Laryngeal apnea in rat pups: effects of age and body temperature.

In neonatal mammals of many species, including human infants, apnea and other reflex responses frequently arise from stimulation of laryngeal receptors by ingested or regurgitated liquids. These reflexes, mediated by afferents in the superior laryngeal nerves (SLNs), are collectively known as the laryngeal chemoreflex (LCR) and are suspected to be responsible for some cases of the sudden infant death syndrome (SIDS). The LCR is strongly enhanced by mild increases in body temperature in decerebrate piglets, a finding that is of interest because SIDS victims are often found in overheated environments. Because of the experimental advantages of studying reflex development and mechanisms in neonatal rodents, we have developed methods for eliciting laryngeal apnea in anesthetized rat pups and have examined the influence of mild hyperthermia in animals ranging in age from 3 to 21 days. We found that apnea and respiratory disruption, elicited either by intralaryngeal water or by electrical stimulation of the SLN, occurred at all ages studied. Raising body temperature by 2-3 degrees C prolonged the respiratory disturbance in response to either stimulus. This effect of hyperthermia was prominent in the youngest animals and diminished with age. We conclude that many studies of the LCR restricted to larger neonatal animals in the past can be performed in infant rodents using appropriate methods. Moreover, the developmental changes in the LCR and in the thermal modulation of the LCR seem to follow different temporal profiles, implying that distinct neurophysiological processes may mediate the LCR and thermal prolongation of the LCR.

Central chemoreflex sensitivity and sympathetic neural outflow in elite breath-hold divers.

Repeated hypoxemia in obstructive sleep apnea patients increases sympathetic activity, thereby promoting arterial hypertension. Elite breath-holding divers are exposed to similar apneic episodes and hypoxemia. We hypothesized that trained divers would have increased resting sympathetic activity and blood pressure, as well as an excessive sympathetic nervous system response to hypercapnia. We recruited 11 experienced divers and 9 control subjects. During the diving season preceding the study, divers participated in 7.3 +/- 1.2 diving fish-catching competitions and 76.4 +/- 14.6 apnea training sessions with the last apnea 3-5 days before testing. We monitored beat-by-beat blood pressure, heart rate, femoral artery blood flow, respiration, end-tidal CO(2), and muscle sympathetic nerve activity (MSNA). After a baseline period, subjects began to rebreathe a hyperoxic gas mixture to raise end-tidal CO(2) to 60 Torr. Baseline MSNA frequency was 31 +/- 11 bursts/min in divers and 33 +/- 13 bursts/min in control subjects. Total MSNA activity was 1.8 +/- 1.5 AU/min in divers and 1.8 +/- 1.3 AU/min in control subjects. Arterial oxygen saturation did not change during rebreathing, whereas end-tidal CO(2) increased continuously. The slope of the hypercapnic ventilatory and MSNA response was similar in both groups. We conclude that repeated bouts of hypoxemia in elite, healthy breath-holding divers do not lead to sustained sympathetic activation or arterial hypertension. Repeated episodes of hypoxemia may not be sufficient to drive an increase in resting sympathetic activity in the absence of additional comorbidities.

Some aspects of clinical relevance in the maturation of respiratory control in infants.

Two reflex mechanisms important for survival are discussed. Brain stem and cardiovascular mechanisms that are responsible for recovery from severe hypoxia (autoresuscitation) are important for survival in acutely hypoxic infants and adults. Failure of this mechanism may be important in sudden infant death syndrome (SIDS), because brain stem-mediated hypoxic gasping is essential for successful autoresuscitation and because SIDS infants appear to attempt to autoresuscitate just before death. A major function of another mechanism is to protect the airway from fluid aspiration. The various components of the laryngeal chemoreflex (LCR) change during maturation. The LCR is an important cause of prolonged apneic spells in infants. Consequently, it also may have a role in causing SIDS. Maturational changes and/or inadequacy of this reflex may be responsible for pulmonary aspiration and infectious pneumonia in both children and adults.

[Obesity-hypoventilation syndrome]. / Syndrome obésité-hypoventilation.

INTRODUCTION: The obesity-hypoventilation syndrome (OHS), or alveolar hypoventilation in the obese, has been described initially as the "Pickwickian syndrome". It is defined as chronic alveolar hypoventilation (PaO2<70 mmHg, PaCO2 > or =45 mmHg) in obese patients (body mass index>30 kg/m2) who have no other respiratory disease explaining the hypoxemia-hypercapnia. BACKGROUND: The large majority of obese subjects are not hypercapnic, even in case of severe obesity (>40 kg/m2). There are three principal causes, which can be associated, explaining alveolar hypoventilation in obese subjects: high cost of respiration and weakness of the respiratory muscles (probably the major cause), dysfunction of the respiratory centers with diminished chemosensitivity, long-term effects of the repeated episodes of obstructive sleep apneas observed in some patients. The role of leptin (hormone produced by adipocytes) in the pathogenesis of this syndrome, has been recently advocated. OHS is generally observed in subjects over 50 years. Its prevalence has markedly increased in recent years, probably due to the present "epidemic" of obesity. The diagnosis is often made after an episode of severe respiratory failure. Comorbidities, favored by obesity, are very frequent: systemic hypertension, left heart diseases, diabetes. VIEWPOINT: OHS must be distinguished from obstructive sleep apnea syndrome (OSAS) even if the two conditions are often associated. OSAS may be absent in certain patients with OHS (20% of the patients in our experience). On the other hand obesity may be absent in certain patients with OSAS. CONCLUSION: Losing weight is the "ideal" treatment of OHS but in fact it cannot be obtained in most patients. Nocturnal ventilation (continuous positive airway pressure and mainly bilevel non invasive ventilation) is presently the best treatment of OHS and excellent short and long-term results on symptoms and arterial blood gases have been recently reported.

Plasticity of central chemoreceptors: effect of bilateral carotid body resection on central CO2 sensitivity.

BACKGROUND: Human breathing is regulated by feedback and feed-forward control mechanisms, allowing a strict matching between metabolic needs and the uptake of oxygen in the lungs. The most important control mechanism, the metabolic ventilatory control system, is fine-tuned by two sets of chemoreceptors, the peripheral chemoreceptors in the carotid bodies (located in the bifurcation of the common carotid arteries) and the central CO2 chemoreceptors in the ventral medulla. Animal data indicate that resection of the carotid bodies results, apart from the loss of the peripheral chemoreceptors, in reduced activity of the central CO2 sensors. We assessed the acute and chronic effect of carotid body resection in three humans who underwent bilateral carotid body resection (bCBR) after developing carotid body tumors. METHODS AND FINDINGS: The three patients (two men, one woman) were suffering from a hereditary form of carotid body tumors. They were studied prior to surgery and at regular intervals for 2-4 y following bCBR. We obtained inspired minute ventilation (Vi) responses to hypoxia and CO2. The Vi-CO2 responses were separated into a peripheral (fast) response and a central (slow) response with a two-compartment model of the ventilatory control system. Following surgery the ventilatory CO2 sensitivity of the peripheral chemoreceptors and the hypoxic responses were not different from zero or below 10% of preoperative values. The ventilatory CO2 sensitivity of the central chemoreceptors decreased by about 75% after surgery, with peak reduction occurring between 3 and 6 mo postoperatively. This was followed by a slow return to values close to preoperative values within 2 y. During this slow return, the Vi-CO2 response shifted slowly to the right by about 8 mm Hg. CONCLUSIONS: The reduction in central Vi-CO2 sensitivity after the loss of the carotid bodies suggests that the carotid bodies exert a tonic drive or tonic facilitation on the output of the central chemoreceptors that is lost upon their resection. The observed return of the central CO2 sensitivity is clear evidence for central plasticity within the ventilatory control system. Our data, although of limited sample size, indicate that the response mechanisms of the ventilatory control system are not static but depend on afferent input and exhibit a large degree of restoration or plasticity. In addition, the permanent absence of the breathing response to hypoxia after bCBR may aggravate the pathological consequences of sleep-disordered breathing.

Acquired attenuation of chemoreceptor function in chronically hypoxic man at high altitude.

To determine whether chronic exposure to hypoxia during adulthood produces alterations in the control of ventilation, measurements of the resting ventilatory response to hypoxia and hypercapnia, as well as ventilatory response to hypoxia during exercise, were carried out in a group of 10 long-term (3-39 yr) non-native residents of Leadville, Colo. (elevation 3100 m). A group of 8 subjects native to Leadville was also studied and 10 low altitude subjects of Denver, Colo. (elevation 1600 m) served as controls. Hypoxic ventilatory drive was measured as the shape parameter A of isocapnic VE-PA(o2) curves. In the non-native high altitude resident this parameter averaged 43% of the value for low altitude controls (P<0.05) denoting a diminished ventilatory response to hypoxia. The degree of attenuation was related to the length of time spent at high altitude. In the high altitude natives the parameter A averaged 9.6% of control (P<0.01). Similarly hypercapnic ventilatory drive as measured by the slope of the isoxic VE-PA(co2) lines was reduced in the non-native residents to 65% of control (P<0.05) and in the natives averaged 54% of control (P<0.01). In contrast with these findings at rest induction of hypoxia during exercise produced an increase in ventilation comparable to that in the controls in both groups of highlanders. Hence chronic exposure to hypoxia during adulthood in man results in marked attenuation of the ventilatory response to hypoxia at rest and this is a function of the length of exposure to hypoxia. This attenuation of the ventilatory response to hypoxia was associated with a decrease in hypercapnic ventilatory drive. The fact that hypoxic ventilatory drive was almost completely absent while hypercapnic drive was only partially reduced parallels closely the more important role of the peripheral chemoreceptors in mediating ventilatory responses to hypoxia than to hypercapnia. This suggests that the alterations in ventilatory control at altitude are due to failure of peripheral chemoreceptor function.

Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men.

The response of ventilation and of heart rate to hypoxia and hypercapnia was determined in eight young normal men age 22-30 yr and eight elderly men age 64-73. The elderly men were selected and carefully screened to eliminate the possibility of cardiopulmonary disease. All the subjects were born at low altitude and had no significant prior exposure to hypoxia. The ventilatory response to hypoxia was measured as the exponential slope constant. k, of regression lines relating the logarithm of incremental ventilation to PAo(2) during isocapnic progressive hypoxia. The heart rate response to hypoxia was measured as the percentage change in heart rate between PAo(2) = 100 and PAo(2) = 40 mm Hg. The ventilatory response to hypercapnia was measured as the slope of regression lines relating ventilation to PAco(2) during rebreathing with PAo(2) > 200 mm Hg. The heart rate response to hypercapnia was measured as the percentage change in heart rate between control values at the start of the rebreathing test and PACO(2) = 55 mm Hg. The ventilatory and heart rate responses to both hypoxia and hypercapnia were significantly decreased in the elderly men as compared to the young men. Hypoxic ventilatory drive was decreased by 51+/-6% (mean +/-SEM: P < 0.001) and hypercapnic drive by 41+/-7% (P < 0.025). The percentage change in heart rate produced by hypoxia was 34+/-5% (mean +/-SEM) in the young normals and 12+/-2% in the old normals (P < 0.005). Similar figures for heart rate in response to hypercapnia were 15+/-3% and -1+/-1% for the young and old normal groups (P < 0.001). We conclude that ventilatory and heart rate responses to hypoxia and hypercapnia diminish with age. These alterations in both ventilatory and circulatory controls could make older individuals more vulnerable to hypoxic disease states.

Tonic chemoreflex activation contributes to the elevated muscle sympathetic nerve activity in patients with chronic renal failure.

OBJECTIVE: Sympathetic activation may contribute to both cardiovascular morbidity and the progression of chronic kidney disease. The role of the chemoreceptors in determining sympathetic nerve discharge in patients with chronic renal failure (CRF) is unknown. We tested the hypothesis that tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in patients with CRF. METHODS: Utilizing a double-blind, randomized, vehicle-controlled design, we examined the effects of chemoreflex deactivation on muscle sympathetic nerve activity (MSNA). We compared effects of breathing 100% oxygen for 15 min with effects of breathing room air for 15 min in 12 stable patients with CRF and in 12 control individuals with similar age, gender, blood pressure and body mass index. RESULTS: The baseline MSNA was elevated significantly in the patients with CRF as compared with the control individuals (50 +/- 2 vs 42 +/- 2 bursts/min; P < 0.05). Reductions in systolic blood pressure and pulse pressure in response to the administration of 100% oxygen were significantly different from those observed during administration of room air in patients with CRF. In patients with CRF, MSNA decreased by 29 +/- 7% (P < 0.01) during hyperoxia but did not change during administration of room air (5 +/- 6%; P = NS). By contrast, neither 100% oxygen or room air changed any measures in control individuals. CONCLUSIONS: Tonic activation of excitatory chemoreflex afferents contributes to increased efferent sympathetic activity to muscle circulation and to blood pressure control in patients with CRF. These findings may have important implications for understanding mechanisms underlying the link between CRF and cardiovascular disease.

Sympathetic chemoreflex responses in obstructive sleep apnea and effects of continuous positive airway pressure therapy.

BACKGROUND: Sympathetic nerve activity is increased in awake and regularly breathing patients with obstructive sleep apnea (OSA). Over time, repetitive hypoxic stress could alter sympathetic chemoreflex function in OSA. METHODS: We determined the responses to acute hypoxia (fraction of inspired oxygen of 0.1, for 5 min), static handgrip exercise, and the cold pressor test (CPT) in 24 patients with OSA (age, 50 +/- 3 years [mean +/- SEM]; apnea-hypopnea index, 47 +/- 6 events per hour) and in 14 age- and weight-matched nonapneic control subjects. Muscle sympathetic nerve activity (MSNA) [peroneal microneurography], BP, and ventilation were monitored. RESULTS: Basal MSNA was higher in OSA patients compared to control subjects (45 +/- 4 bursts per minute vs 33 +/- 4 bursts per minute, respectively; p < 0.05). Furthermore, compared to control subjects, the MSNA responses to hypoxia were markedly enhanced in OSA (p < 0.001). Whereas the ventilatory responses to hypoxia tended to be increased in OSA (p = 0.06), the BP responses did not differ between the groups (p = 0.45). The neurocirculatory reflex responses to handgrip exercise and to the CPT were similar in the two groups (p = not significant). In OSA patients who were retested after 1 to 24 months of continuous positive airway pressure (CPAP) therapy (n = 11), basal MSNA (p < 0.01) and the responses of MSNA to hypoxia (p < 0.01) decreased significantly, whereas the ventilatory responses remained unchanged (p = 0.82). CONCLUSION: These data suggest that the sympathetic responses to hypoxic chemoreflex stimulation are enhanced in OSA and may normalize in part following CPAP therapy.

The ontogeny of hemodynamic responses to prolonged umbilical cord occlusion in fetal sheep.

There is evidence that preterm fetuses have blunted chemoreflex-mediated responses to hypoxia. However, the preterm fetus has much lower aerobic requirements than at term, and so moderate hypoxia may not be sufficient to elicit maximal chemoreflex responses; there are only limited quantitative data on the ontogeny of chemoreflex and hemodynamic responses to severe asphyxia. Chronically instrumented fetal sheep at 0.6 (n = 12), 0.7 (n = 12), and 0.85 (n = 8) of gestational age (GA; term = 147 days) were exposed to 30, 25, or 15 min of complete umbilical cord occlusion, respectively. At all ages, occlusion was associated with early onset of bradycardia, profoundly reduced femoral blood flow and conductance, and hypertension. The 0.6-GA fetuses showed a significantly slower and lesser fall in femoral blood flow and conductance compared with the 0.85-GA group, with a correspondingly reduced relative rise in mean arterial blood pressure. As occlusion continued, the initial adaptation was followed by loss of peripheral vasoconstriction and progressive development of hypotension in all groups. The 0.85-GA fetuses showed significantly more sustained reduction in femoral conductance but also more rapid onset of hypotension than either of the younger groups. Electroencephalographic (EEG) activity was suppressed during occlusion in all groups, but the degree of suppression was less at 0.6 GA than at term. In conclusion, the near-midgestation fetus shows attenuated initial (chemoreflex) peripheral vasomotor responses to severe asphyxia compared with more mature fetuses but more sustained hemodynamic adaptation and reduced suppression of EEG activity during continued occlusion of the umbilical cord.

Two patterns of daily hypoxic exposure and their effects on measures of chemosensitivity in humans.

The purpose of this study was to compare chemoresponses following two different intermittent hypoxia (IH) protocols in humans. Ten men underwent two 7-day courses of poikilocapnic IH. The long-duration IH (LDIH) protocol consisted of daily 60-min exposures to normobaric 12% O(2). The short-duration IH (SDIH) protocol comprised twelve 5-min bouts of 12% O(2), separated by 5-min bouts of room air, daily. Isocapnic hypoxic ventilatory response (HVR) was measured daily during the protocol and 1 and 7 days following. Hypercapnic ventilatory response (HCVR) and CO(2) threshold and sensitivity (by the modified Read rebreathing technique) were measured on days 1, 8, and 14. Following 7 days of IH, the mean HVR was significantly increased from 0.47 +/- 0.07 and 0.47 +/- 0.08 to 0.70 +/- 0.06 and 0.79 +/- 0.06 l.min(-1).%Sa(O(2))(-1) (LDIH and SDIH, respectively), where %Sa(O(2)) is percent arterial oxygen saturation. The increase in HVR reached a plateau after the third day. One week post-IH, HVR values were unchanged from baseline. HCVR increased from 3.0 +/- 0.4 to 4.0 +/- 0.5 l.min(-1).mmHg(-1). In both the hyperoxic and hypoxic modified Read rebreathing tests, the slope of the CO(2)/ventilation plot was unchanged by either intervention, but the CO(2)/ventilation curve shifted to the left following IH. There were no correlations between the changes in response to hypoxia and hypercapnia. There were no significant differences between the two IH protocols for any measures, indicating that comparable changes in chemoreflex control occur with either protocol. These results also suggest that the two methods of measuring CO(2) response are not completely concordant and that the changes in CO(2) control do not correlate with the increase in the HVR.

Unilateral microdialysis of gabazine in the dorsal medulla reverses thermal prolongation of the laryngeal chemoreflex in decerebrate piglets.

The laryngeal chemoreflex (LCR) is elicited by water in the larynx and leads to apnea and respiratory disruption in immature animals. The LCR is exaggerated by the elevation of brain temperature within or near the nucleus of the solitary tract (NTS) in decerebrate piglets. Thermal prolongation of reflex apnea elicited by superior laryngeal nerve stimulation is reduced by systemic administration of GABA(A) receptor antagonists. Therefore, we tested the hypothesis that microdialysis within or near the NTS of gabazine, a GABA(A) receptor antagonist, would reverse thermal prolongation of the LCR. We examined this hypothesis in 21 decerebrate piglets (age 3-13 days). We elicited the LCR by injecting 0.1 ml of water into the larynx before and after each piglet's body temperature was elevated by approximately 2.5 degrees C and before and after 2-5 mM gabazine was dialyzed unilaterally and focally in the medulla. Elevated body temperature failed to prolong the LCR in one piglet, which was excluded from analysis. Elevated body temperature prolonged the LCR in all the remaining animals, and dialysis of gabazine into the region near the NTS (n = 10) reversed the thermal prolongation of the LCR even though body temperature remained elevated. Dialysis of gabazine in other medullary sites (n = 10) did not reverse thermal prolongation of the LCR. Gabazine had no consistent effect on baseline respiratory activity during hyperthermia. These findings are consistent with the hypothesis that hyperthermia activates GABAergic mechanisms in or near the NTS that are necessary for the thermal prolongation of the LCR.

Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice.

We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB-334867. A hypercapnic (5 or 10% CO(2)) or hypoxic (15 or 10% O(2)) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. As expected, hypercapnic chemoreflex in vehicle-treated ORX- KO mice (0.22 +/- 0.03 mlxmin(-1)xg(-1)x% CO(2)(-1)) was significantly blunted compared with that in WT mice (0.51 +/- 0.05 mlxmin(-1)xg(-1)x% CO(2)(-1)). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 +/- 0.03 mlxmin(-1).g(-1)x% CO(2)(-1) for orexin-A and 0.32 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-1) for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 +/- 0.04 mlxmin(-1)xg(-1)x% CO(2)(-1)). On the other hand, hypoxic chemoreflex in vehicle-treated ORX-KO and SB-334867-treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO(2) sensitivity at least during wake periods in mice.

Carotid body function in heart failure.

In this review, we summarize the present state of knowledge of the functional characteristics of the carotid body (CB) chemoreflex with respect to control of sympathetic nerve activity (SNA) in chronic heart failure (CHF). Evidence from both CHF patients and animal models of CHF has clearly established that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in SNA. This adaptive change derives from altered function at the level of both the afferent and central nervous system (CNS) pathways of the reflex arc. At the level of the CB, an elevation in basal afferent discharge occurs under normoxic conditions in CHF rabbits, and the discharge responsiveness to hypoxia is enhanced. Outward voltage-gated K(+) currents (I(K)) are suppressed in CB glomus cells from CHF rabbits, and their sensitivity to hypoxic inhibition is enhanced. These changes in I(K) derive partly from downregulation of nitric oxide synthase (NOS)/NO signaling and upregulation of angiotensin II (Ang II)/Ang II receptor (AT(1)R) signaling in glomus cells. At the level of the CNS, interactions of the enhanced input from CB chemoreceptors with altered input from baroreceptor and cardiac afferent pathways and from central Ang II further enhance sympathetic drive. In addition, impaired function of NO in the paraventricular nucleus of the hypothalamus participates in the increased SNA response to CB chemoreceptor activation. These results underscore the principle that multiple mechanisms involving Ang II and NO at the level of both the CB and CNS represent complementary and perhaps redundant adaptive mechanisms to enhance CB chemoreflex function in CHF.

Interactions between the chemical senses: trigeminal function in patients with olfactory loss.

The intranasal trigeminal and the olfactory system are intimately connected. There is evidence showing that acquired olfactory loss leads to reduced trigeminal sensitivity due to the lack of a central-nervous interaction. Both, the orbitofrontal cortex and the rostral insula appear to be of significance in the amplification of trigeminal input which is missing in patients with olfactory loss. On peripheral levels, however, adaptive mechanisms seem to produce an increase in the trigeminal responsiveness of patients with hyposmia or anosmia.

Parasympathetic dysfunction is associated with baroreflex and chemoreflex impairment in streptozotocin-induced diabetes in rats.

This study explored physiological mechanisms of diabetic dysfunction in baroreceptors and chemoreceptors-mediated hemodynamic responses, and cholinergic neurotransmission in 30-day diabetic rats (n = 14) and controls (n = 14). Basal hemodynamic data and vagal response to electrical stimulation and methacholine injection were also evaluated. Muscarinic receptors were characterized using a radioligand receptor binding assay ([3H]N methylscopolamine). Experimental diabetes (50 mg/kg of STZ, i.v.) decreased systolic, diastolic, and mean arterial pressure and basal heart rate. Heart rate (HR) responses to vagal electrical stimulation (16, 32, and 64 Hz) were 15%, 11%, and 14% higher in diabetics vs non-diabetics, as were HR responses to methacholine injection (-130+/-24, -172+/-18, -206+/-15 bpm vs. -48+/-15, -116+/-12, -151+/-18 bpm, P < 0.05). Muscarinic receptor density was higher (267.4+/-11 vs 193.5+/-22 fmol/mg/prot, P < 0.05) in the atria of diabetic rats than in those of controls; the affinity was similar between groups. Diabetes-induced reduction of reflex responses to baro- (reflex bradycardia: -3.4+/-0.3 and -2.7+/-0.2 bpm/mm Hg; reflex tachycardia: -1.6+/-0.1 and -1.4+/-0.07 bpm/mm Hg, in control and diabetics, P < 0.05) and chemoreceptor stimulation, enhancement of HR responsiveness to cardiac vagal electrical stimulation and methacholine stimulation, plus an increase in the number of atrial muscarinic receptors indicates reduced parasympathetic activity, which is probably derived from central nervous system derangement.

Non-linear dynamics of human periodic breathing and implications for sleep apnea therapy.

A mathematical model of non-obstructive human periodic breathing (Cheyne-Stokes respiration) or central sleep apnea (CSA) is described which focused on explaining recently reported non-linear behavior. Evidence was presented that CHF (chronic heart failure)-CSA and ICSA (idiopathic central sleep apnea) both involved limit cycle oscillations. The validity of applying linear control theory for stabilization must then be re-examined. Critical threshold values and ranges of parameters were predicted which caused a change (bifurcation) from limit cycle periodic breathing to stable breathing. Changes in lung volume were predicted to form a bifurcation during CHF-CSA where stability and instability can involve a lung volume change as small as 0.1 l. CSA therapy based on reducing control loop gain was predicted to be relatively ineffective during stable limit cycle oscillation. The relative ratios of durations of ventilation to apnea (T(v)/T(a)) during periodic breathing were primarily determined by peripheral chemoreceptor dynamics during crescendo, de-crescendo, and apnea phases of CSA.

Chemosensory specific reduction of trigeminal sensitivity in subjects with olfactory dysfunction.

Humans with olfactory loss have been found to exhibit a decreased sensitivity of the chemosensory trigeminal system. It is not clear, whether the reduced trigeminal sensitivity is restricted to the chemosensitive properties of the trigeminal nerve, or whether it reflects a general decrease of trigeminal sensitivity which is also found for cutaneous afferents. To investigate the relationship between cutaneous somatosensory and intranasal chemosensory trigeminal sensitivity, 91 subjects were investigated. Forty-five of them were considered healthy controls, whereas 46 subjects had olfactory dysfunction. Subjects with olfactory dysfunction were found to have higher thresholds for CO2 than controls indicating lower trigeminal chemosensory sensitivity in subjects with olfactory dysfunction. Both etiology and degree of olfactory dysfunction appeared to have an impact on CO2 thresholds. In contrast, no such differences were found with regard to detection thresholds for electrical cutaneous stimulation. These results indicate that the decrease of trigeminal sensitivity in subjects with olfactory dysfunction is specific for chemosensory sensations.

Acute lung injury augments hypoxic ventilatory response in the absence of systemic hypoxemia.

The objective of the present study was to examine the impact of early stages of lung injury on ventilatory control by hypoxia and hypercapnia. Lung injury was induced with intratracheal instillation of bleomycin (BM; 1 unit) in adult, male Sprague-Dawley rats. Control animals underwent sham surgery with saline instillation. Five days after the injections, lung injury was present in BM-treated animals as evidenced by increased neutrophils and protein levels in bronchoalveolar lavage fluid, as well as by changes in lung histology and computed tomography images. There was no evidence of pulmonary fibrosis, as indicated by lung collagen content. Basal core body temperature, arterial Po(2), and arterial Pco(2) were comparable between both groups of animals. Ventilatory responses to hypoxia (12% O(2)) and hypercapnia (7% CO(2)) were measured by whole body plethysmography in unanesthetized animals. Baseline respiratory rate and the hypoxic ventilatory response were significantly higher in BM-injected compared with control animals (P = 0.003), whereas hypercapnic ventilatory response was not statistically different. In anesthetized, spontaneously breathing animals, response to brief hyperoxia (Dejours' test, an index of peripheral chemoreceptor sensitivity) and neural hypoxic ventilatory response were augmented in BM-exposed relative to control animals, as measured by diaphragmatic electromyelograms. The enhanced hypoxic sensitivity persisted following bilateral vagotomy, but was abolished by bilateral carotid sinus nerve transection. These data demonstrate that afferent sensory input from the carotid body contributes to a selective enhancement of hypoxic ventilatory drive in early lung injury in the absence of pulmonary fibrosis and arterial hypoxemia.

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.