Biomedical subjects

Julian F R Paton

Publications and source records attributed to Julian F R Paton.

At least 19 recordsLinked to original sources

PubMed2007

Osmotic regulation of neuronal nitric oxide synthase expression in the rat amygdala: functional role for nitric oxide in adaptive responses?

Water-deprivation-induced osmotic stress leads to activation of a number of adaptive responses. Nitric oxide (NO) has been implicated in the modulation of these responses, as the amygdala has been implicated in ingestive behavior and modulation of autonomic homeostatic functions. Here we investigated the effects of water deprivation on neuronal nitric oxide synthase (nNOS) expression within the rat amygdala; a brain area involved in modulating ingestive behavior and autonomic function. Water deprivation resulted in significant increases in nNOS immunoreactivity (-ir) within different regions of the amygdala compared with euhydrated rats. Maximal increases were observed in the anteroventral (118 +/- 9 vs. 47 +/- 3 neurons), anteriodorsal (133 +/- 9 vs. 77 +/- 3), and posterioventral (175 +/- 5 vs. 71 +/- 5) parts of the medial amygdala. The basomedial nucleus (65 +/- 4 vs. 39 +/- 3) and posterior basolateral nucleus (19 +/- 2 vs. 5 +/- 1) of the amygdala and the capsular (21 +/- 2 vs. 6 +/- 1) and medial (44 +/- 6 vs. 22 +/- 3) parts of the central nucleus of the amygdala also showed increased nNOS-ir in dehydrated rats. Water deprivation had no effect on nNOS-ir in areas such as the cortical, anterior basolateral, and intercalated nuclei of the amygdala. Microinjection of an NO donor, DEA-NONOate, into the central amygdala resulted in a pressor and tachycardic response that was attenuated by a soluble guanylate cyclase inhibitor. These observations suggest that activation of the nitrergic system is prevalent throughout the amygdala following water deprivation and suggest that the up-reguation of nNOS could play a significant role in the integrative response to osmotic stress.

Adaptation, Physiological↗

PubMed2006

Hierarchical recruitment of the sympathetic and parasympathetic limbs of the baroreflex in normotensive and spontaneously hypertensive rats.

The arterial baroreflex acts to buffer acute changes in blood pressure by reciprocal modulation of sympathetic and parasympathetic activity that controls the heart and vasculature. We have examined the baroreflex pressure-function curves for changes in heart rate and non-cardiac sympathetic nerve activity (SNA, thoracic chain T8-12) in artificially perfused in situ rat preparations. We found that the non-cardiac SNA baroreflex is active over a lower range of pressures than the cardiac baroreflex (threshold 66 +/- 1 mmHg versus 82 +/- 5 mmHg and mid-point 77 +/- 3 versus 87 +/- 4 mmHg, respectively, P < 0.05, n = 6). This can manifest as a complete dissociation of the baroreflex limbs at low pressures. This difference between the cardiac and non-cardiac SNA baroreflex is also seen in end-organ sympathetic outflows (adrenal and renal nerves). Recordings of the cardiac vagal (parasympathetic) and the inferior cardiac (sympathetic) nerves identify the cardiac parasympathetic baroreflex component as being active over a higher range of pressures. This difference in the operating range of the baroreflex-function curves is exaggerated in the spontaneously hypertensive rat where the cardiac component has selectively reset by 20-25 mmHg to a higher pressure range (threshold of 104 +/- 4 mmHg and mid-point 113 +/- 4, n = 6). The difference in the pressure-function curves for the cardiac versus the vascular baroreflex indicates that there is a hierarchical recruitment of the output limbs of the baroreflex with a sympathetic predominance at lower arterial pressures.

Animals↗

PubMed2006

Differential sensitivity of excitatory and inhibitory synaptic transmission to modulation by nitric oxide in rat nucleus tractus solitarii.

The nucleus tractus solitarii (NTS) is a key central link in control of multiple homeostatic reflexes. A number of studies have demonstrated that exogenous and endogenous nitric oxide (NO) within NTS regulates visceral function, but further understanding of the role of NO in the NTS is hampered by the lack of information about its intracellular actions. We studied effects of NO in acute rat brainstem slices. Aqueous NO solution (NO(aq)) potentiated electrically evoked excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively) in different neuronal subpopulations and, in some neurones, caused a depolarization. Similar effects were observed using the NO donor diethylamine NONOate (DEA/NO). The threshold NO concentration as determined using an NO electrochemical sensor was estimated as approximately 0.4 nm (EC(50) approximately 0.9 nm) for potentiating glutamatergic EPSPs but approximately 3 nm for monosynaptic GABAergic IPSPs. Bath application of the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) abolished NO(aq)- and DEA/NO-induced potentiation of evoked EPSPs, IPSPs and depolarization. All NO actions were mimicked by the non-NO-dependent guanylate cyclase activator Bay 41-2272. The effects of NO on EPSPs and IPSPs persisted in cells where postsynaptic sGC was blocked by ODQ and therefore were presynaptic, owing to a direct modulation of transmitter release combined with depolarization of presynaptic neurones. Therefore, while lower concentrations of NO may be important for fine tuning of glutamatergic transmission, higher concentrations are required to directly engage GABAergic inhibition. This differential sensitivity of excitatory and inhibitory connections to NO may be important for determining the specificity of the effects of this freely diffusible gaseous messenger.

Animals↗

PubMed2006

Endothelial NO synthase activity in nucleus tractus solitarii contributes to hypertension in spontaneously hypertensive rats.

NO is implicated as a major modulator of central nervous circuits regulating cardiovascular activity. Based on previous data, we hypothesized that overactivity of endothelial NO synthase (eNOS) within the nucleus tractus solitarii (NTS) could contribute to the hypertension in the spontaneously hypertensive rat (SHR). Using real-time PCR, we found that endogenous eNOS mRNA was greater in the NTS of mature, but not juvenile prehypertensive SHRs compared with aged-matched Wistar Kyoto (WKY) rats. To test the functional significance of this, we chronically blocked eNOS activity in the NTS in the adult SHR by in vivo adenoviral-mediated gene transfer of a dominant-negative form of eNOS; data were compared with WKY rats. This resulted in a fall in arterial pressure in the SHR but not WKY rats. In both rat strains, cardiac baroreceptor reflex gain and the high-frequency spectral component of heart rate variability increased. Thus, endogenous eNOS activity in the NTS plays a major role in determining the set point of arterial pressure in the SHR and contributes to maintaining high arterial blood pressure in this animal model of human hypertension.

Aging↗

PubMed2006

Maintenance of eupnea of in situ and in vivo rats following riluzole: a blocker of persistent sodium channels.

We have proposed a "switching" concept for the neurogenesis of breathing in which rhythm generation by a pontomedullary neuronal circuit for eupnea may be switched to a medullary pacemaker system for gasping. This switch involves activation of conductances through persistent sodium channels. Based upon this proposal, eupnea should continue following a blockade of persistent sodium channels. In situ preparations of the decerebrate, juvenile rat were studied in normocapnia, hypocapnia and hypercapnia. Regardless of the level of CO(2) drive, riluzole (1-10 microM), a blocker of persistent sodium channels, caused increases in the frequency and reductions in peak integrated phrenic height. Even 20 microM of riluzole, a concentration four-fold higher than that which eliminates gasping, did not cause a cessation of phrenic discharge. In conscious, rats breathing continued unabated following intravenous administrations of 3-9 mgkg(-1) of riluzole. These administrations did cause sedation. We conclude that conductance through persistent sodium channels plays little role in the neurogenesis of eupnea.

Animals↗

PubMed2006

Disinhibition of the cardiac limb of the arterial baroreflex in rat: a role for metabotropic glutamate receptors in the nucleus tractus solitarii.

The nucleus tractus solitarii (NTS) is the first site of integration for primary baroreceptor afferents, which release glutamate to excite second-order neurones through ionotropic receptors. In vitro studies indicate that glutamate may also activate metabotropic receptors (mGluRs) to modulate the excitability of NTS neurones at pre- and postsynaptic loci. We examined the functional role of metabotropic glutamate receptors (mGluRs) in modulating the baroreceptor reflex in the rat NTS. Using the working heart-brainstem preparation, the baroreflex was activated using brief pressor stimuli and the consequent cardiac (heart rate change) and non-cardiac sympathetic (T8-10 chain) baroreflex gains were obtained. Microinjections of glutamate antagonists were made bilaterally into the NTS at the site of termination of baroreceptor afferents. NTS microinjection of kynurenate (ionotropic antagonist) inhibited both the cardiac and sympathetic baroreflex gains (16 +/- 5% and 59 +/- 11% of control, respectively). The non-selective mGluR antagonist MCPG produced a dose-dependent inhibition of the cardiac gain (30 +/- 3% of control) but not the sympathetic gain. Selective inhibitions of the cardiac gain were also seen with LY341495 and EGLU suggesting the response was mediated by group II mGluRs. This effect on cardiac gain involves attenuation of the parasympathetic baroreflex as it persists in the presence of atenolol. Prior NTS microinjection of bicuculline (GABA(A) antagonist) prevented the mGluR-mediated attenuation of the cardiac gain. These results are consistent with the reported presynaptic inhibition of GABAergic transmission by group II mGluRs in the NTS and constitute a plausible mechanism allowing selective feed-forward disinhibition to increase the gain of the cardiac limb of the baroreflex without changing the sympathoinhibitory component.

Animals↗

PubMed2006

Evidence for cardiovascular autonomic dysfunction in neonates with coarctation of the aorta.

BACKGROUND: Coarctation of the aorta (CoA) is associated with hypertension and abnormalities of blood pressure control, which persist after late repair. Assumptions that neonatal repair would prevent development of blood pressure abnormalities have not been supported by recent data. We hypothesized that early pathological adjustment of autonomic cardiovascular function may already be established in the neonate with coarctation. METHODS AND RESULTS: We studied 8 otherwise well neonates with simple CoA and compared measures of spontaneous baroreflex sensitivity, heart rate variability, and blood pressure variability with 13 healthy newborn babies. Spontaneous baroreflex sensitivity was calculated with sequence methodology from an ECG, and noninvasive blood pressure was recorded with a Portapres. Heart rate variability was determined with time- and frequency-domain measures. Blood pressure variability was measured in the frequency domain. In comparison with normal controls, neonates with CoA had raised blood pressure (78.9+/-3.8 versus 67.1+/-2.1 mm Hg), depressed baroreflex sensitivity (8.7+/-1.5 versus 13.8+/-1.1 ms/mm Hg), reduced heart rate variability (total power 16.5+/-3.1 versus 31.5+/-2.2 ms2), and an increase in the high-frequency component of blood pressure variability (3.1+/-0.3 versus 2.2+/-0. 2 mm Hg2). This is not the pattern expected if neonates with CoA simply had subclinical cardiac failure. CONCLUSIONS: These data suggest that infants with CoA already show signs of pathological adjustment of autonomic cardiovascular homeostasis. Further longitudinal studies are required to determine whether these alterations play a role in the increased risk of late hypertension in these patients.

Aortic Coarctation↗

PubMed2006

Mechanism of nitric oxide action on inhibitory GABAergic signaling within the nucleus tractus solitarii.

The cellular mechanisms mediating nitric oxide (NO) modulation of the inhibitory transmission in the nucleus tractus solitarii (NTS) remain unclear, even though this could be extremely important for various physiological and pathological processes. Specifically, in the NTS NO-evoked glutamate and gamma-aminobutyric acid (GABA) release might contribute to pathological hypertension. In cultured rat brainstem slices, NTS GABAergic neurons were targeted using an adenoviral vector to express enhanced green fluorescent protein and studied with a combination of patch clamp and confocal microscopy. Low nanomolar concentrations of NO increased intracellular Ca2+ concentration ([Ca2+]i) in somata, dendrites, and putative axons of GABAergic neurons, with axons being the most sensitive compartment. This effect was cGMP mediated and not related to depolarization or indirect presynaptic effects on glutamatergic transmission. Blockade of the cyclic adenosine diphosphate ribose (cADPR)/ryanodine-sensitive stores but not the inositol triphosphate-sensitive stores, inhibited NO effect. Since cADPR/ryanodine-sensitive stores are implicated in the Ca2+-induced Ca2+ release, NO can be expected to potentiate GABA release. In support of this notion, a cADPR antagonist abolished the NO-induced potentiation of GABAergic inhibitory postsynaptic potentials in the NTS. Thus, the NO-cGMP-cADPR-Ca2+ pathway, previously described in sea urchin eggs, also operates in mammalian GABAergic neurons. Potentiation of GABA release by NO may have implications for numerous brain functions.

Animals↗

PubMed2006

A decerebrate, artificially-perfused in situ preparation of rat: utility for the study of autonomic and nociceptive processing.

By extending established technology, we have developed a relatively simple in situ preparation from juvenile rat that overcomes some technical restrictions present in vivo (e.g. need for anaesthesia, mechanical instability for intracellular recording and control over the extracellular milieu). The in situ preparation is decerebrate and artificially perfused via the left ventricle with a colloid containing solution. It exhibits an eupneic pattern of respiratory motor activity and demonstrates numerous somatic and visceral reflexes including those evoked by stimulation of the tail, hindlimbs, bladder, baroreceptors and peripheral chemoreceptors. We have employed this preparation to allow recordings from multiple sympathetic motor outflows such as thoracic and lumbar chain, inferior cardiac, splanchnic, renal and adrenal nerves. We show that the sympathetic motor discharge shows strong respiratory modulation and exhibits pronounced reflex modulation indicating intact communication between the periphery, the brainstem and the spinal cord. Further, we have made extracellular and whole cell recordings from neurones in the spinal cord, demonstrating good mechanical stability. The decerebrate, artificially-perfused rat (DAPR) provides a powerful methodology with which to study peripheral and central control of the autonomic nervous system with many of the benefits of an in vitro environment.

Action Potentials↗

PubMed2006

Respiratory rhythm generation during gasping depends on persistent sodium current.

In severe hypoxia, homeostatic mechanisms maintain function of the brainstem respiratory network. We hypothesized that hypoxia involves a transition from neuronal mechanisms of normal breathing (eupnea) to a rudimentary pattern of inspiratory movements (gasping). We provide evidence for hypoxia-driven transformation within the central respiratory oscillator, in which gasping relies on persistent sodium current, whereas eupnea does not depend on this cellular mechanism.

Action Potentials↗

PubMed2006

Reflexly evoked coactivation of cardiac vagal and sympathetic motor outflows: observations and functional implications.

1. The purpose of the present review is to highlight the pattern of activity in the parasympathetic and sympathetic nerves innervating the heart during their reflex activation. 2. We describe the well-known reciprocal control of cardiac vagal and sympathetic activity during the baroreceptor reflex, but point out that this appears to be the exception rather than the rule and that many other reflexes reviewed herein (e.g. peripheral chemoreceptor, nociceptor, diving response and oculocardiac) involve simultaneous coactivation of both autonomic limbs. 3. The heart rate response during simultaneous activation of cardiac autonomic outflows is unpredictable because it does not simply reflect the summation of opposing influences. Indeed, it can result in bradycardia (peripheral chemoreceptor, diving and corneal), tachycardia (nociceptor) and, in some circumstances, can predispose to malignant arrhythmias. 4. We propose that this cardiac autonomic coactivation may allow greater cardiac output during bradycardia (increased ventricular filling time and stronger contraction) than activation of the sympathetic limb alone. This may be important when pumping blood into a constricted vascular tree, such as is the case during the peripheral chemoreceptor reflex and the diving response.

Animals↗

PubMed2006

Optical imaging of medullary ventral respiratory network during eupnea and gasping in situ.

In severe hypoxia, respiratory rhythm is shifted from an eupneic, ramp-like motor pattern to gasping characterized by a decrementing pattern of phrenic motor activity. However, it is not known whether hypoxia reconfigures the spatiotemporal organization of the central respiratory rhythm generator. Using the in situ arterially perfused juvenile rat preparation, we investigated whether the shift from eupnea to gasping was associated with a reconfiguration of the spatiotemporal pattern of respiratory neuronal activity in the ventral medullary respiratory network. Optical images of medullary respiratory network activity were obtained from male rats (4-6 weeks of age). Part of the medullary network was stained with a voltage-sensitive dye (di-2 ANEPEQ) centred both within, and adjacent to, the pre-Bötzinger complex (Pre-BötC). During eupnea, optical signals initially increased prior to the onset of phrenic activity and progressively intensified during the inspiratory phase peaking at the end of inspiration. During early expiration, fluorescence was also detected and slowly declined throughout this phase. In contrast, hypoxia shifted the respiratory motor pattern from eupnea to gasping and optical signals were restricted to inspiration only. Areas active during gasping showed fluorescence that was more intensive and covered a larger region of the rostral ventrolateral medulla compared to eupnea. Regions exhibiting peak inspiratory fluorescence did not coincide spatially during eupnea and gasping. Moreover, there was a recruitment of additional medullary regions during gasping that were not active during eupnea. These results provide novel evidence that the shift in respiratory motor pattern from eupnea to gasping appears to be associated with a reconfiguration of the central respiratory rhythm generator characterized by changes in its spatiotemporal organization.

Analysis of Variance↗

PubMed2005

Characterisation of c-Fos expression in the central nervous system of mice following right atrial injections of the 5-HT3 receptor agonist phenylbiguanide.

Cardiopulmonary receptors relay signals to the central nervous system via vagal and spinal visceral afferents. To date there are no detailed topographical studies in mice indicating the distribution of central neurones activated following stimulation of cardiopulmonary afferents. In anaesthetised mice, we injected the 5-HT(3) receptor agonist phenylbiguanide (PBG), a drug that is known to stimulate cardiopulmonary afferent C-fibres, into the right atrium of the heart and mapped c-Fos expression within specific regions of the central nervous system. Intra-atrial injection of PBG produced a reflex cardiorespiratory response including a pronounced bradycardia and a respiratory depression. Using immunohistochemical detection of the protein product of the immediate-early gene c-fos, we mapped the brain regions affected by cardiopulmonary 5-HT(3) receptor stimulation. Within the nucleus of the solitary tract (nTS) of PBG-injected mice, we detected an increased number of c-Fos-positive nuclei in the dorsolateral and gelatinous parts at the level of the area postrema (-7.48 mm bregma) but not at more rostral or caudal levels (-7.76, -7.20, -6.84 and -6.36 mm bregma) relative to vehicle-injected control mice. In addition, c-Fos expression in the crescent part of the lateral parabrachial nucleus was decreased in PBG-injected mice whereas no significant differences were detected between PBG-injected and control mice in the number of c-Fos-positive nuclei in the dorsal part of the lateral parabrachial nucleus. PBG injections had no significant effects on the number of c-Fos-positive catecholaminergic neurones within the C1/A1, C2/A2, A5, A6 and A7 cell groups. Likewise, PBG injections had no significant effects on c-Fos expression in other central regions involved in cardiorespiratory control or cardiorespiratory reflexes (selected non-catecholaminergic nuclei in the medulla and midbrain periaqueductal gray, the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala). Identification of specific regions of the nTS complex involved in relaying signals from afferent cardiopulmonary C-fibres to the central nervous system will be useful for future studies aimed at understanding neural mechanisms underlying cardiopulmonary reflexes and physiological responses to cardiopulmonary disease.

Animals↗

PubMed2005

Automation of analysis of cardiovascular autonomic function from chronic measurements of arterial pressure in conscious rats.

At present, there is no single software package that provides a comprehensive power spectral analysis of pulse interval (PI) and arterial blood pressure (BP), spontaneous cardiac baroreceptor reflex gain (sBRG) and respiratory rate. Furthermore, scientific validation of the software that is currently commercially available and employed has not been published. We introduce 'Hey-Presto' software, which fully evaluates cardiovascular autonomic function from the BP signal obtained from rats. The program performs power spectral analysis of HR and BP variability, respiratory rate and, based on a time-series method, spontaneous cardiac baroreceptor (sBRG). We have validated Hey-Presto with conventional pharmacological agents to block cardiac vagal and cardiac sympathetic transmission in conscious rats fitted with a radio-telemetery BP transducer. Following administration of atropine (1 mg kg(-1), I.V.), high-frequency (HF) power of the PI decreased (P < 0.01) and was associated with the expected increase in HR. Subsequent cardiac sympathetic blockade (atenolol, 1 mg kg(-1), I.V.) reduced the low frequency (LF) to HF ratio (LF:HF) of the PI (P < 0.01), which was consistent with the observed reduction in HR. We also found that alterations in sBRG after blockade of cardiac autonomic transmission were highly comparable to values computed manually using vasoactive drugs administered intravenously. The software also detected circadian rhythms in sBRG, HF component of the PI, LF:HF of the PI and LF component of the BP as well as BP and HR during continuous 24 h recording. By demonstrating its application to humans, we found appropriate changes in the power of PI and the LF power of the BP during postural changes. These results demonstrate that Hey-Presto allows a fully automated, reliable, fast and comprehensive evaluation of cardiovascular autonomic function based on chronic measurements of BP in rats. Moreover, we have confirmed its versatility by demonstrating its application to man.

Adrenergic beta-Antagonists↗

PubMed2005

Long-term intracellular recordings of respiratory neuronal activities in situ during eupnea, gasping and blockade of synaptic transmission.

For a definitive evaluation of the hypothesis that different neurophysiological mechanisms underlie the neurogenesis of eupnea and gasping, long-term continuous intracellular recordings of respiratory neuronal activities during both respiratory patterns are required. Such recordings in vivo are technically difficult, especially in small mammals, due to mechanical instability of the brainstem and cardiovascular depression that accompany hypoxia-induced gasping. Respiratory-related rhythmic activities of in vitro preparations are confounded by the lack of a clear correspondence with both eupnea and gasping. Here, we describe new methodologies and report on whole cell patch clamp recordings from the ventrolateral medulla and the hypoglossal motor nucleus in situ during multiple bouts of hypoxia-induced gasping. The longevity of recordings (range 20--35 min) also allowed subsequent analysis of neuronal behaviour after blockade of inhibitory and excitatory synaptic activities. We conclude that whole cell patch clamp recordings in the in situ preparation will allow an analysis of both synaptic and ionic conductances of respiratory neurons during defined eupnea and gasping, providing an additional approach to in vitro preparations.

Animals↗

PubMed2005

Water deprivation increases the expression of neuronal nitric oxide synthase (nNOS) but not orexin-A in the lateral hypothalamic area of the rat.

The discovery that the lateral hypothalamic area (LHA) might be important in modulating drinking behavior and fluid balance has led to numerous studies aimed at identifying the key neurotransmitters/neuromodulators and pathways involved. While past studies have demonstrated the presence of neuronal nitric oxide synthase (nNOS) within the LHA, its role in the regulation of fluid homeostasis is not known. In light of this, and the mounting evidence suggesting a role for nitric oxide in osmotic regulation within the hypothalamus, this study sought to determine the effects of 24- and 72-hours of water deprivation on nNOS protein expression within the LHA of the rat with immunohistochemistry. In euhydrated control animals we observed nNOS-like immunoreactivity throughout all levels of the LHA. Following 24 hours of dehydration the number of nNOS-like immunopositive neurons was significantly increased in the rostral but not the caudal regions of LHA. Seventy-two hours of water deprivation lead to further increases in nNOS-like immunoreactivity at different levels of the LHA. Interestingly, however, we observed increased nNOS-like immunoreactivity in the caudal regions of the LHA that was not evident after 24 hours of water deprivation. Double-labeling immunofluorescence histochemistry revealed that the nNOS-like immunoreactive neurons were not colocalized with the orexin-A-containing neurons. These results suggest that an osmotic challenge leads to an upregulation of nNOS immunoreactivity within discrete areas of the LHA. This altered neurochemistry within the LHA further highlights the potential importance of nitric oxide and the LHA in central regulation of fluid homeostasis.

Animals↗

PubMed2005

Dynamic changes in glottal resistance during exposure to severe hypoxia in neonatal rats in situ.

The neural control of respiratory airflow via the vocal fold is characterized by inspiratory abduction and postinspiratory (early expiratory) adduction causing decreases and increases in glottal resistance, respectively. The postinspiratory increase in glottal resistance plays a major role in braking the speed of expiratory airflow, to act against the high recoil pressure of the neonatal rat lung. In the present study, we investigated changes in upper airway patency during severe hypoxia in neonatal rats. We measured dynamic changes in subglottal pressure during normoxic and hypoxic conditions in an arterially perfused brainstem preparation in which we could control gas tensions accurately. Initially, hypoxia (5% O(2), 5% CO(2), and 90% nitrogen) produced an excitatory response in phrenic nerve activity accompanied by augmentation of both inspiratory-related glottal dilation and postinspiratory glottal constriction. Later, during the early stages of hypoxia-induced respiratory depression and initiation of gasping, we observed a massive reduction of the respiratory modulation of glottal resistance. In most preparations, this was transient and replaced by a paradoxic inspiratory-related glottal constriction. We propose that during severe hypoxia in the in situ preparation, paradoxic inspiratory glottal constriction can be observed during gasping, and this may impair ventilation despite the persistence of rhythmic contractions of the respiratory muscles. The latter is of clinical interest, because this may relate to the finding of cot death victims who died as a result of upper airway obstruction but without apparent apnea or rebreathing.

Airway Resistance↗

PubMed2005

Respiratory rhythm entrainment by somatic afferent stimulation.

Respiratory and locomotor patterns are coupled during locomotion. The objectives of this study were to (1) demonstrate that respiratory rhythms are entrained by sensory input from somatic afferents, (2) establish whether the parabrachial nucleus mediates entrainment, (3) examine responses of single respiratory neurons in the ventral respiratory group (VRG) to somatic afferent stimulation, and (4) use a computational model of the pontomedullary respiratory network (Rybak et al., 2004a,b) to suggest neuronal mechanisms for entrainment. We used an in situ preparation in young rats that retained pontomedullary respiratory circuits and spinal pathways transmitting somatosensory input. We demonstrate that rhythmic stimulation of somatic afferents entrains respiratory rhythm on a 1:1 basis (1:1), increasing breathing frequency up to approximately 1.4-2.2 times greater than spontaneous frequency. Stable entrainment occurred only when stimuli were delivered during expiration. Reversible blockade of the lateral parabrachial nucleus eliminated entrainment. Somatic afferent stimulation produced significant increases in the firing rate of augmenting expiratory (E2) neurons but shortened the firing duration of postinspiratory (post-I) neurons. A computational model reproduced 1:1 entrainment and other experimental findings based on the assumption that the somatic afferents initiate early onset of inspiration via activation of medullary E2 neurons. The model also predicted that afferent stimulation evoked transient hyperpolarization of ramp-inspiratory (ramp-I) neurons. This was confirmed experimentally by intracellular recording from ramp-I neurons. Our experimental and modeling results demonstrate that an entrainment pathway from somatic afferents to the VRG via the lateral parabrachial nucleus causes resetting of respiratory rhythm through excitation of E2 and consequent inhibition of post-I neurons.

Afferent Pathways↗