Peripheral Chemoreceptor Response Research Articles

Ventilatory response of peripheral chemoreceptors to hypercapnia during exercise above the respiratory compensation point.

Peripheral hypercapnic chemosensitivity (PHC) is assessed as the change in ventilation in response to a rapid change in carbon dioxide pressures (PCO2). The increase in chemoresponse from rest to sub-respiratory compensation point (RCP) exercise intensities is well-defined but less clear at intensities above the RCP when changes in known ventilatory stimulants occur. Twenty healthy subjects (n=10 females) completed a maximal exercise test on one day and on a subsequent day, transient hypercapnia was used to test PHC at multiple exercise stages. The transient hypercapnia involved two breaths of 10% CO2 repeated five times during each of the following: sitting at rest on the cycle ergometer, cycling at 40% Wmax, cycling at 85% Wmax, at rest on the cycle ergometer immediately following the 85% stage, and cycling at 40% Wmax again following the post-exercise rest. The PHC was not different across exercise intensities (0.98±0.37 vs. 0.91±0.39 vs. 0.92±0.42 L min-1 mmHg-1 for 1st 40% Wmax, 85% Wmax, and 2nd 40% Wmax, respectively (p=0.45). There were no differences in PHC between pre-supra-RCP exercise rest and post-supra-RCP exercise rest (0.52±0.23 vs. 0.53±0.24 L min-1 mmHg-1, p=0.8003). Using a repeated measures correlation to account for within participants changes, there was a significant relationship between the end-tidal PCO2 and PHC for the 85% intensity (r=0.5, p<0.0001) when end-tidal PCO2 was dynamic between the trials. We conclude that the physiological changes (e.g. metabolic milieu, temperature, etc) produced with supra-RCP exercise do not further augment PHC, and that the pre-stimulus end-tidal PCO2 modulates the PHC.

Central CO2 chemosensitivity and CO2 controller gain independently contribute to daytime PCO2 in young subjects with congenital central hypoventilation syndrome.

Whether peripheral chemoreceptor response is altered in congenital central hypoventilation syndrome (CCHS) remains debated. Our aim was to prospectively evaluate both peripheral and central CO2 chemosensitivity and to evaluate their correlations with daytime PCO2 and arterial desaturation during exercise in CCHS. To this end, tidal breathing was recorded in CCHS patients allowing the calculation of loop gain and its components (steady-state controller [assumed to mainly be peripheral chemosensitivity] and plant gains using a bivariate [PETCO2 and ventilation] constrained model), a hyperoxic, hypercapnic ventilatory response test (central chemosensitivity), and a six-minute walk test (arterial desaturation). The results of loop gain were compared to those previously obtained in a healthy group of similar age. The study prospectively included 23 subjects with CCHS, without daytime ventilatory support; the subjects had a median age of 10 (5.6 to 27.4) years (15 females) with moderate polyalanine repeat mutation (PARM: 20/25, 20/26, n=11), severe PARM (20/27, 20/33, n=8), or non-PARM (n=4). As compared to 23 healthy subjects (4.9 to 27.0 years), the subjects with CCHS had a decreased controller gain and an increased plant gain. Mean daytime PETCO2 level of subjects with CCHS correlated negatively to both Log(controller gain) and the slope of CO2 response. Genotype was not related to chemosensitivity. Arterial desaturation on exercise correlated negatively with Log(controller) gain but not with the slope of the CO2 response. In conclusion, we demonstrate that peripheral CO2 chemosensitivity is altered in some patients with CCHS and that the daytime PETCO2 depends on central and peripheral chemoreceptor responses.

Acute effects of increased gut microbial fermentation on the hypoxic ventilatory response in humans

What is the central question of this study? Is there a link between gut microbial fermentation and ventilatory responsiveness to hypoxia in humans? What is the main finding and its importance? Increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to transient hypoxia. These findings imply a capacity for gut microbiota to modulate the peripheral chemoreflex response to hypoxia in humans. Recent animal data indicate the presence of a bidirectional link between gut microbial activity and respiratory control. Nevertheless, the presence of a similar association between gut microbiota and peripheral chemoreceptor responsiveness to hypoxia in humans has not been reported to date. Therefore, we performed a within subject, placebo-controlled study in a group of 16 healthy individuals (eight men; mean±SD age 25.9±5.2years). Participants underwent two tests (in a random order), receiving lactulose, which stimulates gut fermentation, or placebo. Ventilatory and haemodynamic responses to transient hypoxia were evaluated before and 2h after the test meal. The magnitude of these responses was related to the net hydrogen content in the exhaled air, reflecting gut fermentation intensity. A lactulose meal, compared to placebo, caused an increase in the minute ventilation (Hyp-VI; l/min/ ) and breathing rate (Hyp-BR; breaths/min/ ) responses to hypoxia (for Hyp-VI, mean±SD -0.03±0.059 in placebo test vs. 0.05±0.116 in lactulose test, P=0.03; for Hyp-BR, -0.015±0.046 vs. 0.034±0.054, P=0.01). The magnitude of these responses was positively correlated with the lactulose-induced hydrogen excretion (for Hyp-VI, r=0.62, P=0.01; for Hyp-BR, r=0.73, P=0.001). Changes in the resting parameters during normoxia did not differ significantly between the tests. Our results demonstrate that the increased gut microbial fermentation is associated with augmented ventilatory (but not haemodynamic) responses to the transient hypoxia, which implies a capacity for gut microbiota to modulate the peripheral chemoreflex in humans.

Losartan may attenuate altitude-related sleep disturbance

IntroductionSleep disturbance is common at high altitude and likely driven by an exaggerated peripheral chemoreceptor response which leads to apnoeic episodes and arousal. We hypothesised that this heightened response is...

Ventilatory and chemoreceptor responses to hypercapnia in neonatal rats chronically exposed to moderate hyperoxia

Rats reared in hyperoxia hypoventilate in normoxia and exhibit progressive blunting of the hypoxic ventilatory response, changes which are at least partially attributed to abnormal carotid body development. Since the carotid body also responds to changes in arterial CO2/pH, we tested the hypothesis that developmental hyperoxia would attenuate the hypercapnic ventilatory response (HCVR) of neonatal rats by blunting peripheral and/or central chemoreceptor responses to hypercapnic challenges. Rats were reared in 21% O2 (Control) or 60% O2 (Hyperoxia) until studied at 4, 6–7, or 13–14days of age. Hyperoxia rats had significantly reduced single-unit carotid chemoafferent responses to 15% CO2 at all ages; CO2 sensitivity recovered within 7days after return to room air. Hypercapnic responses of CO2-sensitive neurons of the caudal nucleus tractus solitarius (cNTS) were unaffected by chronic hyperoxia, but there was evidence for a small decrease in neuronal excitability. There was also evidence for augmented excitatory synaptic input to cNTS neurons within brainstem slices. Steady-state ventilatory responses to 4% and 8% CO2 were unaffected by developmental hyperoxia in all three age groups, but ventilation increased more slowly during the normocapnia-to-hypercapnia transition in 4-day-old Hyperoxia rats. We conclude that developmental hyperoxia impairs carotid body chemosensitivity to hypercapnia, and this may compromise protective ventilatory reflexes during dynamic respiratory challenges in newborn rats. Impaired carotid body function has less of an impact on the HCVR in older rats, potentially reflecting compensatory plasticity within the CNS.

Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

Intermittent hypoxia causes a persistent increase in sympathetic nerve activity (SNA), which progresses to hypertension in conditions such as obstructive sleep apnea. Orexins (A and B) are hypothalamic neurotransmitters with arousal-promoting and sympathoexcitatory effects. We investigated whether the sustained elevation of SNA, termed sympathetic long-term facilitation, after acute intermittent hypoxia (AIH) is caused by endogenous orexin acting on spinal sympathetic preganglionic neurons. The role of orexin in the increased SNA response to AIH was investigated in urethane-anesthetized, vagotomized, and artificially ventilated Sprague-Dawley rats (n = 58). A spinally infused subthreshold dose of orexin-A (intermittent; 0.1 nmol × 10) produced long-term enhancement in SNA (41.4% ± 6.9%) from baseline. This phenomenon was not produced by the same dose of orexin-A administered as a bolus intrathecal infusion (1 nmol; 7.3% ± 2.3%). The dual orexin receptor blocker, Almorexant, attenuated the effect of sympathetic long-term facilitation generated by intermittent orexin-A (20.7% ± 4.5% for Almorexant at 30 mg∙kg(-1) and 18.5% ± 1.2% for 75 mg∙kg(-1)), but not in AIH. The peripheral chemoreflex sympathoexcitatory response to hypoxia was greatly enhanced by intermittent orexin-A and AIH. In both cases, the sympathetic chemoreflex sensitization was reduced by Almorexant. Taken together, spinally acting orexin-A is mechanistically sufficient to evoke sympathetic long-term facilitation. However, AIH-induced sympathetic long-term facilitation appears to rely on mechanisms that are independent of orexin neurotransmission. Our findings further reveal that the activation of spinal orexin receptors is critical to enhance peripheral chemoreceptor responses to hypoxia after AIH.

Maternal Protein Restriction Increases Respiratory and Sympathetic Activities and Sensitizes Peripheral Chemoreflex in Male Rat Offspring1–3

Background: Maternal protein restriction in rats increases the risk of adult offspring arterial hypertension through unknown mechanisms.Objectives: The aims of the study were to evaluate the effects of a low-protein (LP) diet during pregnancy and lactation on baseline sympathetic and respiratory activities and peripheral chemoreflex sensitivity in the rat offspring.Methods: Wistar rat dams were fed a control [normal-protein (NP); 17% protein] or an LP (8% protein) diet during pregnancy and lactation, and their male offspring were studied at 30 d of age. Direct measurements of baseline arterial blood pressure (ABP), heart rate (HR), and respiratory frequency (Rf) as well as peripheral chemoreflex activation (potassium cyanide: 0.04%) were recorded in pups while they were awake. In addition, recordings of the phrenic nerve (PN) and thoracic sympathetic nerve (tSN) activities were obtained from the in situ preparations. Hypoxia-inducible factor 1α (HIF-1α) expression was also evaluated in carotid bifurcation through a Western blotting assay.Results: At 30 d of age, unanesthetized LP rats exhibited enhanced resting Rf (P = 0.001) and similar ABP and HR compared with the NP rats. Despite their similar baseline ABP values, LP rats exhibited augmented low-frequency variability (∼91%;P = 0.01). In addition, the unanesthetized LP rats showed enhanced pressor (P = 0.01) and tachypnoeic (P = 0.03) responses to peripheral chemoreflex activation. The LP rats displayed elevated baseline tSN activity (∼86%;P = 0.02) and PN burst frequency (45%;P = 0.01) and amplitude (53%;P = 0.001) as well as augmented sympathetic (P = 0.01) and phrenic (P = 0.04) excitatory responses to peripheral chemoreflex activation compared with the NP group. Furthermore, LP rats showed an increase of ∼100% in HIF-1α protein density in carotid bifurcation compared with NP rats.Conclusion: Sympathetic-respiratory overactivity and amplified peripheral chemoreceptor responses, potentially through HIF-1α–dependent mechanisms, precede the onset of hypertension in juvenile rats exposed to protein undernutrition during gestation and lactation.

Should we be ‘Doping’ the peripheral chemoreceptors?

The carotid body chemoreceptors are located bilaterally at the bifurcation of the common carotid artery and are primarily known for their ability to sense and respond to changes in the partial pressure of oxygen in arterial blood. As such, peripheral chemoreceptor hyperactivity has been widely studied in adults with sleep apnoea, who are exposed to multiple, acute hypoxic events during sleep. In response to intermittent falls in the arterial partial pressure of oxygen, patients with sleep apnoea present with increases in heart rate, blood pressure, sympathetic activity and ventilation (e.g. measures of increased carotid chemoreceptor sensitivity). This observed upregulation at the level of the carotid chemoreceptors in response to repeated activation is unlike the typical downregulation/desensitization responses seen in many other physiological systems. In addition to hypoxia, a broad range of factors are now emerging as potent stimulators of carotid body afferent activity (e.g. hypercapnia, hypoglycaemia, hyperinsulinaemia, hypoperfusion). Thus it may not be surprising that carotid chemoreceptor hyperactivity was recently implicated in the pathophysiology of a variety of other cardiovascular and metabolic diseases, such as hypertension, heart failure, insulin resistance and diabetes. In this context, perhaps it is useful to think of these conditions as ‘diseases of sympathoexcitation’ or possibly carotid body-mediated sympathoexcitation. Along these lines, therapies focused on desensitization of the carotid chemoreceptors have shown provocative and successful results in animal models. For example, carotid body denervation appears to prevent the development of hypertension and insulin resistance in a rodent model of overfeeding (Ribeiro et al. 2013) and can eventually improve cardiac function in models of heart failure (Del Rio et al. 2013). Yet, whether denervation is beneficial in long-term treatment of such disorders in humans is still an open question. This is especially true given not all (heart failure) patients respond to chemoreceptor-desensitizing therapies (van de Borne et al. 1996), nor do all patients respond positively to other types of invasive denervation procedures (Joyner, 2012). So how might we identify patients that are likely to respond to carotid body desensitization or even denervation? In this edition of The Journal of Physiology, Niewinski and colleagues used systemic low-dose dopamine in young, healthy humans to lower afferent activity at the level of the peripheral chemoreceptors (Niewinski et al. 2014). Although such doses appear to have minimal impact on basal measures of heart rate, blood pressure, or minute ventilation in healthy adults, low-dose dopamine blunts peripheral chemoreceptor responsiveness to hypoxia as measured by changes in both ventilation and haemodynamic variables. Additionally, when the dopamine infusion was stopped, a transient rise in ventilation was observed – possibly due to release of an accumulating pool of neurotransmitters, given that the post-infusion increase in ventilation correlated with basal levels of carotid chemoreceptor sensitivity. The practicality of low-dopamine as a long-term therapy for ‘diseases of sympathoexcitation’ is questionable. However, techniques used by Niewinski and colleagues in the present investigation could be important in identifying which patients respond to desensitization of the carotid chemoreceptors and are thus potential candidates for carotid body denervation (Niewinski et al. 2013). Since the present investigation is limited to young healthy adults, future studies will be necessary to examine the impact of low-dose dopamine on ventilatory and haemodynamic parameters in disease states known to exhibit increased chemoreceptor activation at baseline. Until then, it is unclear how much patient-to-patient variability exists, what benefit low-dose dopamine has over other clinical measures, and whether a clinical test could be developed using this approach. Furthermore, one must not forget that the carotid chemoreceptors are important in sensing and responding to a number of peripheral stimuli (e.g. hypoglycaemia, hyperinsulinaemia, hyperthermia, hypoperfusion). Thus, removal or desensitization may not only blunt sympathoexcitatory and ventilatory responses to hypoxia (thus impacting natural responses to this environmental stressor), but may impact human physiology in ways that are not fully realized (Johnson & Joyner, 2013). Finally, ‘diseases of sympathoexcitation’ are complex and have effects on multiple organ systems. Because of this, it is hard to imagine that modulation of carotid body afferent activity alone will be sufficient to treat and/or reverse most or all of them.

Peripheral Chemoreceptor Responsiveness and Hypoxic Pulmonary Vasoconstriction in Humans

Studies in animals have shown that interruption of carotid body afferent hypoxic signaling or efferent CNS activity to the lung enhances hypoxic pulmonary vasoconstriction (HPV). Whether a similar influence of the CNS on HPV strength is present in humans has never been studied, owing to the invasive nature of physical neural ablation or nonspecific systemic effects of pharmacological blockade of putative neural pathways. In order to demonstrate a peripheral chemoreceptor-mediated modulation of HPV in man, we hypothesized that individuals with high hypoxic ventilatory responsiveness, indicative of strong peripheral hypoxic chemosensitivity, should have less HPV in response to inspired hypoxia. In 15 healthy men and women, we measured the normobaric poikilocapnic hypoxic ventilatory response (HVR; L min(-1) % SPo2(-1)) during 15 min of hypoxia (FIo2=0.12). On the following day, we then measured pulmonary artery systolic pressure (PASP) using echosonography while subjects randomly breathed 0.21, 0.18, 0.15, and 0.12 FIo2, each for periods of 15 min. We chose this strategy to obtain an equivalent stimulus for HPV in all subjects, using SPo2 as a surrogate for alveolar Po2. HPV was assessed as PASP at a common interpolated arterial oxygen saturation (SPo2) of 85%. We recorded a sufficient six-fold range of HVR (0.05-0.30, mean 0.13 L min(-1) % SPo2(-1)) similar to previously published data on normobaric, poikilocapnic HVR. HPV at SPo2 of 85% was 28.5 mmHg (range 21.7-41.3). There was a significant inverse relationship between poikilocapnic HVR and HPV (p=0.006, R(2)=0.38). Previous studies of individuals with susceptibility to high altitude pulmonary edema (HAPE) have suggested that both low HVR and high HPV are important risk factors. We show that these two responses are inversely correlated and conclude that a greater magnitude of peripheral chemoreceptor response to hypoxia limits hypoxic pulmonary vasoconstriction in healthy subjects.

Treatment of Central Sleep Apnea in US Veterans

There are no standard therapies for the management of central sleep apnea (CSA). Either positive pressure therapy (PAP) or supplemental oxygen (O(2)) may stabilize respiration in CSA by reducing ventilatory chemoresponsiveness. Additionally, increasing opioid use and the presence of comorbid conditions in US veterans necessitates investigations into alternative titration protocols to treat CSA. The goal was to report on the effectiveness of titration with PAP, used alone or in conjunction with O(2), for the management of CSA associated with varying comorbidities and opioid use. This was a retrospective chart review over 3 years, performed at a VA sleep disorders center. The effects of CPAP, CPAP+O(2), and BPAP+O(2), used in a step-wise titration protocol, on consecutive patients diagnosed with CSA were studied. CSA was diagnosed in 162 patients. The protocol was effective in eliminating CSA (CAI ≤ 5/h) in 84% of patients. CPAP was effective in 48%, while CPAP+O(2) combination was effective in an additional 25%, and BPAP+O(2) in 11%. The remaining 16% were non-responders. Forty-seven patients (29%) were on prescribed opioid therapy for chronic pain, in whom CPAP, CPAP+O(2), or BPAP+O(2) eliminated CSA in 54%, 28%, and 10% cases, respectively. CPAP, CPAP+O(2), and BPAP+O(2) each produced significant declines in the AHI, CAI, and arousal index, and an increase in the SpO(2). The data demonstrate that using a titration protocol with CPAP and then PAP with O(2) effectively eliminates CSA in individuals with underlying comorbid conditions and prescription opioid use. Comparative studies with other therapeutic modalities are required.

Influence of antenatal smoking exposure on the newborn response to a hypoxic challenge

<h3>Aims</h3> Infants of mothers who smoked during pregnancy have an increased risk of sudden infant death; a possible explanation is that such infants have neurodevelopmental abnormalities of ventilatory control. Our aim was to test the hypothesis that infants of mothers who had smoked antenatally compared to infants of non-smoking mothers would have a poorer ventilatory response to hypoxia. <h3>Methods</h3> Infants were recruited before maternity unit discharge and assigned to one of two groups based on maternal smoking history. A pneumotachograph and face mask were placed over the infant9s mouth and nose. During quiet sleep, the infants were switched from breathing room air to 15% oxygen (hypoxic challenge), which was maintained for five minutes unless the oxygen saturation level fell below 85%. Changes in oxygen saturation, heart rate, respiratory rate, tidal and minute volume and end tidal CO2 (ETCO2) were assessed. <h3>Results</h3> Ten infants of smoking mothers (median gestational age of 39 (36-41) weeks) and 10 infants of non smoking mothers (39 (37-42) weeks) were studied. The median birth weight of the infants of the smoking mothers was lower than that of infants of the non-smoking mothers (2450 (1924-3790) grams versus 3299 (2560-4320) grams, p=0.04). The infants were studied at similar postnatal ages (median 30 (10-120) versus 32 (10-100) hours), p=0.7. The two groups had comparable baseline tidal breathing, oxygen saturation, heart rate and ETCO2 levels. In response to the hypoxic challenge, the two groups had similar falls in their oxygen saturation and increases in heart rate. There was a biphasic response in minute ventilation to the hypoxic challenge. There was no significant differences in the initial percentage increase in minute ventilation between the two groups (median 29% (range 17-40) versus 23% (2-35), p=0.23, but the subsequent percentage decrease in minute volume in the infants of the smoking mothers was greater than that of the infants of the non-smoking mothers (median 32 % (range 0-99) versus 0%(−20-32)), p=0.03. <h3>Conclusion</h3> These results suggest intrauterine exposure to tobacco smoking may result in impairment of the infant peripheral chemoreceptor response.

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

We tested the hypothesis that exposure to neonatal intermittent hypoxia (n-IH) in rat pups alters central integrative processes following acute and intermittent peripheral chemoreceptor activation in adults. Newborn male rats were exposed to n-IH or normoxia for 10 consecutive days after birth. We then used both awake and anesthetized 3- to 4-mo-old rats to record ventilation, blood pressure, and phrenic and splanchnic nerve activities to assess responses to peripheral chemoreflex activation (acute hypoxic response) and long-term facilitation (LTF, long-term response after intermittent hypoxia). In anesthetized rats, phrenic and splanchnic nerve activities and hypoxic responses were also recorded with or without intact carotid body afferent signal (bilateral chemodenervation) or in response to electrical stimulations of the carotid sinus nerve. In awake rats, n-IH alters the respiratory pattern (higher frequency and lower tidal volume) and increased arterial blood pressure in normoxia, but the ventilatory response to repeated hypoxic cycles was not altered. In anesthetized rats, phrenic nerve responses to repeated hypoxic cycles or carotid sinus nerve stimulation were not altered by n-IH; however, the splanchnic nerve response was suppressed by n-IH compared with control. In control rats, respiratory LTF was apparent in anesthetized but not in awake animals. In n-IH rats, respiratory LTF was not apparent in awake and anesthetized animals. Following intermittent electrical stimulation, however, phrenic LTF was clearly present in n-IH rats, being similar in magnitude to controls. We conclude that, in adult n-IH rats: 1) arterial blood pressure is elevated, 2) peripheral chemoreceptor responses to hypoxia and its central integration are not altered, but splanchnic nerve response is suppressed, 3) LTF is suppressed, and 4) the mechanisms involved in the generation of LTF are still present but are masked most probably as the result of an augmented inhibitory response to hypoxia in the central nervous system.

Post-ingestive effect of plant phenolics on the feeding behaviour of the honeybee Apis cerana

As the staple food of honey bees, honey is rich in plant phenolics derived from pollen, nectar and resin. Most studies concentrate on the temporary response of bees' peripheral chemoreceptors to these chemicals, and the post-ingestive effects of plant phenolics are largely ignored. In the present study, a series of feeding experiments are conducted to test whether plant phenolics modulate the response thresholds and rhythmic behaviour of the honeybee Apis cerana (Ruttner). The results of the study demonstrate that bees fed with syrup containing high concentrations of phenlics reduce their response thresholds greatly, and shift their feeding rhythms significantly. Because the forager response thresholds determine their foraging choice, and their rhythmic behaviour is required for timing visits to flowers, enhanced plant phenolics as a result of global environment change may change the bees' pollination service in our changing world.

Effect of Intermittent Hypercapnia on Respiratory Control in Rat Pups

Preterm infants are subject to fluctuations in blood gas status associated with immature respiratory control. Intermittent hypoxia during early postnatal life has been shown to increase chemoreceptor sensitivity and destabilize the breathing pattern; however, intermittent hypercapnia remains poorly studied. Therefore, to test the hypothesis that intermittent hypercapnia results in altered respiratory control, we examined the effects of daily exposure to intermittent hypercapnia on the ventilatory response to subsequent hypercapnic and hypoxic exposure in neonatal rat pups. Exposure cycles consisted of 5 min of intermittent hypercapnia (5% CO₂, 21% O₂, balance N₂) followed by 10 min of normoxia. Rat pups were exposed to 18 exposure cycles each day for 1 week, from postnatal day 7 to 14. We analyzed diaphragm electromyograms (EMGs) from pups exposed to subsequent acute hypercapnic (5% CO₂) and hypoxic (12% O₂) challenges. In response to a subsequent hypercapnia challenge, there was no significant difference in the ventilatory response between control and intermittent hypercapnia-exposed groups. In contrast, intermittent hypercapnia-exposed rat pups showed an enhanced ventilatory response to hypoxic challenge with an increase in minute EMG to 118 ± 14% of baseline versus 107 ± 13% for control pups (p < 0.05). We speculate that prior hypercapnic exposure may increase peripheral chemoreceptor response to subsequent hypoxic exposures and result in perturbed neonatal respiratory control.

Role of hypoxia in muscle function and muscular dystrophy

Respiratory insufficiency contributes significantly to the morbidity and, is the commonest cause of mortality, in Duchene's muscular dystrophy (DMD). However, surprisingly little is known mechanistically about 1, basic respiratory physiology in the mdx (DMD‐mouse model) &amp;, 2, effects of hypoxia (high altitude) on muscle function.To rigorously evaluate mdx respiration, we custom‐built a plethysmograph (with 1 microlitre sensitivity) and exposed awake adult mdx and control mice to graded levels of hypoxia and hypercapnia to determine respiratory rate (RR), tidal volume (VT), and minute ventilation (VE), HVR and HCVR. Additionally, phrenic nerve discharges were recorded from anesthetized mice to understand the integrated ventilatory response of central and peripheral chemoreceptors. Significant abnormalities were found in mdx mice respiratory parameters during normoxia as well as a blunting of the HVR reflex. Finally, we found anatomical, physiological and transcriptome‐level changes in muscle of animals exposed to hypoxia and high altitude (Mt. Marmolejo &amp; Mt. McKinley). These observations support our hypotheses that dystrophic mice have respiratory abnormalities and that hypoxia itself may contribute as a ‘second‐hit’ to muscle patho‐physiology in DMD.

A Full Term Infant with Cyanotic Episodes

A Full Term Infant with Cyanotic Episodes

Lamotrigine and phenytoin, but not amiodarone, impair peripheral chemoreceptor responses to hypoxia

Amiodarone, lamotrigine, and phenytoin, common antiarrhythmic and antiepileptic drugs, inhibit a persistent sodium current in neurons (I(NaP)). Previous results from our laboratory suggested that I(NaP) is critical for functionality of peripheral chemoreceptors. In this study, we determined the effects of therapeutic levels of amiodarone, lamotrigine, and phenytoin on peripheral chemoreceptor and ventilatory responses to hypoxia. Action potentials (APs) of single chemoreceptor afferents were recorded using suction electrodes advanced into the petrosal ganglion of an in vitro rat peripheral chemoreceptor complex. AP frequency (at Po(2) approximately 150 Torr and Po(2) approximately 90 Torr), conduction time, duration, and amplitude were measured before and during perfusion with therapeutic dosages of the drug or vehicle. Hypoxia-induced catecholamine secretion within the carotid body was measured using amperometry. With the use of whole body plethysmography, respiration was measured in unanesthesized rats while breathing room air, 12% O(2), and 5% CO(2), before and after intraperitoneal administration of amiodarone, lamotrigine, phenytoin, or vehicle. Lamotrigine (10 microM) and phenytoin (5 microM), but not amiodarone (5 microM), decreased chemoreceptor AP frequency without affecting other AP parameters or magnitude of catecholamine secretion. Similarly, lamotrigine (5 mg/kg) and phenytoin (10 mg/kg) blunted the hypoxic but not the hypercapnic ventilatory response. In contrast, amiodarone (2.5 mg/kg) did not alter the ventilatory response to hypoxia or hypercapnia. We conclude that lamotrigine and phenytoin at therapeutic levels impair peripheral chemoreceptor function and ventilatory response to acute hypoxia. These are consistent with I(NaP) serving an important function in AP generation and may be clinically important in the care of patients using these drugs.

Neurokinin-1 receptor-expressing neurons in the ventral medulla are essential for normal central and peripheral chemoreception in the conscious rat

Neurokinin-1 receptor immunoreactive (NK1R-ir) neurons and processes are widely distributed within the medulla, prominently at central chemoreceptor sites. Focal lesions of NK1R-ir neurons in the medullary raphe or the retrotrapezoid nucleus partially reduced the CO(2) response in conscious rats. We ask if NK1R-ir cells and processes over a wide region of the ventral medulla are essential for central and peripheral chemoreception by cisterna magna injection of SSP-SAP, a high-affinity version of substance P-saporin. After 22 days, NK1R-ir cell loss was -79% in the retrotrapezoid nucleus and -65% in the A5 region, which lie close to the ventral surface, and -38% in the medullary raphe and -49% in the pre-Bötzinger complex/rostral ventral respiratory group, which lie deeper. Dorsal chemoreceptor sites, the caudal nucleus tractus solitarius and the A6 region, were unaffected. At 8 and 22 days, these lesions produced 1) hypoventilation during air breathing in wakefulness ( approximately 8%) and in non-rapid eye movement (NREM) ( approximately 9%) and rapid eye movement ( approximately 14%) sleep, as measured over a 4-h period; 2) a substantially reduced ventilatory response to 7% CO(2) by 61% in wakefulness and 46-57% in NREM sleep; and 3) a decreased ventilatory response to 12% O(2) by 40% in wakefulness and 35% in NREM sleep at 8 days, with partial recovery by 22 days. NK1R-ir neurons in the ventral medulla are essential for normal central chemoreception, provide a drive to breathe, and modulate the peripheral chemoreceptor responses. These effects are not state dependent.

Ventilatory Responses to Hypoxia and Hypercapnia in Stable Methadone Maintenance Treatment Patients

Methadone is a long-acting mu-opioid and is an effective treatment for heroin addiction. Opioids depress respiration, and patients receiving methadone maintenance treatment (MMT) have higher mortality than the general population. Few studies have investigated ventilatory responses to both hypercapnia and hypoxia in these patients. We measured hypercapnic ventilatory response (HCVR) and hypoxic ventilatory response (HVR) and investigated possible factors associated with both in clinically stable patients receiving MMT. Patients receiving long-term, stable doses of methadone recruited from a statewide MMT program, and normal, non-opioid-using subjects matched for age, sex, height, and body mass index were studied with HCVR and HVR. Fifty MMT patients and 20 normal subjects were studied, and significantly decreased HCVR and increased HVR were found in MMT patients compared to normal subjects (HCVR [mean +/- SD], l.27 +/- 0.61 L/min/mm Hg vs 1.64 +/- 0.57 L/min/mm Hg [p = 0.01]; HVR, 2.14 +/- 1.58 L/min/% arterial oxygen saturation measured by pulse oximetry [Sp(O2)] vs 1.12 +/- 0.7 L/min/% Sp(O2) [p = 0.008]). Respiratory rate and not tidal volume changes were the major physiologic responses contributing to both HCVR and HVR differences between the groups. Variables associated with HCVR in the MMT patients are as follows: obstructive sleep apnea/hypopnea index (t = 5.1, p = 0.00001), Pa(CO2) (t = - 3.6, p = 0.001), body height (t = 2.6, p = 0.01) and alveolar-arterial oxygen pressure gradient (t = 2.5, p = 0.02). Variables associated with HVR in MMT patients are body height (t = 3.2, p = 0.002) and Pa(CO2) (t = - 2.8, p = 0.008). Stable long-term MMT patients have blunted central and elevated peripheral chemoreceptor responses. The mechanisms and clinical significance of these findings need further investigation.

Peripheral Chemoreceptors and Sudden Infant Death Syndrome: A Wide Open Problem

This review will focus on the basic mechanisms of the peripheral chemoreceptors elicited by studies on mature chemoreceptors and on the alterations observed in these structures related to sudden infant death. The integrated response of the peripheral chemoreceptors consists of the transduction of alterations in the chemical milieu, regulating the temperature of their environment to alterations in cardiovascular and respiratory performance. Over the years, much has been written about the relative importance of the carotid and aortic bodies in the peripheral chemoreceptor response, and it is therefore worthwhile to consider the current state-of-the-art on that issue. Several lines of evidence have suggested that abnormalities in chemoreception may play a role in central hypoventilation syndromes. The sudden infant death syndrome (SIDS) involves a failure of respiration and affects infants in their early postnatal months. Unstable respiratory activity during sleep, prolonged sleep apnea, and oropharyngeal/laryngeal dysfunction induced by liquid stimulation of the upper airways have been postulated to be implicated in its genesis. It has also been found that in comparison with normal infants, infants suffering from the “aborted syndrome” (near-miss infants) are hypoventilated during quiet sleep, and have an impaired ventilatory response to carbon dioxide breathing.