Postnatal changes in the cardiorespiratory response and ability to autoresuscitate from hypoxic and hypothermic exposure in mammals

Most mammals are born immature and a great deal of maturational changes must occur early in the early postnatal life to prepare for life as an adult. In addition to the obvious changes such as physical and musculoskeletal growth, a myriad of physiological changes including the cardiorespiratory responses to hypoxia and hypothermia must also occur. The most intriguing developmental effect is perhaps the change in the ability to autoresuscitate, or spontaneous recovery from cardiorespiratory arrest induced by extreme hypoxia or hypothermia. For decades the ability of young animals to autoresuscitate from cardiorespiratory arrest induced by hypoxic or hypothermic exposure has been documented. In some mammalian species, including rats and humans, this ability is lost over development while others retain this ability. This review will examine the changes that occur in the cardiorespiratory response to hypoxia and hypothermia and the change to the ability to autoresuscitate from cardiorespiratory arrest over early postnatal development. Furthermore, the review will explore some of the potential neuroanatomical, neurochemical and neurophysiological changes during early postnatal development that might contribute to the altered reflex response to hypoxia and hypothermia and the ability to autoresuscitate.10 page(s

Stimulating peripheral afferents to evoke cardiorespiratory reflex responses in the in situ arterially perfused preparation

The in situ arterially perfused rodent preparation is an innovation that has allowed for significant progress in the study of cardiorespiratory reflex circuitry. This preparation provides a number of advantages over other preparations. The retention of peripheral cardiorespiratory afferents enables the study of reflex circuitry that is not possible in in vitro slice preparations. In addition, the in situ arterially perfused preparation provides unsurpassed mechanical stability of the brainstem compared with the in vivo preparation. This stability allows for better cellular recordings for prolonged periods. Here, the basic technique for the in situ arterially perfused preparation including recording of a number of cardiovascular and respiratory parameters is described. In addition, some of the common techniques for stimulating peripheral afferent nerves that produce different cardiovascular and respiratory reflex responses are discussed.18 page(s

Mechanism of sympathetic activation and blood pressure elevation in humans and animals following acute intermittent hypoxia

Sleep apnea is associated with repeated episodes of hypoxemia, causing marked increase in sympathetic nerve activity and blood pressure. Considerable evidence suggests that intermittent hypoxia (IH) resulting from apnea is the primary stimulus for sympathetic overactivity in sleep apnea patients. Several IH protocols have been developed either in animals or in humans to investigate mechanisms underlying the altered autonomic regulation of the circulation. Most of these protocols involve several days (10-40 days) of IH exposure, that is, chronic intermittent hypoxia (CIH). Recent data suggest that a single session of IH exposure, that is, acute intermittent hypoxia (AIH), is already capable of increasing tonic sympathetic nerve output (sympathetic long-term facilitation, LTF) and altering chemo- and baroreflexes with or without elevation of blood pressure. This indicates that IH alters the autonomic neurocirculatory at a very early time point, although the mechanisms underlying this neuroplasticity have not been explored in detail. The purpose of this chapter is to briefly review the effects of AIH on sympathetic LTF and alteration of autonomic reflexes in comparison with the studies from CIH studies. We will also discuss the potential central and peripheral mechanism underlying sympathetic LTF.16 page(s

Effects of postnatal development, temperature and the pons on respiratory rhythm and pattern generation in rat pups

Episodic breathing is common in premature infants and is found in fetal rats but rarely reported in postnatal (P) in vitro preparations. We discovered that episodic breathing patterns were common (>60%) in in vitro pontomedullary-spinal cord preparations at 27°C from rat pups on the day of birth (P0), but the occurrence of this breathing pattern declined with postnatal development. Chemical inhibition and physical removal of the pons eliminated the episodic breathing pattern at P0. Interestingly, episodic breathing patterns could be restored in older preparations (P2 – P4) by decreasing temperature (23°C), with or without the pons. In preparations held at 27°C, with a continuous rhythm, an episodic rhythm could be produced by activating GABA receptors (100μM GABA). In preparations with an episodic pattern, antagonism of opioid receptors by naloxone (1–5μm) did not affect the episodic rhythm while blockade of GABAA receptors by bicuculline (BIC, 10μM) converted the episodic rhythm to a continuous rhythm. However, in preparations held at 23°C, BIC (10μM) had the opposite effect, promoting episodicity. Together, these data suggest the mechanisms required for episodic rhythm generation are intrinsic to the medulla, and are modulated by postnatal development, temperature sensitive mechanisms (such as TRP channels) and pontine factors. Funded by NSERC (Canada).1 page(s

Intrathecal melanin-concentrating hormone reduces sympathetic tone and blocks cardiovascular reflexes

Melanin-concentrating hormone (MCH) is a neuropeptide that acts to increase feeding behavior and decrease energy expenditure. The role of MCH in central cardiorespiratory regulation is still poorly understood. Experiments were conducted on urethane-anesthetized, vagotomized, and artificially ventilated male Sprague-Dawley rats (n = 22) to ascertain whether MCH modulates sympathetic vasomotor tone, as well as barosympathetic, chemosympathetic, and somatosympathetic reflexes at the level of the spinal cord. Intrathecal injection of 10 μl of MCH produced a dose-dependent hypotension, bradycardia, and sympathoinhibition. Peak response was observed following administration of 1 mM MCH, causing a decrease in mean arterial pressure of 39 ± 2 mmHg (P < 0.001), splanchnic sympathetic nerve activity of 78 ± 11% (P < 0.001), and heart rate of 87 ± 11 beats per minute (bpm) (P < 0.01). The two peaks of the somatosympathetic reflex were decreased by intrathecal MCH, 7 ± 3% (P < 0.01) and 31 ± 6% (P < 0.01), respectively, and the spinal component of the reflex was accentuated 96 ± 23% (P < 0.05), with respect to the baseline for MCH, compared with the two peaks and spinal component of the somatosympathetic reflex elicited following saline injection with respect to the baseline for saline. MCH decreased the sympathetic gain to 120 s of hyperoxic hypercapnea (10% CO₂ in 90% O₂) and to 10-12 s poikilocapneic anoxia (100% N2) from 0.74 ± 0.14%/s to 0.23 ± 0.04%/s (P < 0.05) and 16.47 ± 3.2% to 4.35 ± 1.56% (P < 0.05), respectively. There was a 34% decrease in gain and a 62% decrease in range of the sympathetic baroreflex with intrathecal MCH. These data demonstrate that spinal MCH blunts the central regulation of sympathetic tone and adaptive sympathetic reflexes.9 page(s

Acute intermittent hypoxia induced neural plasticity in respiratory motor control

Summary: Respiratory neural networks can adapt to rapid environmental change or be altered over the long term by various inputs. The mechanisms that underlie the plasticity necessary for adaptive changes in breathing remain unclear. Acute intermittent hypoxia (AIH)-induced respiratory long-term facilitation (LTF) is one of the most extensively studied types of respiratory plasticity. Acute intermittent hypoxia-induced LTF is present in several respiratory motor outputs, innervating both pump muscles (i.e. diaphragm) and valve muscles (i.e. tongue, pharynx and larynx). Long-term facilitation is present in various species, including humans, and the expression of LTF is influenced by gender, age and genetics. Serotonin plays a key role in initiating and modulating plasticity at the level of respiratory motor neurons. Recently, multiple intracellular pathways have been elucidated that are capable of giving rise to respiratory LTF. These mainly activate the metabolic receptors coupled to Gq ('Q' pathway) and Gs ('S' pathway) proteins. Herein, we discuss AIH-induced respiratory LTF in animals and humans, as well as recent advances in our understanding of the synaptic and intracellular pathways underlying this form of plasticity. We also discuss the potential to use intermittent hypoxia to induce functional recovery following cervical spinal injury.8 page(s

Recurrent laryngeal nerve activity exhibits a 5-HT-mediated long-term facilitation and enhanced response to hypoxia following acute intermittent hypoxia in rat

A progressive and sustained increase in inspiratory-related motor output ("long-term facilitation") and an augmented ventilatory response to hypoxia occur following acute intermittent hypoxia (AIH). To date, acute plasticity in respiratory motor outputs active in the postinspiratory and expiratory phases has not been studied. The recurrent laryngeal nerve (RLN) innervates laryngeal abductor muscles that widen the glottic aperture during inspiration. Other efferent fibers in the RLN innervate adductor muscles that partially narrow the glottic aperture during postinspiration. The aim of this study was to investigate whether or not AIH elicits a serotonin-mediated long-term facilitation of laryngeal abductor muscles, and if recruitment of adductor muscle activity occurs following AIH. Urethane anesthetized, paralyzed, unilaterally vagotomized, and artificially ventilated adult male Sprague-Dawley rats were subjected to 10 exposures of hypoxia (10% O 2 in N 2, 45 s, separated by 5 min, n = 7). At 60 min post-AIH, phrenic nerve activity and inspiratory RLN activity were elevated (39 ± 11 and 23 ± 6% above baseline, respectively). These responses were abolished by pretreatment with the serotonin-receptor antagonist, methysergide (n = 4). No increase occurred in time control animals (n = 7). Animals that did not exhibit postinspiratory RLN activity at baseline did not show recruitment of this activity post-AIH (n = 6). A repeat hypoxia 60 min after AIH produced a significantly greater peak response in both phrenic and RLN activity, accompanied by a prolonged recovery time that was also prevented by pretreatment with methysergide. We conclude that AIH induces neural plasticity in laryngeal motoneurons, via serotonin-mediated mechanisms similar to that observed in phrenic motoneurons: the so-called "Q-pathway". We also provide evidence that the augmented responsiveness to repeat hypoxia following AIH also involves a serotonergic mechanism.13 page(s

The ventilatory response to hypoxia and hypercapnia is absent in the neonatal fat-tailed dunnart

At birth, the newborn fat-tailed dunnart relies on cutaneous gas exchange to meet metabolic demands, with continuous lung ventilation emerging several days later. We hypothesised that the delayed expression of lung ventilation (V-E) in these animals is in part due to a low responsiveness of the respiratory control system to blood gas perturbations. To address this hypothesis, we assessed the ventilatory and metabolic response to hypoxia (10% O₂) and hypercapnia (5% CO₂) using closed-system respirometry from birth to 23 days postpartum (P). Neonatal fat-tailed dunnarts displayed no significant hypoxic or hypercapnic ventilatory responses at any age. Regardless, significant hyperventilation through a suppression of metabolic rate (VO₂) was observed at birth in response to hypercapnia and in response to hypoxia at all ages, except P12. Therefore, reliance on cutaneous gas exchange during early life may be partially attributed to reduced chemosensitivity or a lack of central integration of chemosensitive afferent information. This may be in part due to the relative immaturity of this species at birth, compared with other mammals.6 page(s