Peripheral Chemosensitivity Research Articles

Arterial oxygen saturation during ascending to altitude under various conditions: Lessons from the field

When hypoxia increases during ascending in the mountains, ventilatory control and the related oxygenation may be challenged. The pre-treatment by intermittent hypoxia will elevate ventilation and offset hypoxemia and acetazolamide may inhibit peripheral chemosensitivity and act through central mechanisms. To study these effects in the field, one well-trained male mountaineer performed four ascents from low (1300m) to higher altitude (2600m): (1) under control conditions, (2) after intermittent hypoxia, (3) after pre-treatment with acetazolamide, and (4) after intermittent hypoxia+acetazolamide. When ascending under control conditions a cascading decrease of arterial oxygen saturation (SaO(2)) has been observed probably because of the alternating dominance of peripheral and central mechanisms of ventilatory control. While the pre-treatment with intermittent hypoxia prolonged the constant SaO(2) periods, the intake of acetazolamide eliminated this respiratory periodicity. Oxygen desaturation was best prevented by acetazolamide which was also associated with faster ascent times compared to control conditions.

A “love triangle” elicited by electrochemistry: complex interactions among cardiac sympathetic afferent, chemo-, and baroreflexes

there are three major cardiovascular reflexes: the baroreflex, chemoreflex, and cardiac sympathetic afferent reflex (CSAR). This commentary provides a brief overview of these three reflexes and also discusses the interplay among them. In addition, it outlines the potential centrally integrative

Dose‐dependent effect of dobutamine on chemoreflex activity in healthy volunteers

beta-adrenergic agonists increase peripheral chemoreceptor sensitivity in humans. We tested the hypothesis that beta(1)-agonist-related increase in peripheral chemoreflex sensitivity is selective and dose-dependent. Using a double-blind, placebo-controlled, randomized, crossover study, we examined the effects of dobutamine (n = 17 healthy subjects) at perfusion rates of 2.5 microg kg(-1) min(-1) (D2.5) and 7.5 microg kg(-1) min(-1) (D7.5) on ventilation, haemodynamics and sympathetic nerve activity during normoxia, isocapnic hypoxia, posthypoxic maximal voluntary end-expiratory apnoea, hyperoxic hypercapnia and cold pressor test (CPT). We analysed the effect of pretreatment with atenolol on dobutamine-evoked chemosensitivity. Dobutamine dose-dependently increased ventilation (placebo 6.7 +/- 0.5 vs. D2.5 7.8 +/- 0.4 vs. D7.5 8.7 +/- 0.4 l min(-1), P < 0.005) during normoxia, enhanced the ventilatory (placebo 14.4 +/- 0.6 vs. D2.5 17.3 +/- 0.8 vs. D7.5 22.5 +/- 1.9 l min(-1), P < 0.0001) and sympathetic (placebo + 215 +/- 31 vs. D2.5 + 285 +/- 19 vs. D7.5 + 395 +/- 50% of baseline, P < 0.03) responses at the fifth minute of isocapnic hypoxia and enhanced the sympathetic response to apnoea performed after hypoxia (increase after 5 min of hypoxia: + 290 +/- 43% for placebo vs.+ 360 +/- 21% for D2.5 vs. 537 +/- 69% for D7.5, P < 0.05). No differences were observed between dobutamine and placebo in the responses to hyperoxic hypercapnia and CPT. Atenolol inhibited the dobutamine-related hyperventilation and apnoea shortening during normoxia and hypoxia. Dobutamine enhances peripheral chemosensitivity at low infusion rates selectively and in a dose-dependent manner. There is a beta(1) adrenoceptor component in dobutamine-evoked increase in peripheral chemosensititivity; however, a contribution of additional adrenoceptor subtypes cannot be excluded.

Effect of five nights of normobaric hypoxia on cardiovascular responses to acute isocapnic hypoxia in humans: relationship to ventilatory chemosensitivity

The aim of this study was to elucidate (1) the cardiovascular responses to acute isocapnic hypoxia stimuli following five nights of normobaric poikilocapnic hypoxia, and (2) whether the changes in the cardiovascular responses to hypoxia are correlated to the change in acute hypoxic ventilatory (AHVR) chemosensitivity. Twelve male subjects [26.6 ± 4.1 (SD) years] slept 8–9 h day−1 overnight for five consecutive days at a simulated altitude of 4300 m (FiO2 = ∼13.8%). Using the technique of dynamic end-tidal forcing, the AHVR was assessed twice, prior to and immediately after the hypoxic exposure. During each AHVR test, mean arterial blood pressure (MAP) and heart rate (HR) were measured continuously using finger photoplethysmography and an ECG monitor, respectively. Immediately following the exposure, AHVR and MAP sensitivities were increased by 1.80 ± 1.30 l min−1 %−1 (p < 0.01) and 0.69 ± 0.40 mmHg %−1 (p < 0.05), respectively, and there were significant correlations between the increases in the AHVR and MAP sensitivities (r = 0.67; p < 0.05). In summary, following five nights of normobaric hypoxia, there is an enhanced MAP response to hypoxic stimuli. The relationship between the enhanced AHVR and MAP sensitivity raises the possibility of a common pathway in the regulation of peripheral chemosensitivity and MAP responses during periods of isocapnic hypoxia.

Syndromes d’apnées du sommeil et pathologie cardiovasculaire

Sleep-disordered breathing is very common and is associated with an increased risk of cardiovascular disease, cardiac arrhythmia and stroke. There are two types of sleep apnea: obstructive and central. The objective of this review is to provide a broad perspective of the pathophysiological and clinical aspects of the two types of apnea and to discuss their cardiovascular adverse effects. The diagnosis of sleep apnea syndrome is based on polysomnography, and severity is measured with an apnea-hypopnea index that counts the total number of apneas per hour of sleep. Recent large epidemiologic studies have shown that sleep apnea affects about 16% of men and 5% of women between 30 and 65 years of age. Obstructive sleep apnea is characterized by abnormal collapse of the pharyngeal airway during sleep, snoring, vigorous inspiratory efforts causing frequent arousal, and excessive daytime drowsiness. Central sleep apnea with Cheyne-Stokes respiration is a form of periodic breathing with frequent periods of hyperventilation, and carries a poor prognosis in patients with heart failure. Obstructive apnea can also have substantial health consequences. Although the exact mechanism linking sleep apnea with cardiovascular disease is unknown, there is evidence that obstructive apnea is associated with a group of proinflammatory and prothrombic factors that are also important in the development of atherosclerosis. Nocturnal and daytime sympathetic activity is elevated after sleep apnea. Autonomic abnormalities include an increased resting heart rate, decreased cardiac rhythm activity, and increased blood pressure variability. Obstructive apnea is associated with endothelial dysfunction, increased C-reactive protein and cytokine expression, elevated fibrinogen levels and decreased fibrinolytic activity. Enhanced platelet activity and aggregation, leukocyte adhesion and accumulation of endothelial cells are common in both obstructive apnea and atherosclerosis. Surges in sympathetic activity, blood pressure, ventricular wall tension and afterload adversely affect ventricular function. Many studies have shown that patients with obstructive apnea have an increased incidence of daytime hypertension, and this syndrome is recognized as an independent risk factor for hypertension. Obstructive apnea is associated with myocardial ischemia (silent or symptomatic), acute coronary events, stroke and transient ischemic attacks, cardiac arrhythmia, pulmonary hypertension and heart failure. Central sleep apnea is frequent in severe heart failure. Most heart failure patients with pulmonary congestion chronically hyperventilate because of stimulation of vagal irritant receptors and central and peripheral chemosensitivity. When PaCO2 falls below the threshold required to stimulate breathing, the central drive to respiratory muscles and air inflow ceases and central apnea ensues. Apnea, hypoxia, CO2 retention and arousals provoke elevated sympathetic activity, increased afterload and elevated left ventricular transmural pressure, and promote the progression of heart failure. Tentative relationships have been identified between central apnea and markers of inflammation, oxidative stress and endothelial dysfunction. Recent mid-terms trials showed that nocturnal use of positive airway pressure in patients with the two types of apnea alleviates symptoms, reduces sympathetic activity, improves ventricular function and quality of life, and reduces daytime drowsiness. More studies are needed to understand the mechanisms underlying the relationship between sleep apnea and cardiovascular disease, but clinicians should be aware of this link and should attempt to identify patients with these syndromes.

Peripheral chemoreceptor control of ventilation following sustained hypoxia in young and older adult humans.

The rate and duration of peripheral chemoreceptor resensitization following sustained hypoxia was characterized in young and older (74-year-old) adults. In addition, cerebral blood velocity (CBV) was measured in young subjects during and following the relief from sustained hypoxia. Following 20 min of sustained eucapnic hypoxia (50 mmHg), subjects were re-exposed to brief (1.5 min) hypoxic pulses (50 mmHg), and the magnitude of the ventilatory response was used to gauge peripheral chemosensitivity. Five minutes after the relief from sustained hypoxia, ventilation (V(E)) increased to 40.3 +/- 4.5% of the initial hypoxic ventilatory response, and by 36 min V(E) increased to 100%, indicating that peripheral chemosensitivity to hypoxia was restored. The V(E) response magnitude plotted versus time demonstrated that V(E), hence peripheral chemosensitivity, was restored at a rate of 1.9% per minute. Cerebral blood flow (CBF, inferred from CBV) remained constant during sustained hypoxia and increased by the same magnitude during the hypoxic pulses, suggesting that CBF has a small, if any, impact on the decline in V(E) during hypoxia and its subsequent recovery. To address the issue of whether hypoxic pulses affect subsequent challenges, series (continuous hypoxic pulses at various recovery intervals) and parallel (only 1 pulse per trial) methods were used. There were no differences in the ventilatory responses between the series and parallel methods. Older adults demonstrated a similar rate of recovery as in the young, suggesting that ageing in active older adults does not affect the peripheral chemoreceptor response.

Regulation of External Respiration and Gas Exchange during a 20-Day Exposure to Sessions of Intermittent Normobaric Hypoxia

A study was made of the effects of a 20-day course of intermittent normobaric hypoxia (INH) on the parameters of gas exchange and the regulation of respiration in healthy volunteers. A phasic change in oxygen consumption at rest was observed: it decreased on the 10th day of the INH course and increased on the 20th day, with a parallel increase in the efficiency of pulmonary ventilation. According to the hypercapnic test, the ventilatory response threshold decreased, whereas ventilatory sensitivity increased; these effects were most pronounced during the first ten days of INH training and still detectable in recovery. It was assumed that the first phase of training (up to the tenth day) is associated with compensatory activation of pulmonary ventilation owing to an increase in peripheral and central chemosensitivity to the CO2 stimulus. In the second phase, which was associated with further slight changes in the parameters of external respiration, the gas exchange level is restored owing to an adaptive increase in efficiency of oxygen utilization in cells and tissues.

Cardiovascular consequences of sleep-disordered breathing: past, present and future: report of a workshop from the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute.

Sleep-disordered breathing (SDB), which includes obstructive sleep apnea (OSA) as its most extreme variant, is characterized by intermittent episodes of partial or complete obstruction of the upper airway during sleep that disrupts normal ventilation and sleep architecture and is typically associated with snoring and daytime sleepiness. SDB is common, with an incidence in middle-aged men and women of 4% and 2%, respectively.1 Major risk factors for SDB include obesity, male gender, increasing age, and abnormalities of craniofacial morphology.2 There is an increasing perception that SDB/OSA via various mechanisms increases cardiovascular morbidity and mortality (Figure 1). However, many risk factors for SDB/OSA, such as obesity and male gender, are the same as for hypertension and cardiovascular disease.3 Thus, only recently has there been converging evidence that SDB is a risk factor for their development.4–6 Moreover, there is increasing information to indicate that SDB/OSA is linked to metabolic, vascular, hematologic, and genetic markers associated with increased cardiovascular disease risk. In addition, central sleep apnea (CSA), another form of SDB, appears to be an important factor that influences morbidity and mortality among those with heart failure (HF). Nevertheless, responsible mechanisms, the role of SDB as a risk factor “independent” of associated comorbidities, and whether treatment of SDB will mitigate this risk are unknown and remain to be determined. Figure 1. This illustrates the range of cardiovascular diseases and potential mechanisms that may be associated with sleep-disordered breathing. As illustrated in this figure, there is likely an interaction between multiple potential mechanisms, particularly in individuals who may have a genetic susceptibility for sleep-disordered breathing. This report summarizes the proceedings of a workshop sponsored by the National Center on Sleep Disorders Research and the National Heart, Lung, and Blood Institute on September 12 to 13, 2002, to assess a broad array …

Behavioral influences and physiological indices of ventilatory control in subjects with idiopathic hyperventilation.

Idiopathic hyperventilation has been defined as a respiratory-related psychophysiological complaint. This study attempted to clarify relationships between psychological and physiological variables in this condition. Participants demonstrated increased anxiety, depression, and symptoms consistent with hyperventilation. This was associated with a reduced peripheral chemosensitivity (isocapnic hypoxic rebreathe; -0.84 +/- 0.5 min-1.%O2(-1)), which was normalized with experimentally increased pCO2. Resting CO2 sensitivity was close to normal (2.1 +/- 1.0 min-1.mmHg-1). Breath hold time was significantly reduced versus controls (20.4 s +/- 12 s vs. 63 s +/- 31 s), and resting PETCO2 was correlated with the anxiety score. Also, the ventilatory response to moderate intensity exercise was augmented (vs. controls). The normalcy of pulmonary and chemoreceptor responses suggests that psychological factors may initiate this hyperventilation, which may become a conditioned response with an increased drive to breathe.

Variation in human ventilatory control-genetic influence on the hypoxic ventilatory response.

Studies in human subjects have shown considerable variation in the ventilatory response to hypoxia among individuals. The potential influence of genetic factors was initially suggested by the finding of clusters of low responses in families of patients with unexplained hypoventilation and endurance athletes. Further evidence of a genetic effect was evident in studies which found greater similarity of hypoxic ventilatory response in monozygotic than in dizygotic twins. The apparently selective effect on the hypoxic versus the hypercapnic response suggests that the genetic influence is related to peripheral chemosensitivity. Studies in cats and rats also point to a genetic effect on the carotid body.

Effect of domperidone on ventilation and polycythemia after 5 weeks of chronic hypoxia in rats.

Chronically hypoxic humans and some mammals have attenuated ventilatory responses, which have been associated with high dopamine level in carotid bodies. Alveolar hypoventilation and blunted ventilatory response have been recognized to be at the basis of Chronic Mountain Sickness by generating arterial hypoxemia and polycythemia. To investigate whether dopamine antagonism could decrease the hemoglobin concentration by stimulating resting ventilation (VE) and/or hypoxic ventilatory response, 18 chronically hypoxic rats (5 weeks, PB=433 Torr) were studied with and without domperidone treatment (a peripheral dopamine antagonist). Acute and prolonged treatment significantly increased poikilocapnic ventilatory response to hypoxia (RVE ml/min/kg=VE at 0.1 FI(O(2))-VE at 0.21 FI(O(2))), from 506+/-36 to 697+/-48; and from 394+/-37 to 660+/-81, respectively. In addition, Domperidone treatment decreased hemoglobin concentration from 21.6+/-0.29 to 18.9+/-0.19 (P<0.01) in rats chronically exposed to hypobaric hypoxia. Our study suggests that the stimulant effect of D(2)-R blockade on ventilatory response to hypoxia seems to compensate the low hypoxic peripheral chemosensitivity after chronic exposure and the latter in turn decrease hemoglobin concentration.

Inspiratory neural drive response to hypoxia adequately estimates peripheral chemosensitivity in OSAHS patients.

The aim of the present study was to examine the relationships between the responses to progressive isocapnic hypoxia and hypoxic withdrawal test in patients with obstructive sleep apnoea-hypopnoea syndrome (OSAHS) and to analyse the determinants of carotid body sensitivity in OSAHS. Nineteen consecutive OSAHS patients and 13 healthy subjects were selected. Ventilatory (delta V'I/Sa,O2/BSA) and inspiratory neural drive (delta P0.1/Sa,O2) responses to progressive isocapnic hypoxia were determined. Peripheral chemosensitivity was evaluated by the hypoxic withdrawal test, which measures the decrease in ventilation caused by two breaths of 100% oxygen (%delta V'I). Withdrawal response and ventilatory and inspiratory neural drive responses to hypoxia were lower in OSAHS patients than in control subjects. In patients with OSAHS, %delta V'I correlated significantly with delta V'I/Sa,O2/BSA and with delta P0.1/Sa,O2. On stepwise multiple linear regression analysis, a strong correlation between %delta V'I and delta P0.1/Sa,O2 was found. Moreover, %delta V'I, delta V'I/Sa,O2/BSA and delta P0.1/Sa,O2 were significantly correlated with minimum arterial oxygen saturation and with arousal index. Obstructive sleep apnoea-hypopnoea syndrome patients have a strong relationship between peripheral chemosensitivity and respiratory response to hypoxia, suggesting that hypoxic stimulation of central chemoreceptors is minimally relevant in obstructive sleep apnoea-hypopnoea syndrome. Moreover, sensitivity of the carotid body in patients with obstructive sleep apnoea-hypopnoea syndrome is related to sleep disruption and to nocturnal hypoxia.

Effects of carotid and aortic chemoreceptor denervation in newborn piglets.

The objective of the present study was to test the hypothesis that in neonatal piglets there would be no hypoventilation after sham denervation or aortic denervation (AOD) alone, but there would be transient hypoventilation after carotid body denervation (CBD) and the hypoventilation would be greatest after combined carotid and aortic denervation (CBD+AOD). There was a significant (P < 0.05) hypoventilation in CBD and CBD+AOD piglets denervated at 5, 15, and 25 days of age. The hypoventilation in CBD+AOD piglets denervated at 5 days of age was greater (P < 0.05) than that of all other groups. Conversely, sham-denervated and AOD piglets did not hypoventilate after denervation. Injections of sodium cyanide showed that aortic chemoreceptors were a site of recovery of peripheral chemosensitivity after CBD. This aortic sodium cyanide response was abolished by prior injection of a serotonin 5a receptor blocker. Residual peripheral chemosensitivity after CBD+AOD was localized to the left ventricle. We conclude that 1) aortic chemoreceptors contribute to eupneic breathing in piglets that were carotid denervated at 5 days of age and 2) there are multiple sites of residual peripheral chemosensitivity after CBD.

Peripheral chemosensitivity in mutant mice deficient in nitric oxide synthase.

Nitric oxide (NO) is endogenously generated from two constitutively expressed nitric oxide synthase (NOS) isoforms, i.e., neuronal (NOS-1) and endothelial (NOS-3). Both isoforms are localized within the carotid body. Previous studies have shown endogenously generated NO modulates carotid body activity. In the present study, we examined the relative contribution of NO generated by NOS-1 and NOS-3 in respiratory reflexes arising from the carotid body. Experiments were performed on mutant mice deficient in NOS-1 or NOS-3. Wild-type (WT) mice, which contained both isoforms, served as controls. Respiration was monitored in unanesthetized mice by plethysmography. In anaesthetized mice, efferent phrenic nerve activity was monitored as index of breathing. We examined the effects of hypoxia (12% O2), cyanide and brief hyperoxia (Dejour's test) on respiration. In NOS-1 mutant mice, the ventilatory response to hypoxia (12% O2) were significantly augmented, compared to wild-type (WT) mice. By contrast, NOS-3 mutant mice displayed significantly blunted respiratory responses to hypoxia compared to WT controls. The responses to cyanide were augmented in NOS-1; whereas they were blunted in NOS-3 mutant mice. Respiratory depression in response to brief hyperoxia was more pronounced in NOS-1, while it was nearly absent in NOS-3 mutant mice. These results demonstrate that NO produced by the neuronal and endothelial NOS isoforms have different modulatory roles in carotid body chemosensitivity.

Dopaminergic modulation of ventilation in obese Zucker rats.

To investigate the hypothesis that the impaired respiratory drive noted in morbid obesity was attributable to altered dopaminergic mechanisms acting on peripheral and/or central chemoreflex sensitivity, seven obese and seven lean Zucker rats were studied at 11 wk of age. Ventilation (VE) was measured by the barometric technique during hyperoxic (100% O(2)), normoxic (21% O(2)), hypoxic (10% O(2)), and hypercapnic (7% CO(2)) exposures after the administration of vehicle (control), haloperidol [Hal, 1 mg/kg, a central and peripheral dopamine (Da) receptor antagonist], or domperidone (Dom, 0.5 mg/kg, a peripheral Da receptor antagonist). In both lean and obese rats, Hal increased tidal volume and decreased respiratory frequency during hyperoxia or normoxia, resulting in an unchanged VE. In contrast, Dom did not affect tidal volume, frequency, or VE during hyperoxia or normoxia. During hypoxia, however, VE significantly increased from 1,132 +/- 136 to 1,348 +/- 98 ml. kg(-1). min(-1) (P < 0.01) after the administration of Dom in obese rats, whereas no change was observed in lean rats. Hal significantly decreased VE during hypoxia compared with control in lean but not obese rats. In both lean and obese rats, Hal decreased VE in response to hypercapnia, whereas Dom had no effect. Our major findings suggest that peripheral chemosensitivity to hypoxia in obese Zucker rats is reduced as a result of an increased dopaminergic receptor modulation in the carotid body.

Mortality after carotid body denervation in rats.

Carotid body denervation (CBD) in neonatal goats and piglets results in minimal irregular breathing and no fatalities. Redundancy and/or plasticity of peripheral chemosensitivity and a relatively mature ventilatory control system at birth may contribute to the paucity of CBD effects in these species. In the present study, we tested the hypothesis that CBD mortality would be greater in neonates of a less mature species such as the rat. We found that the mortality in rats denervated at 2-3 and 7-8 days of age was significantly higher (P < 0.05) than in sham-CBD rats. In all surviving rats, pulmonary ventilation during hypoxia was lower in CBD than in sham operated rats 2 days after denervation. In surviving rats denervated during the 7th and 8th postnatal days, there was also reduced weight gain and pulmonary ventilation during eupnea, including apneas up to 20 s in duration. However, the effects of CBD were compensated within 3 wk after denervation. Local injections of NaCN indicated that aortic chemoreceptors might have been one of the sites of recovery of peripheral chemosensitivity. We concluded that CBD has higher mortality in newborn rats than in other mammals, possibly because of the relative immaturity of these animals at birth. Nonetheless, in survivors there was enough redundancy and plasticity in the control of breathing to eventually compensate for the consequences of CBD.

Augmented peripheral chemosensitivity and periodic breathing pattern are related to elevated levels of the Ob gen product leptin in patients with chronic heart failure Wolfram Doehner, Mathias Rauchhaus, Karl Egerer, Waldemar Banasiak, Andrew J. S. Coats, Stefan D. Anker, Massimo F. Piepoli, Piotr Ponikowski. NHLI, London, United Kingdom, Cardiac Dept. Military Hospital, Wroclaw, Poland

Augmented peripheral chemosensitivity and periodic breathing pattern are related to elevated levels of the Ob gen product leptin in patients with chronic heart failure Wolfram Doehner, Mathias Rauchhaus, Karl Egerer, Waldemar Banasiak, Andrew J. S. Coats, Stefan D. Anker, Massimo F. Piepoli, Piotr Ponikowski. NHLI, London, United Kingdom, Cardiac Dept. Military Hospital, Wroclaw, Poland

Changes in Chemoreflex Characteristics Following Acute Carbonic Anhydrase Inhibition in Humans a Rest

The effect of carbonic anhydrase (CA) inhibition with acetazolamide (ACZ, 10 mg kg(-1) I.V.) on the peripheral and central chemosensitivity and breathing pattern was investigated in four women and three men aged 25 +/- 3 years using a modified version of Read's rebreathing technique. Subjects were exposed to dynamic increases in CO2 in hypoxic and hyperoxic backgrounds during control conditions and following acute CA inhibition. All manoeuvres were repeated twice and averaged for data analysis. The central chemoreflex sensitivities, estimated from the slopes of the ventilatory response to CO2 during hyperoxic rebreathing, increased following acute CA inhibition (control vs. ACZ treatment: 1.87 +/- 0.66 vs. 4.07 +/- 1.03 l x min(-1) (mmHg CO2)(-1), P < 0.05). The increased slope was reflected by an increase in the rate of rise of tidal volume and breathing frequency. Furthermore with ACZ, there was a left-ward shift of the ventilation vs. end-tidal PCO2 curve during hyperoxic hypercapnia but not hypoxic hypercapnia. The peripheral chemoreflex sensitivity was isolated by subtracting the hyperoxic slope (central only) from the hypoxic slope (central and peripheral). Following ACZ administration, the peripheral chemosensitivity was blunted (control vs. ACZ treatment: 3.66 +/- 0.92 vs. 1.33 +/- 0.46 l x min(-1) (mmHg CO2)(-1), P < 0.05). In conclusion, acute CA inhibition enhanced the central chemosensitivity to CO2 but diminished the peripheral chemosensitivity.

Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest

The effect of carbonic anhydrase (CA) inhibition with acetazolamide (ACZ, 10 mg kg-1 I.V.) on the peripheral and central chemosensitivity and breathing pattern was investigated in four women and three men aged 25 ± 3 years using a modified version of Read's rebreathing technique. Subjects were exposed to dynamic increases in CO2&gt; in hypoxic and hyperoxic backgrounds during control conditions and following acute CA inhibition. All manoeuvres were repeated twice and averaged for data analysis. The central chemoreflex sensitivities, estimated from the slopes of the ventilatory response to CO2 during hyperoxic rebreathing, increased following acute CA inhibition (control vs. ACZ treatment: 1.87 ± 0.66 vs. 4.07 ± 1.03 l min-1 (mmHg CO2)-1, P &lt; 0.05). The increased slope was reflected by an increase in the rate of rise of tidal volume and breathing frequency. Furthermore with ACZ, there was a left-ward shift of the ventilation vs. end-tidal PCO2 curve during hyperoxic hypercapnia but not hypoxic hypercapnia. The peripheral chemoreflex sensitivity was isolated by subtracting the hyperoxic slope (central only) from the hypoxic slope (central and peripheral). Following ACZ administration, the peripheral chemosensitivity was blunted (control vs. ACZ treatment: 3.66 ± 0.92 vs. 1.33 ± 0.46 l min-1 (mmHg CO2)-1, P &lt; 0.05). In conclusion, acute CA inhibition enhanced the central chemosensitivity to CO2 but diminished the peripheral chemosensitivity.

Ventilatory responses to specific CNS hypoxia in sleeping dogs.

Our study was concerned with the effect of brain hypoxia on cardiorespiratory control in the sleeping dog. Eleven unanesthetized dogs were studied; seven were prepared for vascular isolation and extracorporeal perfusion of the carotid body to assess the effects of systemic [and, therefore, central nervous system (CNS)] hypoxia (arterial PO(2) = 52, 45, and 38 Torr) in the presence of a normocapnic, normoxic, and normohydric carotid body during non-rapid eye movement sleep. A lack of ventilatory response to systemic boluses of sodium cyanide during carotid body perfusion demonstrated isolation of the perfused carotid body and lack of other significant peripheral chemosensitivity. Four additional dogs were carotid body denervated and exposed to whole body hypoxia for comparison. In the sleeping dog with an intact and perfused carotid body exposed to specific CNS hypoxia, we found the following. 1) CNS hypoxia for 5-25 min resulted in modest but significant hyperventilation and hypocapnia (minute ventilation increased 29 +/- 7% at arterial PO(2) = 38 Torr); carotid body-denervated dogs showed no ventilatory response to hypoxia. 2) The hyperventilation was caused by increased breathing frequency. 3) The hyperventilatory response developed rapidly (<30 s). 4) Most dogs maintained hyperventilation for up to 25 min of hypoxic exposure. 5) There were no significant changes in blood pressure or heart rate. We conclude that specific CNS hypoxia, in the presence of an intact carotid body maintained normoxic and normocapnic, does not depress and usually stimulates breathing during non-rapid eye movement sleep. The rapidity of the response suggests a chemoreflex meditated by hypoxia-sensitive respiratory-related neurons in the CNS.