by E18, mRNA, receptor protein, and functional coupling to G-proteins were confirmed using guanylyl-5'-O-(␥-[35 S]thio)-triphosphate binding. There were no major changes in receptor numbers or distribution of A 1 receptors or mRNA in rat pups subjected to caffeine exposure. We conclude that respiration is already modulated by adenosine A 1 receptors at the level of the medulla oblongata in the fetal period in an age-dependent manner. Furthermore, long-term maternal caffeine intake during gestation seems to increase the pontine inhibition of, and the activity of, respiratory rhythm-generating neuronal networks in medulla oblongata without detectable changes in expression of A 1 -receptor number or A 1 -receptor mRNA. Fetal respiratory movements are episodic and progressively more inhibited toward the end of pregnancy when periods without respiratory movements dominate (1). Respiratory activity must be generated continuously from birth. New tactile stimuli, such as light, cooling, removal of the umbilical circulation, arousal, air in the upper and lower airways, increased pulmonary blood flow, increased oxygen consumption, vagal input from mechanoreceptors, are all involved in the initiation and maintenance of breathing (2). This transition of respiratory control is probably related to modulatory factors affecting the CPG for respiration located in the brain stem (rostral ventrolateral medulla oblongata).Adenosine is one of the neuromodulators involved in respiratory control and may be especially important around birth (3-5). Centrally applied adenosine analogs depress respiratory rate and depth (6 -8) via adenosine A 1 receptors in the brain stem (5, 9). Circulating levels of adenosine decrease immediately after birth (3), correlating to decreased extracellular levels in the brain (10), and a decrease of adenosinergic inhibition may contribute to the establishment of postnatal breathing.Furthermore, the effect of adenosine is antagonized by caffeine in doses resem...

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“…The ventilatory response to hypoxia has been previously characterized in anesthetized piglets, and the current responses of diaphragm amplitude and frequency are consistent with prior studies (12)(13)(14)(15). A gradual increase in heart rate accompanied hypoxic exposure in these earlier studies (12,13).…”

Section: Discussionsupporting

confidence: 84%

Effects of Hypoxia on Respiratory Neural Output and Lower Esophageal Sphincter Pressure in Piglets

et al. 2002

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We have previously documented anatomic and functional relationships between ventilatory and autonomic neural output. Therefore, we hypothesized in this study that hypoxia-induced changes in respiratory neural output are associated with changes in autonomic regulation of lower esophageal sphincter (LES) pressure. Respiratory neural output, heart rate, and LES pressure were measured before and during a 3-min exposure to 8% oxygen (balance nitrogen) in 12 3-to 7-d-old piglets. Respiratory neural output was determined from diaphragmatic electromyogram and LES pressure from an esophageal catheter. Studies were repeated after atropine administration in eight animals. Hypoxic exposure resulted in significant increases in diaphragmatic amplitude, respiratory rate, and minute diaphragmatic activity as well as heart rate. The biphasic response of diaphragm amplitude peaked at 1 min, whereas the responses of respiratory frequency and heart rate were sustained. Hypoxia caused a 50% increase in LES pressure (p Ͻ 0.05), which was eliminated by i.v. atropine administration. Development of apnea during subsequent hyperoxic exposure was always followed by a decline in LES pressure. Hypoxia-induced increase in respiratory neural output and accompanying increase in heart rate are associated with enhanced constrictive output to the LES. Blockade by atropine implicates a peripheral cholinergic mechanism for this LES response. We speculate that whereas hypoxia in the presence of enhanced respiratory neural output seems to be protective against reflux, decreased respiratory drive and accompanying apnea may be associated with a decline in LES tone and predispose to gastroesophageal reflux. Neuroanatomic studies have identified that neuronal circuits involved in coordination of respiratory control are linked to parasympathetic motor output from vagal preganglionic neurons in the brainstem (1, 2). A functional role for such interconnections has been documented in several species, including puppies and piglets (3, 4). For example, hypoxic stimulation in piglets is associated with an increase in both phrenic neural output and contractile responses in peripheral airways and/or lung parenchyma, which are cholinergically mediated (5). This is consistent with the clinical observation that an acute reduction in inspired oxygen may lead to airway constriction in infants with chronic lung disease (6).Vagal preganglionic neurons, including neurons of the DMV, also contribute preganglionic parasympathetic motor innervation to the LES (7). Therefore, alterations in respiratory neural output elicited by chemoreceptor stimulation might be expected to modulate LES pressure. This would be of particular interest during early maturation, as recurrent apnea with resultant desaturation and gastroesophageal reflux are both common in premature infants, although their relationship is controversial (8 -11) and difficult to simulate in an animal model. In the current study, we therefore used a piglet model to test the hypothesis that hypoxia-induced changes in r...

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Postnatal development of the pattern of respiratory and cardiovascular response to systemic hypoxia in the piglet: the roles of adenosine.

Cited by 55 publications

References 39 publications

Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

Perinatal Respiratory Control and Its Modulation by Adenosine and Caffeine in the Rat

Effects of Hypoxia on Respiratory Neural Output and Lower Esophageal Sphincter Pressure in Piglets

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