Augmented Ventilatory Response Research Articles

Ventilatory response to head-down-tilt in healthy human subjects.

Postural fluid shifts may directly affect respiratory control via a complex interaction of baro- and chemo-reflexes, and cerebral blood flow. Few data exist concerning the steady state ventilatory responses during head-down tilt. We examined the cardiorespiratory responses during acute 50° head-down tilt (HDT) in 18 healthy subjects (mean [SD] age 27 [10] years). Protocol 1 (n=8, two female) was 50° HDT from 60° head-up posture sustained for 10min, while exposed to normoxia, normoxic hypercapnia (5% CO2), hypoxia (12% inspired O2) or hyperoxic hypercapnia (95% O2, 5% CO2). Protocol 2 (n=10, four female) was 50° HDT from supine, sustained for 10min, while breathing either medical air or normoxic hypercapnic (5% CO2) gas. Ventilation ( , pneumotachograph), end-tidal O2 and CO2 concentration and blood pressure (Finapres) were measured continuously throughout each protocol. Middle cerebral artery blood flow velocity (MCAv; transcranial Doppler) was also measured during protocol 2. Ventilation increased significantly (P<0.05) compared to baseline during HDT in both hyperoxic hypercapnia (protocol 1 by mean [SD] 139 [26]%) and normoxic hypercapnia (protocol 1 by mean [SD] 131 [21]% and protocol 2 by 129 [23]%), despite no change in or from baseline. No change in was observed during HDT with medical air or hypoxia, and there was no significant change in MCAv during HDT compared to baseline. The absence of change in cerebral blood flow leads us to postulate that the augmented ventilatory response during steep HDT may involve mechanisms related to cerebral venous pressure and venous outflow.

Chronic Hyperoxia Augments the Hypercapnic Ventilatory Response in Adult Rats

Rats exposed to 4 – 14 days of 60% O2 as adults exhibit a modest enhancement of their hypoxic ventilatory response (HVR) (Danielson &amp; Bavis, Physiology 38(S1): 5730119, 2023). To determine whether this plasticity is unique to the HVR or a general increase in excitability of the respiratory control system, we tested the hypothesis that chronic hyperoxia would also enhance the hypercapnic ventilatory response (HCVR). The ventilatory response to 7% CO2 was measured by whole-body plethysmography in adult, Sprague-Dawley rats immediately after 4 and 14 days of exposure to 60% O2 or an equivalent time period in room air. Baseline ventilation and the HCVR were unchanged after 4 days of hyperoxia. The HCVR was increased after 14 days (Treatment × FICO2, P=0.004), with hypercapnic ventilation being approximately 15% greater than in control rats. However, this effect was no longer significant after accounting for variation in metabolic rate, and the HCVR was fully recovered when rats were restudied four weeks after they were returned to room air. In a follow-up experiment, pulse oximetry was performed in isoflurane-anesthetized rats breathing room air or 12% O2. Exposure to 4 – 14 days of 60% O2 did not impair gas exchange, so augmented ventilatory responses likely reflect changes in the neural control of breathing and/or metabolism rather than differences in the levels of hypoxemia and hypercapnia experienced by rats during the tests. In conclusion, chronic hyperoxia elicits plasticity in both the HVR and HCVR of adult rats, but these responses recover in less than one month after rats are returned to room air. Supported by NIH grant P20 GM-103423 (Maine INBRE). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute hyperoxia reveals tonic influence of peripheral chemoreceptors on systemic vascular resistance in heart failure patients

Peripheral chemoreceptors’ (PCh) hyperactivity increases sympathetic tone. An augmented acute ventilatory response to hypoxia, being a marker of PCh oversensitivity, was also identified as a marker of poor prognosis in HF. However, not much is known about the tonic (chronic) influence of PCh on cardio-respiratory parameters. In our study 30 HF patients and 30 healthy individuals were exposed to 100% oxygen for 1 min during which minute ventilation and hemodynamic parameters were non-invasively recorded. Systemic vascular resistance (SVR) and mean arterial pressure (MAP) responses to acute hyperoxia differed substantially between HF and control. In HF hyperoxia caused a significant drop in SVR in early stages with subsequent normalization, while increase in SVR was observed in controls. MAP increased in controls, but remained unchanged in HF. Bilateral carotid bodies excision performed in two HF subjects changed the response to hyperoxia towards the course seen in healthy individuals. These differences may be explained by the domination of early vascular reaction to hyperoxia in HF by vasodilation due to the inhibition of augmented tonic activity of PCh. Otherwise, in healthy subjects the vasoconstrictive action of oxygen remains unopposed. The magnitude of SVR change during acute hyperoxia may be used as a novel method for tonic PCh activity assessment.

Mice That Express a KCNQ2 Channel Gain‐of‐Function Variant (R201C) Exhibit a Blunted Ventilatory Response to CO 2

The KCNQ1-5 (Kv7)family of voltage gated K+ channels activate at subthreshold voltages and are important determinants of resting membrane potential. In particular, both loss- and gain-of-function KCNQ2 pathogenic variants are associated with neurodevelopmental disorders characterized by seizures, myoclonus, disordered breathing and early mortality. To understand how KCNQ2 channels regulate breathing and contribute to mortality, we developed a conditional mouse line that expresses a KCNQ2 gain-of-function mutation (R201C) that in humans causes severe respiratory problems reminiscent of congenital central hypoventilation syndrome (CCHS). Considering CCHS involves disruption of neurons in the retrotrapezoid nucleus (RTN) that regulate breathing in response to changes in CO2/H+ (i.e., function as respiratory chemoreceptors), we first used fluorescent in situ hybridization to confirm that Kcnq2 channels are expressed by chemosensitive RTN neurons identified based on location and expression of Phox2b. Next, we used whole-body plethysmography to characterize baseline breathing and the ventilatory response to CO2 or low O2 in control (N=6) and Phox2bcre::Kcnq2R201C/+ (N=4) mice (P30; mixed sex). We found that Phox2bcre::Kcnq2R201C/+ mice show diminished ventilatory response to graded increases in CO2. In 7% CO2 (balance O2), Phox2bcre::Kcnq2R201C/+ mice show noticeably reduced respiratory frequency (283.9 ± 26.8 bpm for Phox2bcre::Kcnq2R201C/+ compared to 359.5 ± 16.86 bpm for controls); tidal volume (0.024 ± 0.005 ml/g for Phox2bcre::Kcnq2R201C/+ compared to 0.031 ± 0.003 ml/g for control), and minute ventilation (6.9 ± 1.97 ml/min/g for Phox2bcre::Kcnq2R201C/+ compared to 11.08 ± 1.58 ml/min/g for control). Interestingly, Phox2bcre::Kcnq2R201C/+ mice also show an augmented ventilatory response to hypoxia compared to control mice. In 10% O2 (5 min exposure), Phox2bcre::Kcnq2R201C/+ mice show increased respiratory frequency (Phox2bcre::Kcnq2R201C/+ 268.5 ± 5.073 bpm compared to 223.4 ± 15.84 bpm for controls); tidal volume (0.014 ± 0.001 ml/g for Phox2bcre::Kcnq2R201C/+ compared to control 0.013 ± 0.001 ml/g), and minute ventilation (3.81 ± 0.361 ml/min/g for Phox2bcre::Kcnq2R201C/+ compared to 2.95 ± 0.235 ml/min/g for control). These results suggest mice expressing the KCNQ2 variant R201C in Phox2b expressing neurons recapitulate the hypoventilatory phenotype exhibited by patients caring this variant. Our results also suggest peripheral chemoreceptor drive partially compensates for diminished central drive in Phox2bcre::Kcnq2R201C/+ mice.

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.

Loss of cell adhesion molecule CHL1 improves homeostatic adaptation and survival in hypoxic stress

Close homologue of L1 (CHL1) is a transmembrane cell adhesion molecule that is critical for brain development and for the maintenance of neural circuits in adults. Recent studies revealed that CHL1 has diverse roles and is involved in the regulation of recovery after spinal cord injury. CHL1 expression was downregulated in the cerebral cortex, hypothalamus, and brain stem after the induction of acute hypoxia (AH). In the current study, we sought to address the role of CHL1 in regulating homeostasis responses to hypoxia using CHL1-knockout (CHL1−/−) mice. We found that, compared with wild-type littermates, CHL1−/− mice showed a dramatically lower mortality rate and an augmented ventilatory response after they were subjected to AH. Immunofluorescence staining revealed that CHL1 was expressed in the carotid body (CB), the key oxygen sensor in rodents, and CHL1 expression level in the CB as assayed by western blot was decreased after hypoxic exposure. The number of glomus cells and the expression of tyrosine hydroxylase (a marker for glomus cells) in the CB of CHL1−/− mice appeared to be increased compared with CHL1+/+ mice. In addition, in the ex vivo CB preparation, hypoxia induced a significantly greater afferent nerve discharge in CHL1−/− mice compared with CHL1+/+ mice. Furthermore, the arterial blood pressure and plasma catecholamine levels of CHL1−/− mice were also significantly higher than those of CHL1+/+ mice. Our findings first demonstrate that CHL1 is a novel intrinsic factor that is involved in CB function and in the ventilatory response to AH.

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.

Influence of Locomotor Muscle Metaboreceptor Stimulation on the Ventilatory Response to Exercise in Heart Failure

Whether locomotor muscle afferent neural activity contributes to exercise hyperpnea and symptoms of dyspnea in heart failure (HF) is controversial. We examined the influence of metaboreceptor stimulation on ventilation with and without maintaining end-exercise end-tidal CO(2) levels. Eleven patients with HF aged 51+/-5 years (ejection fraction, 32+/-3%; New York Heart Association class, 1.6+/-0.2) and 11 age- and gender-matched healthy control participants aged 43+/-3 years were studied. Participants underwent 3 steady-state cycling sessions at 60% of peak oxygen consumption for 4 minutes. The first exercise session was a baseline control trial. Bilateral thigh tourniquets were inflated to suprasystolic pressure at end exercise for 2 minutes during 2 of the trials (regional circulatory occlusion) with the addition of inspired CO(2) to maintain end-exercise partial pressure of end-tidal CO(2) during 1 trial (regional circulatory occlusion+CO(2)). Minute ventilation was measured continuously throughout each trial. At 2 minutes postexercise during the baseline control trial in patients with HF, minute ventilation was 54% of end exercise, whereas the control group averaged 41% (P=0.11). During regional circulatory occlusion in patients with HF, minute ventilation was 60% of end exercise; however, the control group averaged 35% (P<0.001). During regional circulatory occlusion+CO(2), the minute ventilation of patients with HF averaged 67% of end exercise, whereas the control group averaged 44% (P<0.001). These data suggest that increased afferent neural activity from the large locomotor muscles associated with metabolites generated during exercise contribute to the augmented ventilatory response to exercise in patients with HF.

Carotid body potentiation induced by intermittent hypoxia: Implications for cardiorespiratory changes induced by sleep apnoea

1. The most usual form of chronic hypoxia in humans is the intermittent hypoxia resulting from obstructive sleep apnoea (OSA). The OSA syndrome is a highly prevalent sleep breathing disorder that is considered an independent risk factor for hypertension and cardiovascular diseases. Endothelial dysfunction, oxidative stress, inflammation and sympathetic activation have been proposed as potential mechanisms involved in the onset of the hypertension. However, evidence for a unique pathogenic mechanism has been difficult to establish in OSA patients because of concomitant comorbidities. Thus, animal models have been developed to study the pathological consequences of exposure to chronic intermittent hypoxia (CIH). 2. Because OSA patients and animals exposed to CIH show augmented ventilatory, sympathetic and cardiovascular responses to acute hypoxia, it has been proposed that enhanced carotid body responsiveness to hypoxia is involved in the autonomic changes induced by OSA and in the development of the hypertension. Recently, this proposal has received further support from recordings of carotid body chemosensory neural discharges in situ and in vitro showing that exposure of animals to CIH increases basal carotid body chemosensory discharges and enhances the chemosensory response to hypoxia. 3. In the present brief review, we discuss the evidence supporting an important role for the carotid body in the progression of cardiorespiratory changes induced by OSA and the contribution of oxidative stress, endothelin-1 and pro-inflammatory molecules in the potentiation of the carotid body chemosensory function induced by CIH.

Effect of exercise-induced muscle damage on ventilatory and perceived exertion responses to moderate and severe intensity cycle exercise

This study examined the effect of exercise-induced muscle damage (EIMD) on ventilatory and perceived exertion responses to cycle exercise. Ten healthy, physically active men cycled for 6 min at moderate intensity and to exhaustion at severe intensity before and 48 h after eccentric exercise (100 squats with a load corresponding to 70% of body mass). Changes in ventilation and ratings of perceived exertion (RPE) were calculated for each individual and expressed against time (moderate and severe exercise) and as a percentage of time to exhaustion (severe exercise). Ventilation increased during moderate exercise at 48 h V(E); 34.5 +/- 5.0 to 36.3 +/- 3.8 l min(-1), P < 0.05) but increases in RPE were not significant. During severe exercise at 48 h, time to exhaustion (TTE) was reduced and V(E) (87.1 +/- 14.1 to 93.8 +/- 11.7 l min(-1)) and RPE (15.5 +/- 1.3 to 16.1 +/- 1.4) were elevated (P < 0.05). When expressed as a percentage of TTE, the differences in ventilation and RPE values disappeared. Findings indicate that the augmented ventilatory response to cycle exercise following EIMD may be an important cue in informing effort perception during high-intensity exercise but not during moderate-intensity exercise.

Prenatal hypoxia preconditioning improves hypoxic ventilatory response and reduces mortality in neonatal rats

Severe hypoxia/ischemia is a major cause of neonatal cardiorespiratory dysfunction and mortality. We tested whether prenatal hypoxia preconditioning would augment hypoxic and hypercapnic ventilatory responses, and thereby reduce neonatal mortality. Pregnant rats at 19 days' gestation were exposed to six episodes of intermittent hypoxia (10-min of 15% O(2) followed by 10-min of normoxia/episode, PPC), or room air (CON) per day until delivery. The ventilatory responses to 1 min of 10% O(2) and 10% CO(2), and 5 min of 5% O(2) were performed in anesthetized pups. The conscious pups were exposed to 5% O(2) for approximately 105 min, and their mortality and dry/wet weight of the lung and brain were evaluated. We found that augmented ventilatory responses to 1 min of 10% O(2) and 10% CO(2) were similar in the two groups (P>0.05). In contrast, 5 min of 5% O(2) initially caused a ventilatory peak response followed by a decline that was markedly diminished (35%, P=0.013) by PPC. PPC also significantly decreased neonatal mortality by 22% (P=0.044) as compared with CON. We conclude that prenatal hypoxia preconditioning reduces neonatal mortality apparently by improving the severe hypoxic ventilatory response.

320 Augmented ventilatory response to CO2 and impaired respiratory stability during exercise in patients with central sleep apnoea and chronic heart failure methods

320 Augmented ventilatory response to CO2 and impaired respiratory stability during exercise in patients with central sleep apnoea and chronic heart failure methods

Morning attenuation in cerebrovascular CO2 reactivity in healthy humans is associated with a lowered cerebral oxygenation and an augmented ventilatory response to CO2

We hypothesized that, in healthy subjects without pharmacological intervention, an overnight reduction in cerebrovascular CO(2) reactivity would be associated with an elevated hypercapnic ventilatory [ventilation (VE)] responsiveness and a reduction in cerebral oxygenation. In 20 healthy male individuals with no sleep-related disorders, continuous recordings of blood velocity in the middle cerebral artery, arterial blood pressure, VE, end-tidal gases, and frontal cortical oxygenation using near infrared spectroscopy were monitored during hypercapnia (inspired CO(2), 5%), hypoxia [arterial O(2) saturation (Sa(O(2))) approximately 84%], and during a 20-s breath hold to investigate the related responses to hypercapnia, hypoxia, and apnea, respectively. Measurements were conducted in the evening (6-8 PM) and in the early morning (6-8 AM). From evening to morning, the cerebrovascular reactivity to hypercapnia was reduced (5.3 +/- 0.6 vs. 4.6 +/- 1.1%/Torr; P < 0.05) and was associated with a reduced increase in cerebral oxygenation (r = 0.39; P < 0.05) and an elevated morning hypercapnic VE response (r = 0.54; P < 0.05). While there were no overnight changes in cerebrovascular reactivity or VE response to hypoxia, there was greater cerebral desaturation for a given Sa(O(2)) in the morning (AM, -0.45 +/- 0.14 vs. PM, -0.35 +/- 0.14%/Sa(O(2)); P < 0.05). Following the 20-s breath hold, in the morning, there was a smaller surge middle cerebral artery velocity and cerebral oxygenation (P < 0.05 vs. PM). These data indicate that normal diurnal changes in the cerebrovascular response to CO(2) influence the hypercapnic ventilatory response as well as the level of cerebral oxygenation during changes in arterial Pco(2); this may be a contributing factor for diurnal changes in breathing stability and the high incidence of stroke in the morning.

Augmented Chemosensitivity in Black-Eyed White Mitf mi-bw Mice, Lacking Melanocytes

Microphthalmia-associated transcription factor (Mitf) is responsible for differentiation of melanocytes, and a recessive Mitf mutant, black-eyed white (bw) mouse, is characterized by the lack of melanocytes in the skin and inner ear. To search for the hitherto unknown roles of melanocytes, we analysed the ventilatory responses of unanaesthetized bw mice by whole body plethysmography. During air breathing, bw mice showed lower breathing frequency and larger tidal volume, compared with age-matched wild-type mice, although there was no difference in the minute ventilation. Importantly, bw mice present normal haematocrit values and red blood cell counts. We next measured the immediate ventilatory responses to acute hypoxia (10% O2) and to hyperoxic hypercapnia (10% CO2). Hypoxic and hypercapnic ventilatory responses represent the functions of the chemoreceptors in the carotid body and the brainstem, respectively. The bw mice retain the peripheral hypoxic and central hypercapnic sensing functions, but exhibited augmented ventilatory responses to both hypoxia and hypercapnia. Unexpectedly, RT-PCR analysis has shown the expression of melanocyte-specific Mitf mRNA in the brain of bw mice, suggesting the presence of leptomeningeal melanocytes. These findings suggest a functional link between skin melanocytes and the central respiratory controller that generates respiratory rhythm and pattern.

Ventilatory and circulatory responses at the onset of exercise after eccentric exercise

The purpose of this study was to clarify whether delayed onset muscle soreness (DOMS) and muscle damage after eccentric exercise (ECC) could affect the ventilatory and circulatory responses at the onset of exercise, and whether those effects would continue after the disappearance of DOMS. Ten males participated in this study. We measured ventilatory and circulatory responses at the onset of exercise, for the first 20 s, during knee extension-relaxation voluntary exercise (VOL) and passive movement (PAS), which was achieved by the experimenter alternatively pulling ropes connected to the subjects' ankles for the same period and frequency as during VOL. VOL and PAS were performed before, 2 days after, and 7 days after ECC. The following results were found: (1) the gain of minute ventilation at the onset of VOL at 2 days after ECC was significantly larger than that of before ECC; (2) the gain of minute ventilation at 7 days after ECC during both VOL and PAS was also enhanced significantly as compared to that of before ECC; and (3) heart rate and blood pressure responses were unchanged throughout the experimental period. In conclusion, ventilatory response at the onset of exercise is augmented during DOMS and EIMD after ECC and the enhanced ventilatory response continued after the disappearance of DOMS. It is suggested that enhanced ventilatory response during exercise after ECC is attributed to at least the changes in neural factors and that the mechanisms inducing these augmented ventilatory responses should be different during the period after ECC.

Cardiovascular and ventilatory acclimatization induced by chronic intermittent hypoxia: A role for the carotid body in the pathophysiology of sleep apnea

Patients with obstructive sleep apnea (OSA) show augmented ventilatory, sympathetic and cardiovascular responses to hypoxia. The facilitatory effect of chronic intermittent hypoxia (CIH) on the hypoxic ventilatory response has been attributed to a potentiation of the carotid body (CB) chemosensory response to hypoxia. However, it is a matter of debate whether the effects induced by CIH on ventilatory responses to hypoxia are due to an enhanced CB activity. Recently, we studied the effects of short cyclic hypoxic episodes on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes repeated during 8 hours for 4 days. Our results showed that CIH selectively enhanced ventilatory and carotid chemosensory responses to acute hypoxia. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low/high frequency ratio and an increased variability in the low frequency band of heart rate variability, similar to what is observed in OSA patients. Thus, it is likely that the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia.

Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia.

The carotid body (CB) chemoreceptors may play an important role in the enhanced hypoxic ventilatory response induced by chronic intermittent hypoxia (CIH). We studied the effects of cyclic hypoxic episodes of short duration on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes (PO2 approximately 75 Torr) repeated during 8 h for 2-4 days. Cats were anaesthetized with sodium pentobarbitone (40 mg kg(-1) i.p., followed by 8-12 mg i.v.), and ventilatory and cardiovascular responses to NaCN (0.1-100 microg kg(-1) i.v.) and several isocapnic levels of oxygen (PO2 approximately 20-740 Torr) were studied. After studying the reflex responses, we recorded the CB chemosensory responses induced by the same stimuli. Results showed that CIH for 4 days selectively enhanced cat CB ventilatory (VT and VI) responses to hypoxia, while responses to NaCN remained largely unchanged. Similarly, basal CB discharges and responses to acute hypoxia (PO2 < 100 Torr) were larger in CIH than in control cats, without modification of the responses to NaCN. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia or hyperoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low-/high-frequency ratio and an increase of the power spectral distribution of low frequencies of heart rate variability. Thus, the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia, as well as to modified heart rate variability due to early changes in autonomic activity.

Impaired left ventricular filling predicts augmented ventilatory response to exercise in patients with chronic heart failure

Impaired left ventricular filling predicts augmented ventilatory response to exercise in patients with chronic heart failure

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha.

To investigate whether the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O(2)-regulated HIF-1 alpha subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a(+/-) mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a(+/-) mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a(+/-) mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a(+/-) mice. Thus partial HIF-1 alpha deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.

Microinjection of acetazolamide into the fastigial nucleus augments respiratory output in the rat.

The rostral fastigial nucleus (FNr) of the cerebellum facilitates the respiratory response to hypercapnia. We hypothesized that some FNr sites are chemosensitive to focal tissue acidosis and contribute, at least partially, to respiratory modulation. Minute ventilation (VE) was recorded in 21 anesthetized and spontaneously breathing rats. Acetazolamide (AZ; 50 microM) was microinjected unilaterally into the FNr while an isocapnic condition was maintained throughout the experiment. AZ (1 or 20 nl) injection into the FNr significantly elevated VE (46.0 +/- 6.7%; P < 0.05), primarily via an increase in tidal volume (31.7 +/- 3.8%; P < 0.05), with little effect on arterial blood pressure. This augmented ventilatory response was initiated at 6.3 +/- 0.8 min and reached the peak at 19.7 +/- 4.1 min after AZ administration. The same dose of AZ delivered into the interposed and lateral cerebellar nuclei, or vehicle injection into the FNr, failed to elicit detectable cardiorespiratory responses. To determine whether the ventilatory response to AZ injection into the FNr resulted from an increase in respiratory central drive, the minute phrenic nerve activity (MPN) was recorded in seven paralyzed and ventilated rats. Similar to VE, MPN was increased by 38.9 +/- 8.9% (P < 0.05) after AZ administration. Our results suggest that elevation of CO2/H+ within the FNr facilitates respiratory output, supporting the presence of ventilatory chemoreception in rat FNr.