Ventilatory responses to hypoxia and hypercapnia in awake rats pretreated with capsaicin.

Ventilatory responses to hypoxia and hypercapnia were measured by indirect plethysmography in unanesthetized unrestrained adult rats injected neonatally with capsaicin (50 mg/kg) or vehicle. Such capsaicin treatment ablates a subpopulation of primary afferent fibers containing substance P and various other neuropeptides. Ventilation was measured while the rats breathed air, 12% O2 in N2, 8% O2 in N2, 5% CO2 in O2, or 8% CO2 in O2. Neonatal treatment with capsaicin caused marked alterations in both the magnitude and composition of the hypoxic but not hypercapnic ventilatory response. The increase in minute ventilation evoked by hypoxia in the vehicle-treated rats resulted entirely from an increase in respiratory frequency. In the capsaicin-treated rats the hypoxic ventilatory response was significantly reduced owing to an attenuation of the frequency response. Although both groups responded to hypoxia with a shortening in inspiratory and expiratory times, rats treated with capsaicin displayed less shortening of both respiratory phases. By contrast, hypercapnia induced a brisk ventilatory response in the capsaicin-treated group that was similar in magnitude and pattern to that observed in the vehicle-treated group. Analysis of the components of the hypercapnic ventilatory responses revealed no significant differences between the two groups. We, therefore, conclude that neuropeptide-containing C-fibers are essential for the tachypnic component of the ventilatory response to hypoxia but not hypercapnia.     

A mathematical model of CO2 effect on cardiovascular regulation

The effect of changes in arterial CO2 tension on the cardiovascular system is analyzed by means of a mathematical model. The model is an extension of a previous one that already incorporated the main reflex and local mechanisms triggered by O2 changes. The new aspects covered by the model are the O2-CO2 interaction at the peripheral chemoreceptors, the effect of local CO2 changes on peripheral resistances, the direct central neural system (CNS) response to CO2, and the control of central chemoreceptors on ventilation and tidal volume. A statistical comparison between model simulation results and various experimental data has been performed. This comparison suggests that the model is able to simulate the acute cardiovascular response to changes in blood gas content in a variety of conditions (normoxic hypercapnia, hypercapnia during artificial ventilation, hypocapnic hypoxia, and hypercapnic hypoxia). The model ascribes the observed responses to the complex superimposition of many mechanisms simultaneously working (baroreflex, peripheral chemoreflex, CNS response, lung-stretch receptors, local gas tension effect), which may be differently activated depending on the specific stimulus under study. However, although some experiments can be reproduced using a single basal set of parameters, reproduction of other experiments requires a different combination of the mechanism strengths (particularly, a different strength of the local CO2 mechanism on peripheral resistances and of the CNS response to CO2). Starting from these results, some assumptions to explain the striking differences reported in the literature are presented. The model may represent a valid support for the interpretation of physiological data on acute cardiovascular regulation and may favor the synthesis of contradictory results into a single theoretical setting.     

The affinity of hemoglobin for oxygen affects ventilatory responses in mutant mice with Presbyterian hemoglobinopathy

The purpose of this study was to test whether chronically enhanced O2 delivery to tissues, without arterial hyperoxia, can change acute ventilatory responses to hypercapnia and hypoxia. The effects of decreased hemoglobin (Hb)-O2 affinity on ventilatory responses during hypercapnia (0, 5, 7, and 9% CO2 in O2) and hypoxia (10 and 15% O2 in N2) were assessed in mutant mice expressing Hb Presbyterian (mutation in the beta-globin gene, beta108 Asn --> Lys). O2 consumption during normoxia, measured via open-circuit methods, was significantly higher in the mutant mice than in wild-type mice. Respiratory measurements were conducted with a whole body, unrestrained, single-chamber plethysmograph under conscious conditions. During hypercapnia, there was no difference between the slopes of the hypercapnic ventilatory responses, whereas minute ventilation at the same levels of arterial PCO2 was lower in the Presbyterian mice than in the wild-type mice. During both hypoxic exposures, ventilatory responses were blunted in the mutant mice compared with responses in the wild-type mice. The effects of brief hyperoxia exposure (100% O2) after 10% hypoxia on ventilation were examined in anesthetized, spontaneously breathing mice with a double-chamber plethysmograph. No significant difference was found in ventilatory responses to brief hypoxia between both groups of mice, indicating possible involvement of central mechanisms in blunted ventilatory responses to hypoxia in Presbyterian mice. We conclude that chronically enhanced O2 delivery to peripheral tissues can reduce ventilation during acute hypercapnic and hypoxic exposures.     

Effects of the addition of carbon dioxide on manifestations of acute hypoxia in rats

In pentobarbitalized rats, hypoxia induced by inhalation of O2 8%-N2 92%, produces a transient hyperventilation which is followed by a respiratory depression and an apnea. A cardiovascular collapse is then observed. Correction of the hypocapnia depending on the initial hyperventilation, by inhalation of a gas mixture containing 4% CO2 maintains the hyperventilation and suppresses the cardiovascular collapse. Carbon dioxide activity is both a direct one by stimulation of respiratory centers and an indirect one by increasing the sensitivity of the peripheral arterial chemoreceptors to hypoxia. Four percent carbon dioxide just compensating hypocapnia are sufficient to prevent apnea and vascular collapse. The increase of this concentration up to hypercapnia complicates the interpretation of the results by addition of hypoxic and hypercapnic effects.     

Stress-induced attenuation of the hypercapnic ventilatory response in awake rats.

To test the hypothesis that stress alters the performance of the respiratory control system, we compared the acute (20 min) responses to moderate hypoxia and hypercapnia of rats previously subjected to immobilization stress (90 min/day) with responses of control animals. Ventilatory measurements were performed on awake rats using whole body plethysmography. Under baseline conditions, there were no differences in minute ventilation between stressed and unstressed groups. Rats previously exposed to immobilization stress had a 45% lower ventilatory response to hypercapnia (inspiratory CO(2) fraction = 0.05) than controls. In contrast, stress exposure had no statistically significant effect on the ventilatory response to hypoxia (inspiratory O(2) fraction = 0.12). Stress-induced attenuation of the hypercapnic response was associated with reduced tidal volume and inspiratory flow increases; the frequency and timing components of the response were not different between groups. We conclude that previous exposure to a stressful condition that does not constitute a direct challenge to respiratory homeostasis can elicit persistent (> or =24 h) functional plasticity in the ventilatory control system.     

Branchial chemoreceptors mediate ventilatory responses to hypercapnic acidosis in channel catfish

The effects of hyperoxic hypercapnia on cardiovascular and ventilatory variables and blood gas and acid/base parameters were examined in conscious and anesthetized spontaneously breathing (ASB) channel catfish, Ictalurus punctatus. These separate experiments were designed to determine: (1) if channel catfish show a ventilatory response to hypercapnic acidosis when blood O(2) content is maintained in conscious animals; and (2) whether branchial receptors innervated by cranial nerves IX and X mediate this response. The combination of high O(2) and CO(2) tensions allowed the cardioventilatory effects of hypercapnic acidosis to be assessed independently of Root or Bohr mediated changes in blood O(2) content. In the absence of significant changes in dorsal or ventral aorta O(2) content, hyperoxic hypercapnia significantly stimulated ventilation, relative to hyperoxic exposure. Hypercapnic acidosis, however, had no significant effects on blood pressure or heart rate. Branchial denervation in ASB fish abolished the ventilatory response to hypercapnic acidosis. The results indicate that hypercapnic acidosis independently stimulates ventilation in channel catfish. This response is mediated by CO(2)/pH-sensitive branchial receptors innervated by cranial nerves IX and X.     

Pattern of the ventilatory response to transient hypoxia in man: differences from transient hypercapnic test.

The pattern of change in ventilatory variables after inhalation of pure N2 for two breaths was studied in normal children and adults. In six subjects the trends of change were compared to the ventilatory response to transient hypercapnia. We observed differences in the patterns of increasing ventilation with an initial abrupt increase of tidal volume for transient hypoxia and a progressive change for hypercapnia. In both cases respiratory frequency was progressively but unsystematically enhanced. A highly significant positive correlation was demonstrated between individual sensitivities to CO2 and O2, with a greater response to hypercapnia (5.6 time) than to hypoxia. Finally, a very short-latency decrease in expiratory duration occurred in the first breath after inhalation of hypercapnic mixture, supporting the recent data of Cunningham et al. (1977).     

Heart rate variability responses to hypoxic and hypercapnic exposures in different mouse strains.

Heart rate variability (HRV) is a well-characterized, noninvasive means of assessing cardiac autonomic nervous system activity. This study examines the basic cardiac responses to hypoxic and hypercapnic challenges in seven strains of commonly used inbred mice (A/J, BALB/cJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, and FVB/J). Adult male mice, 8-12 wk of age, were chronically instrumented to a femoral artery catheter for the continuous measurement of systemic arterial blood pressure and heart rate. Mice were exposed to multiple 4-min periods of hypoxia (10% O2), hypercapnia (5% CO2), and combined hypoxia/hypercapnia (10% O2 + 5% CO2). HRV was derived from pulse intervals of the blood pressure tracings. Hypoxia induced increases in high-frequency HRV power and decreased low-frequency (LF) HRV power in most strains. Hypercapnia led to decreased high-frequency HRV power and increased LF HRV power in most strains. Strain differences were most notable in regard to the concomitant exposures of hypoxia and hypercapnia, with FVB/J mice mirroring their own response to hypercapnia alone, whereas CBA/J mice mirrored their own responses to hypoxia. As blood pressure is most likely the driving factor for heart rate changes via the baroreflex pathway, it is interesting that LF, considered to reflect cardiac sympathetic activity, was negatively correlated with heart rate, suggesting that LF changes are driven by baroreflex oscillation and not necessarily by absolute sympathetic or parasympathetic activity to the heart. These findings suggest that genetic background can influence the centrally mediated cardiovascular responses to basic hypoxic and hypercapnic challenges.     

知母宁对慢性低氧高二氧化碳大鼠肺小动脉胶原代谢的影响

目的:研究知母宁对慢性低O2高CO2大鼠肺小动脉Ⅰ、Ⅲ型胶原代谢的影响,并探讨其可能机制。方法:将SD大鼠36只随机分为正常对照组,4周低O2高CO2组,4周低O2高CO2+知母宁组。采用图像分析、氯胺T法、免疫组化、组织原位杂交技术等方法,监测各组大鼠肺动脉平均压(mPAP)、颈动脉平均压(mCAP)、肺细小动脉显微和超微结构、血CO浓度,血清及肺组织血红素氧合酶-1(HO-1)活性,肺组织羟脯氨酸含量,肺小动脉Ⅰ、Ⅲ型胶原及其基因表达的变化。结果:低O2高CO2组mPAP升高,肺细小动脉管壁增厚,管腔变小,中膜平滑肌细胞和外膜胶原纤维增生,肺血管重建形成,肺匀浆羟脯氨酸含量升高,肺小动脉Ⅰ型胶原及其mRNA表达增加;知母宁组上述变化均明显减轻(P均0.01)。此外,低O2高CO2组全血CO含量、血浆及肺组织匀浆HO-1活性升高,知母宁组上述指标较低O2高CO2组进一步升高(P均0.01)。三组间mCAP,Ⅲ型胶原及其mRNA表达无显著差异(P0.05)。结论:知母宁降低慢性低O2高CO2性肺动脉高压,减轻肺血管结构重建与其抑制肺动脉Ⅰ型胶原增殖有关,上调内源性CO/HO体系的表达为其可能重要机制。     

Protein remodeling of extracellular matrix in rat myocardium during four-day hypoxia: the effect of concurrent hypercapnia

The combination of long-term hypercapnia and hypoxia decreases pulmonary vascular remodeling and attenuation of right ventricular (RV) hypertrophy. However, there is limited information in the literature regarding the first stages of acclimatization to hypercapnia/hypoxia. The purpose of this study was to investigate the effect of four-day hypoxia (10% O2) and hypoxia/hypercapnia (10% O2 + 4.4% CO2) on the protein composition of rat myocardium. Expression of the cardiac collagen types and activities of matrix metalloproteinases (MMPs) and of their tissue inhibitor TIMP-1 were followed. The four-day hypoxia changed protein composition of the right ventricle only in the hypercapnic condition; remodeling was observed in the extracellular matrix (ECM) compartments. While the concentrations of pepsin-soluble collagenous proteins in the RV were elevated, the concentrations of pepsin-insoluble proteins were decreased. Furthermore, the four-day hypoxia/hypercapnia increased the synthesis of cardiac collagen due to newly synthesized forms; the amount of cross-linked particles was not affected. This type of hypoxia increased cardiac collagen type III mRNA, while cardiac collagen type I mRNA was decreased. MMP-2 activity was detected on the zymographic gel through appearance of two bands; no differences were observed in either group. mRNA levels for MMP-2 in the RV were significantly lower in both the hypoxic and hypoxic/hypercapnic animals. mRNA levels for TIMP-1 were reduced in the RV of both the hypoxic and hypoxic/hypercapnic animals. Hypoxia with hypercapnia increased the level of mRNA (6.5 times) for the atrial natriuretic peptide (ANP) predominantly in the RV. The role of this peptide in remodeling of cardiac ECM is discussed.     

Hypercapnia does not affect functional residual capacity enlargement induced by chronic hypoxia

To determine whether changes in partial pressure of CO2 participate in mechanism enlarging the lung functional residual capacity (FRC) during chronic hypoxia, we measured FRC and ventilation in rats exposed either to poikilocapnic (group H, F(I)O2 0.1, F(I)CO2 <0.01) or hypercapnic (group H+CO2, F(I)O2 0.1, F(I)CO2 0.04-0.05) hypoxia for the three weeks and in the controls (group C) breathing air. At the end of exposure a body plethysmograph was used to measure ventilatory parameters (V'(E), f(R), V(T)) and FRC during air breathing and acute hypoxia (10 % O2 in N2). The exposure to hypoxia for three weeks increased FRC measured during air breathing in both experimental groups (H: 3.0+/-0.1 ml, H+CO2: 3.1+/-0.2 ml, C: 1.8+/-0.2 ml). During the following acute hypoxia, we observed a significant increase of FRC in the controls (3.2+/-0.2 ml) and in both experimental groups (H: 3.5+/-0.2 ml, H+CO2: 3.6+/-0.2 ml). Because chronic hypoxia combined with chronic hypercapnia and chronic poikilocapnic hypoxia induced the same increase of FRC, we conclude that hypercapnia did not participate in the FRC enlargement during chronic hypoxia.     

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.     

Fructose feeding and intermittent hypoxia affect ventilatory responsiveness to hypoxia and hypercapnia in rats.

We hypothesized that, in male rats, 10% fructose in drinking water would depress ventilatory responsiveness to acute hypoxia (10% O2 in N2) and hypercapnia (5% CO2 in O2) that would be depressed further by exposure to intermittent hypoxia. Minute ventilation (Ve) in air and in response to acute hypoxia and hypercapnia was evaluated in 10 rats before fructose feeding (FF), during 6 wk of FF, and after FF was removed for 2 wk. During FF, five rats were exposed to intermittent air and five to intermittent hypoxia for 13 days. Six rats given tap water acted as control and were exposed to intermittent air and subsequently intermittent hypoxia. In FF rats, plasma insulin levels increased threefold in the rats exposed to intermittent hypoxia and during washout returned to levels observed in rats exposed to intermittent air. During FF, ventilatory responsiveness to acute hypoxia was depressed because of decreased tidal volume (Vt) responsiveness. During washout, Ve decreased as a result of decreased Vt and frequency of breathing, and the ventilatory responsiveness to hypoxia in intermittent hypoxia rats did not recover. In all rats, the ventilatory responses to hypercapnia were decreased during FF and recovered after washout because of an increased Vt responsiveness. In the control group, hypoxic responsiveness was not depressed after intermittent hypoxia and was augmented after washout. Thus FF attenuated the ventilatory responsiveness of conscious rats to hypoxia and hypercapnia. Intermittent hypoxia interacted with FF to increase insulin levels and depress ventilatory responses to acute hypoxia that remained depressed during washout.     

Interactions between hypoxia and hypercapnic acidosis on calcium signaling in carotid body type I cells

The effects of hypercapnic acidosis and hypoxia on intracellular Ca(2+) concentration ([Ca(2+)](i)) were determined with Indo 1 in enzymatically isolated single type I cells from neonatal rat carotid bodies. Type I cells responded to graded hypoxic stimuli with graded [Ca(2+)](i) rises. The percentage of cells responding was also dependent on the severity of the hypoxic stimulus. Raising CO(2) from 5 to 10 or 20% elicited a significant increase in [Ca(2+)](i) in the same cells as those that responded to hypoxia. Thus both stimuli can be sensed by each individual cell. When combinations of hypoxic and acidic stimuli were given simultaneously, the responses were invariably greater than the response to either stimulus given alone. Indeed, in most cases, the response to hypercapnia was slightly potentiated by hypoxia. These data provide the first evidence that the classic synergy between hypoxic and hypercapnic stimuli observed in the intact carotid body may, in part, be an inherent property of the type I cell.     

Somatostatin inhibits the ventilatory response to hypoxia in humans

The effects of a 90-min infusion of somatostatin (1 mg/h) on ventilation and the ventilatory responses to hypoxia and hypercapnia were studied in six normal adult males. Minute ventilation (VE) was measured with inductance plethysmography, arterial 02 saturation (SaO2) was measured with ear oximetry, and arterial PCO2 (Paco2) was estimated with a transcutaneous CO2 electrode. The steady-state ventilatory response to hypoxia (delta VE/delta SaO2) was measured in subjects breathing 10.5% O2 in an open circuit while isocapnia was maintained by the addition of CO2. The hypercapnic response (delta VE/delta PaCO2) was measured in subjects breathing first 5% and then 7.5% CO2 (in 52-55% O2). Somatostatin greatly attenuated the hypoxic response (control mean -790 ml x min-1.%SaO2 -1, somatostatin mean -120 ml x min-1.%SaO2 -1; P less than 0.01), caused a small fall in resting ventilation (mean % fall - 11%), but did not affect the hypercapnic response. In three of the subjects progressive ventilatory responses (using rebreathing techniques, dry gas meter, and end-tidal Pco2 analysis) and overall metabolism were measured. Somatostatin caused similar changes (mean fall in hypoxic response -73%; no change in hypercapnic response) and did not alter overall O2 consumption nor CO2 production. These results show an hitherto-unsuspected inhibitory potential of this neuropeptide on the control of breathing; the sparing of the hypercapnic response is suggestive of an action on the carotid body but does not exclude a central effect.     

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.     

Hypercapnic and hypoxic ventilatory responses in long-term streptozotocin-diabetic rats during conscious and pentobarbital-induced anesthetic states

To clarify the diabetes mellitus (DM)-associated changes in the respiratory neuronal control system, acute ventilatory responses to progressively increasing hypercapnia (6%) and hypoxia (10%) were compared between normal (N) and streptozotocin (60 mg/kg, i.v.) -DM rats for a long period up to 28 weeks. The same comparison was conducted during the anesthetic state induced with pentobarbital (35 mg/kg, i.p.). During the conscious state, basic ventilatory parameters, such as respiratory rate, tidal volume and minute ventilation, were not impaired in DM rats, but ventilatory responses to hypercapnia and hypoxia were reduced significantly at 16 weeks and later after streptozotocin injection. The reduced responses in DM rats were not recovered by insulin treatment (5-6 U/body, s.c., daily). During the anesthetic state, both hypoxic and hypercapnic responses were depressed more intensely in N rats than in DM rats, resulting in an equivalent level of the response in the two groups. The present study demonstrated that ventilatory responses to hypercapnia and hypoxia were reduced in a long-term DM condition. This may be derived from the impairment of the peripheral and central chemosensitivity. The reduction in ventilatory responses was exaggerated during the anesthetic state.     

Peripheral chemoreceptor contributions to sympathetic and cardiovascular responses during hypercapnia

We tested the hypothesis that integrated sympathetic and cardiovascular reflexes are modulated by systemic CO2 differently in hypoxia than in hyperoxia (n = 7). Subjects performed a CO2 rebreathe protocol that equilibrates CO2 partial pressures between arterial and venous blood and that elevates end tidal CO2 (PET(CO2)) from approximately 40 to approximately 58 mmHg. This test was repeated under conditions where end tidal oxygen levels were clamped at 50 (hypoxia) or 200 (hyperoxia) mmHg. Heart rate (HR; EKG), stroke volume (SV; Doppler ultrasound), blood pressure (MAP; finger plethysmograph), and muscle sympathetic nerve activity (MSNA) were measured continuously during the two protocols. MAP at 40 mmHg PET(CO2) (i.e., the first minute of the rebreathe) was greater during hypoxia versus hyperoxia (P < 0.05). However, the increase in MAP during the rebreathe (P < 0.05) was similar in hypoxia (16 +/- 3 mmHg) and hyperoxia (17 +/- 2 mmHg PET(CO2)). The increase in cardiac output (Q) at 55 mmHg PET(CO2) was greater in hypoxia (2.61 +/- 0.7 L/min) versus hyperoxia (1.09 +/- 0.44 L/min) (P < 0.05). In both conditions the increase in Q was due to elevations in both HR and SV (P < 0.05). Systemic vascular conductance (SVC) increased to similar absolute levels in both conditions but rose earlier during hypoxia (> 50 mmHg PET(CO2)) than hyperoxia (> 55 mmHg). MSNA increased earlier during hypoxic hypercapnia (> 45 mmHg) compared with hyperoxic hypercapnia (> 55 mmHg). Thus, in these conscious humans, the dose-response effect of PET(CO2) on the integrated cardiovascular responses was shifted to the left during hypoxic hypercapnia. The combined data indicate that peripheral chemoreceptors exert important influence over cardiovascular reflex responses to hypercapnia.     

Carbon dioxide effects on the ventilatory response to sustained hypoxia

We examined the interrelation between CO2 and the ventilatory response to moderate (80% arterial saturation) sustained hypoxia in normal young adults. On a background of continuous CO2-stimulated hyperventilation, hypoxia was introduced and sustained for 25 min. Initially, with the introduction of hypoxia onto hypercapnia, there was a brisk additional increase in inspiratory minute ventilation (VI) to 284% of resting VI, but the response was not sustained and hypoxic VI declined by 36% to a level intermediate between the initial increase and the preexisting hypercapnic hyperventilation. Through the continuous hypercapnia, the changes in hypoxic ventilation resulted from significant alterations in tidal volume (VT) and mean inspiratory flow (VT/TI) without changes in respiratory timing. In another experiment, sustained hypoxia was introduced on the usual background of room air, either with isocapnia or without maintenance of end-tidal CO2 (ETCO2) (poikilocapnic hypoxia). Regardless of the degree of maintenance of ETCO2, during 25 min of sustained hypoxia, VI showed an initial brisk increase and then declined by 35-40% of resting VI to a level intermediate between the initial response and resting room air VI. For both isocapnia and poikilocapnic conditions, the attenuation of VI was an expression of a diminished VT. Thus the decline in ventilation with sustained hypoxia occurred regardless of the background ETCO2, suggesting that the mechanism underlying the hypoxic decline is independent of CO2.     

Cardiorespiratory responses to hypoxia in intact and bilaterally vagotomized pigeons

Bilateral, cervical vagotomy in birds denervates, among other receptors, the carotid bodies. To test whether such neural section removes sensitivity to hypoxia, we measured respiratory, cardiovascular, and blood gas responses to hypoxia at 84-, 70-, and 49-Torr inspiratory O2 partial pressure (PIO2) in five pigeons with intact vagi and in five bilaterally, cervically vagotomized pigeons. Normoxic respiratory frequency (fresp) and expiratory flow rate (VE) were decreased after vagotomy. Intact pigeons showed large increases in VE in response to hypoxia, effected mostly by increases in fresp. VE also increased greatly in response to hypoxia in vagotomized pigeons, but increases were largely the result of tidal volume. O2 consumption, CO2 production, and respiratory exchange ratio increased slightly in all pigeons during hypoxia. Normoxic heart rate was greater after vagotomy; cardiac output increased in all pigeons in response to hypoxia, but stroke volume increased only in intact pigeons. During normoxia, arterial and mixed venous O2 partial pressure, O2 concentration, and pH were lower and arterial and mixed venous CO2 partial pressure was higher, after vagotomy. In all pigeons during hypoxia, arterial and mixed venous O2 and CO2 partial pressure and O2 concentration decreased and arterial and mixed venous pH increased; changes were roughly parallel in intact and vagotomized pigeons. The arteriovenous O2 concentration differences during normoxia and hypoxia were similar in all pigeons. We conclude that bilateral, cervical vagotomy in the pigeon causes hypoventilation and tachycardia during normoxia, but strong respiratory and cardiovascular responses to hypoxia are still present.