Increase In Minute Ventilation Research Articles

A potential early physiological marker for CNS oxygen toxicity: hyperoxic hyperpnea precedes seizure in unanesthetized rats breathing hyperbaric oxygen

Hyperbaric oxygen (HBO(2)) stimulates presumptive central CO2-chemoreceptor neurons, increases minute ventilation (V(min)), decreases heart rate (HR) and, if breathed sufficiently long, produces central nervous system oxygen toxicity (CNS-OT; i.e., seizures). The risk of seizures when breathing HBO(2) is variable between individuals and its onset is difficult to predict. We have tested the hypothesis that a predictable pattern of cardiorespiration precedes an impending seizure when breathing HBO2. To test this hypothesis, 27 adult male Sprague-Dawley rats were implanted with radiotelemetry transmitters to assess diaphragmatic/abdominal electromyogram, electrocardiogram, and electroencephalogram. Seven days after surgery, each rat was placed in a sealed, continuously ventilated animal chamber inside a hyperbaric chamber. Both chambers were pressurized in parallel using poikilocapnic 100% O(2) (animal chamber) and air (hyperbaric chamber) to 4, 5, or 6 atmospheres absolute (ATA). Breathing 1 ATA O(2) initially decreased V(min) and HR (Phase 1 of the compound hyperoxic ventilatory response). With continued exposure to normobaric hyperoxia, however, V(min) began increasing toward the end of exposure in one-third of the animals tested. Breathing HBO2 induced an early transient increase in V(min) (Phase 2) and HR during the chamber pressurization, followed by a second significant increase of V(min) ≤8 min prior to seizure (Phase 3). HR, which subsequently decreased during sustained hyperoxia, showed no additional changes prior to seizure. We conclude that hyperoxic hyperpnea (Phase 3 of the compound hyperoxic ventilatory response) is a predictor of an impending seizure while breathing poikilocapnic HBO(2) at rest in unanesthetized rats.

Induction of dyspnea evokes increased anxiety and maladaptive breathing in individuals with high anxiety sensitivity and suffocation fear

Although respiratory symptoms are relevant for diagnosis and etiology of panic disorder, anxiety responses and breathing behavior evoked by induction of dyspnea have rarely been studied. Therefore, dyspnea sensations and affective evaluations evoked by inspiratory resistive loads of different intensities were first assessed in 23 individuals with high versus 24 participants with low anxiety sensitivity (AS). High AS participants with high fear of suffocation rated loads of the same physical intensity as more unpleasant and reported more intense feelings of dyspnea and more respiratory and panic symptoms than low AS individuals. In the second experiment assessing physiological responses to physically comparable loads, high suffocation fear participants showed an increase in minute ventilation to compensate for fear-induced air hunger. This ventilation behavior results in increased frequency of dyspnea sensations, thus increasing fear of suffocation.

Increasing brain serotonin corrects CO2 chemosensitivity in methyl‐CpG‐binding protein 2 (Mecp2)‐deficient mice

Mice deficient in the transcription factor methyl-CpG-binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO2 chemosensitivity, which may contribute to their breathing abnormalities. In addition, patients with Rett syndrome and male mice that are null for Mecp2 show reduced levels of brain serotonin (5-HT). Serotonin is known to play a role in central chemosensitivity, and we hypothesized that increasing the availability of 5-HT in this mouse model would improve their respiratory response to CO2. Here we determined the apnoeic threshold in heterozygous Mecp2-deficient female mice and examined the effects of blocking 5-HT reuptake on the CO2 response in Mecp2-null male mice. Studies were performed in B6.129P2(C)-Mecp2(τm1.1Bird) null males and heterozygous females. In an in situ preparation, seven of eight Mecp2-deficient heterozygous females showed arrest of phrenic nerve activity when arterial CO2 was lowered to 3%, whereas the wild-types maintained phrenic nerve amplitude at 53 ± 3% of maximal. In vivo plethysmography studies were used to determine CO2 chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO2. The percentage increase in minute ventilation in response to increased inspired CO2 was less in Mecp2(-/y) than in Mecp2(+/y) mice. Pretreatment with citalopram, a selective 5-HT reuptake inhibitor (2.5 mg kg(-1) i.p.), 40 min prior to CO2 exposure, in Mecp2(-/y) mice resulted in an improvement in CO2 chemosensitivity to wild-type levels. These results suggest that decreased 5-HT in Mecp2-deficient mice reduces CO2 chemosensitivity, and restoring 5-HT levels can reverse this effect.

Morphine has latent deleterious effects on the ventilatory responses to a hypoxic-hypercapnic challenge.

This study explored the concept that morphine has latent deleterious actions on the ventilatory control systems that respond to a hypoxic-hypercapnic challenge. In this study, we examined the ventilatory responses elicited by hypoxic-hypercapnic challenge in conscious rats at a time when the effects of morphine (10 mg/kg) on arterial blood-gas chemistry and minute ventilation had subsided. Morphine induced pronounced changes in arterial blood-gas chemistry (e.g., an increase in pCO2, decreases in pO2 and sO2) and decreases in minute ventilation. Despite the complete resolution of the morphine-induced changes in arterial blood-gas chemistry and minute ventilation and almost complete resolution of the effects on peak inspiratory flow and peak expiratory flow, subsequent exposure to hypoxic-hypercapnic challenge elicited markedly blunted increases in minute ventilation and in peak inspiratory and expiratory flows. These findings demonstrate that (1) the changes in arterial blood-gas chemistry elicited by morphine parallel changes in minute ventilation rather than PIF and PEF, and (2) morphine has latent untoward effects on the ventilatory responses to hypoxic-hypercapnic challenge. These novel findings raise the possibility that patients deemed to have recovered from the acute ventilatory depressant effects of morphine may still be susceptible to the latent effects of this opioid analgesic. The mechanisms underlying these latent effects remain to be elucidated.

Management of asthma during pregnancy

Asthma is an inflammatory lung condition that is the most common chronic disease affecting pregnancy. The changes in pulmonary physiology during pregnancy include increased minute ventilation, decreased functional residual capacity, increased mucus production, and airway mucosa hyperemia and edema. Pregnancy is also associated with a physiological suppression of the immune system. Many studies have described the heterogeneous immune system response in women with asthma during pregnancy, which partly explains why asthma has been shown to worsen, improve, or remain stable in equal proportions of women during pregnancy. Asthma may be associated with poor maternal and fetal outcomes. However, better maternal and fetal outcomes are observed with better asthma control. Asthma controller medications are generally thought to be safe during pregnancy, but limited data are available for some of the medicines. Newer medications like omalizumab open avenues for the treatment of asthma, but also pose a challenge, as there is limited experience with their use. Therefore, a multidisciplinary approach, including obstetricians, asthma specialists, and pediatricians should collaborate with the patient to carefully weigh the risks and benefits to determine an optimal management plan for each individual patient. The aim of this review article is to summarize the most recent literature about the immunological changes that occur during pregnancy, physiological and clinical implications of asthma on pregnancy, and asthma management and medication use in pregnant women.

Short-Term Effects of Humidification Devices on Respiratory Pattern and Arterial Blood Gases During Noninvasive Ventilation

The impact of humidification devices on ventilatory and arterial blood gases parameters during noninvasive ventilation (NIV) remains controversial. The aim of the study was to compare the short-term impact of heat and moisture exchangers (HMEs) and heated humidifiers (HHs) during NIV for either hypercapnic or hypoxemic acute respiratory failure. Consecutive subjects receiving NIV were successively treated with HME and HH in randomized order for 30 min each. At the end of each period, arterial blood gases were measured and ventilatory parameters were recorded. Eighty-one subjects were enrolled, of whom 52 were hypercapnic (with or without acidosis) and 29 hypoxemic. Minute ventilation was greater with the HME, in comparison with the HH (15 [12-18] vs 12 [10-16] median [interquartile range], P < .001), while P(aCO(2)) was increased when using HME, indicating a dead space effect. This effect was observed in all subjects, but was more pronounced in hypercapnic subjects (P(aCO(2)) 62 ± 17 mm Hg with HME vs 57 ± 14 with HH, P < .001). In a subgroup of 19 subjects with respiratory acidosis, alveolar hypoventilation improved only with the HH. The amplitude of the dead space impact was a function of the degree of hypercapnia. Use of an HME decreased CO(2) elimination during NIV, despite increased minute ventilation, especially in hypercapnic subjects.

Treating exercise oscillatory ventilation in heart failure: the detail that may matter

Over the last 15 yrs, cardiologists have had to face a progressive recognition that abnormalities in the ventilatory response to exercise are relevant features of the heart failure syndrome [1]. Prior pathophysiology studies have defined the mechanistic role of the lung (impaired perfusion and increased minute ventilation ( V ′E)) [2] and of the periphery (increased chemo/metaboreflex sensitivity) [3] as determinants of the inefficient ventilatory response and early exercise termination. A wealth of literature has indeed brought evidence that, whatever the predominant substrate, the increase in V ′E relative to carbon dioxide production ( V ′CO2), primarily measured as the slope of this relationship, is a powerful indicator of disease severity [1, 4] that extends beyond peak oxygen uptake ( V ′O2), since its prognostic power is retained even when peak V ′O2 is near the normal range [5]. The consistency of these observations has substantially contributed to broadening the use of exercise gas exchange analysis for the clinical assessment and estimation of prognosis for the wide spectrum of heart failure populations [6]. As ventilation inefficiency has become an established matter of interest for heart failure specialists, further details have emerged as part of the picture, the most remarkable being exertional oscillatory ventilation (EOV) [7–12], a phenomenon originally described as anecdotal [13–15], and now considered a marker of disease severity even stronger than …

Hypoxic ventilatory response in Tac1−/− neonatal mice following exposure to opioids

Morphine is the dominating analgetic drug used in neonates, but opioid-induced respiratory depression limits its therapeutic use. In this study, we examined acute morphine effects on respiration during intermittent hypoxia in newborn Tac1 gene knockout mice (Tac1-/-) lacking substance P and neurokinin A. In vivo, plethysmography revealed a blunted hypoxic ventilatory response (HVR) in Tac1-/- mice. Morphine (10 mg/kg) depressed the HVR in wild-type animals through an effect on respiratory frequency, whereas it increased tidal volumes in Tac1-/- during hypoxia, resulting in increased minute ventilation. Apneas were reduced during the first hypoxic episode in both morphine-exposed groups, but were restored subsequently in Tac1-/- mice. Morphine did not affect ventilation or apnea prevalence during baseline conditions. In vitro, morphine (50 nM) had no impact on anoxic response of brain stem preparations of either strain. In contrast, it suppressed the inspiratory rhythm during normoxia and potentiated development of posthypoxic neuronal arrest, especially in Tac1-/-. Thus this phenotype has a higher sensitivity to the depressive effects of morphine on inspiratory rhythm generation, but morphine does not modify the reactivity to oxygen deprivation. In conclusion, although Tac1-/- mice are similar to wild-type animals during normoxia, they differed by displaying a reversed pattern with an improved HVR during intermittent hypoxia both in vivo and in vitro. These data suggest that opioids and the substance P-ergic system interact in the HVR, and that reducing the activity in the tachykinin system may alter the respiratory effects of opioid treatment in newborns.

The impact of traffic volume, composition, and road geometry on personal air pollution exposures among cyclists in Montreal, Canada

Cyclists may experience increased exposure to traffic-related air pollution owing to increased minute ventilation and close proximity to vehicle emissions. The aims of this study were to characterize personal exposures to air pollution among urban cyclists and to identify potential determinants of exposure including the type of cycling lane (separated vs on-road), traffic counts, and meteorological factors. In total, personal air pollution exposure data were collected over 64 cycling routes during morning and evening commutes in Montreal, Canada, over 32 days during the summer of 2011. Measured pollutants included ultrafine particles (UFPs), fine particles (PM(2.5)), black carbon (BC), and carbon monoxide (CO). Counts of diesel vehicles were important predictors of personal exposures to BC, with each 10 vehicle/h increase associated with a 15.0% (95% confidence interval (CI): 5.7%, 24.0%) increase in exposure. Use of separated cycling lanes had less impact on personal exposures with a 12% (95% CI: -43%, 14%) decrease observed for BC and smaller decreases observed for UFPs (mean: -1.3%, 95% CI: -20%, 17%) and CO (mean: -5.6%, 95% CI: -17%, 4%) after adjusting for meteorological factors and traffic counts. On average, PM(2.5) exposure increased 7.8% (95% CI: -17%, 35%) with separate cycling lane use, but this estimate was imprecise and not statistically significant. In general, our findings suggest that diesel vehicle traffic is an important contributor to personal BC exposures and that separate cycling lanes may have a modest impact on personal exposure to some air pollutants. Further evaluation is required, however, as the impact of separate cycling lanes and/or traffic counts on personal exposures may vary between regions.

Control of breathing and blood pressure by parafacial neurons in conscious rats

The retrotrapezoid nucleus (RTN), located in the parafacial region, contains glutamatergic neurons that express the transcriptor factor Phox2b and that are suggested to be central respiratory chemoreceptors. Studies in anaesthetized animals or in vitro have suggested that RTN neurons are important in the control of breathing by influencing respiratory rate, inspiratory amplitude and active expiration. However, the contribution of these neurons to cardiorespiratory control in conscious rats is not clear. Male Holtzman rats (280-300 g, n = 6-8) with bilateral stainless-steel cannulae implanted into the RTN were used. In conscious rats, the microinjection of the ionotropic glutamatergic agonist NMDA (5 pmol in 50 nl) into the RTN increased respiratory frequency (by 42%), tidal volume (by 21%), ventilation (by 68%), peak expiratory flow (by 24%) and mean arterial pressure (MAP, increased by 16 ± 4, versus saline, 3 ± 2 mmHg). Bilateral inhibition of the RTN neurons with the GABA(A) agonist muscimol (100 pmol in 50 nl) reduced resting ventilation (52 ± 34, versus saline, 250 ± 56 ml min(-1) kg(-1) with absolute values) and attenuated the respiratory response to hypercapnia and hypoxia. Muscimol injected into the RTN slightly reduced resting MAP (decreased by 13 ± 7, versus saline, increased by 3 ± 2 mmHg), without changing the effects of hypercapnia or hypoxia on MAP and heart rate. The results suggest that RTN neurons activate facilitatory mechanisms important to the control of ventilation in resting, hypoxic or hypercapnic conditions in conscious rats.

S-Nitrosoglutathione reductase is a key enzyme in hypoxic and post-hypoxic ventilatory signaling

The endogenous S-nitrosothiol, S-nitrosoglutathione (GSNO), regulates the activities of cell proteins by S-nitrosylation of key cysteine residues. There is compelling evidence that this S-nitrosothiol plays a role in ventilatory function including that bilateral microinjections of GSNO into the nucleus tractus solitarius of conscious rats, elicit profound increases in minute ventilation (MV). Exposure of mice to a hypoxic challenge elicits a robust increase in MV that declines during the challenge (roll-off) whereas return to room-air results in enhanced ventilation (short-term facilitation, STF). Since GSNOR catalyzes the GSH/NADH-dependent metabolism of GSNO to the disulfide, we hypothesize that increased GSNOR activity and enhanced degradation of GSNO, underlies ventilatory roll-off and diminished expression of STF. The first objective of this study was to examine the hypoxic ventilatory responses of wild-type C57BL6, GSNOR +/− and GSNOR −/− mice during exposure to a hypoxic challenge (10% O2, 90% N2 for 15 min) and upon return to room-air. In brief, ventilatory roll-off was virtually absent in the GSNOR +/− and GSNOR −/− mice whereas, STF was augmented. Our second on-going objective to collect biochemical evidence from WT, GSNOR +/− and GSNOR −/− mice as to whether an increase in GSNOR in the brainstem, lung and diaphragm contribute to the above ventilatory responses. The data includes changes in total S-nitrosothiol abundance, GSNOR activity, GSH/GSSG levels and NADH/NAD + levels. This study, which is the first pertaining to determination of the hypoxic ventilatory response, roll off and STF in GSNOR +/− or GSNOR −/− mice, provides compelling evidence for key rolls of GSNOR and GSNO in ventilatory responses.

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

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

Effect of sublingual nitrate on respiratory reflexes arising from stimulation of juxta-pulmonary capillary (J) receptors by i.v. lobeline and short duration exercise

Juxta-pulmonary capillary (J or pulmonary C fiber) receptors are stimulated by an increase in pulmonary blood flow and give rise to respiratory acceleration and related sensations and inhibit exercise. However, the reverse, i.e., the effect of reducing pulmonary blood flow on their reflexes, is as yet not known. This was investigated by carrying out a placebo-controlled study on the acute effects of a single dose (0.4mg) of sublingual glyceryl nitrate (GTN), known to shift blood from the central to the peripheral circulation, on the respiratory parameters of exercising healthy subjects and on their responses to i.v. lobeline.In 10 subjects, GTN use delayed the first appearance of respiratory sensations from 9.08±0.9min to 11min (P=0.002), reduced the increase in minute ventilation by the end of 10min of exercise (P=0.003) and increased its duration by 1–4s and doubled it in the remaining one subject. In a majority of 8 of them, the effect of GTN on i.v. lobeline-induced respiratory reflexes and sensations was a significant increase in the dose required (P=0.006) for producing threshold effects and in the latency of their appearance (P=0.003). The latter feature points to a reduction in blood flow in the lung parenchyma where these receptors are located and to which they are sensitive. As this would have led to a reduced stimulation of these receptors, it would account for the delayed appearance of respiratory symptoms, a reduction in ventilatory increase and prolongation of exercise duration.We demonstrated a mechanism of reducing the stimulus level of J receptors by reducing pulmonary blood flow by means of pharmacological sequestration with GTN use, which then led to a reduction in the magnitude of respiratory and viscerosomatic reflexes, while noting at the same time that changes in blood flow in the pulmonary bed do not directly influence limb muscles, tendons and joints which also determine exercise output.

GAL‐021 –induced respiratory stimulation is associated with increases in carotid sinus nerve and phrenic motoneuron activity in rats

GAL‐021 is a novel respiratory stimulant that increases minute ventilation in rats, mice, and Cynomolgus monkeys. We hypothesized that GAL‐021 increases minute ventilation via mechanisms at the level of the carotid body. Using in vivo electrophysiological techniques, we examined the dose‐dependence of the effects of GAL‐021 (0.01 – 3 mg/kg, IV) on carotid sinus nerve (CSN) activity and phrenic motoneuron activity in mechanically ventilated, vagotomized, and neuromuscularly paralyzed adult rats, and on tidal volume (VT) in anesthetized spontaneously breathing rats. GAL‐021 dose‐dependently increased CSN (ED50 0.13 mg/kg) and phrenic nerve neurogram amplitude (ED50 0.08 mg/kg), values in reasonable accord with effects on VT (ED50 0.04 mg/kg). Thus, GAL‐021 is virtually equipotent in stimulating the afferent, efferent and effector components of the ventilatory response. When administered to conscious rats 7 days after either bilateral CSN transection or sham operation, the ventilatory effects (VT and frequency) of GAL‐021 (0.2 mg/kg, IV) were markedly diminished in the CSN transected rats compared to sham‐operated controls. Collectively, these data suggest that GAL‐021 stimulates breathing, at least in part, by effects on the carotid body resulting in increased carotid sinus nerve activity.

GAL‐021, a novel respiratory stimulant, attenuates opioid–induced respiratory depression without compromising analgesia

Opioid‐induced respiratory depression (OIRD) is a common side effect of opioid analgesics and can be life‐threatening, especially during the perioperative period and sleep. Current therapy for OIRD includes administering opioid antagonists and/or decreasing subsequent opioid doses, both of which can compromise analgesia. Here, we describe a novel respiratory stimulant, GAL‐021, that increases minute ventilation (Vmin) and reverses OIRD without diminishing analgesia. GAL‐021 administered as an IV bolus (0.01 – 3 mg/kg) to anesthetized rats or by infusion (0.01 – 0.4 mg/kg/min × 60‐min) to conscious rats increased Vmin, tidal volume (VT), and respiratory frequency (f). In anesthetized rats, the ED50 for increasing Vmin was 140 μg/kg. In conscious rats, OIRD was induced with morphine (10 mg/kg, IV), which increased PaCO2 and decreased Vmin, VT, f, pH, and PaO2 for up to 2 hours. Subsequent infusion of GAL‐021 (0.03 – 0.4 mg/kg/min, IV) resulted in dose‐dependent diminution of the evoked respiratory depression for the duration of the infusion (20 min). The increase in Vmin induced by GAL‐021 was due to an increase in VT but not f. Termination of GAL‐021 infusion restored OIRD. In contrast, GAL‐021 did not diminish morphine‐induced analgesia assessed by the tail‐flick assay. These data demonstrate that GAL‐021 stimulates breathing in conscious and anesthetized rats and reverses OIRD without attenuating analgesia.

GAL‐021 acts as a novel respiratory stimulant in non‐human primates

Opioid‐induced respiratory depression (OIRD) is a common side effect of opioid‐induced analgesia and can be life‐threatening, especially during the perioperative period and sleep. Current therapy for OIRD includes administering opioid antagonists and/or decreasing subsequent opioid doses, both of which can compromise analgesia. We have demonstrated that GAL‐021, a novel respiratory stimulant, increases minute ventilation (Vmin) and reverses OIRD in rats, without diminishing opioid‐induced analgesia. Here, we describe the effects of GAL‐021 in Cynomolgus monkeys. In isoflurane‐anesthetized opioid‐naïve monkeys, GAL‐021 administered by IV bolus (0.01 – 0.3 mg/kg) or infusion (0.02 – 0.1 mg/kg/min) increased Vmin, tidal volume, and respiratory frequency. In conscious animals, OIRD was induced by morphine (2.4 – 3.2 mg/kg, slow IV bolus), titrated in each animal to decrease Vmin by 20 to 30% and increase ETCO2 by 10 mmHg. Administration of GAL‐021 15‐min post‐morphine diminished OIRD in a dose‐dependent manner. Loading GAL‐021 at 0.1 mg/kg/min × 5 min and maintaining infusion at 0.05 mg/kg/min × 10 min reduced OIRD by 75%. In contrast, loading at 0.2 mg/kg/min × 5 min and maintaining infusion at 0.1 mg/kg/min × 10 min returned ETCO2 to pre‐morphine levels. These data demonstrate that GAL‐021 stimulates respiration in conscious and anesthetized monkeys and is capable of reversing OIRD in non‐human primates.

Comparison of the respiratory effects of GAL‐021 in BK α subunit knockout (Slo1−/ −) and wild‐type mice

GAL‐021 is a novel respiratory stimulant that increases minute ventilation (Vmin) in rats and Cynomolgus monkeys. Transecting the carotid sinus nerve decreases this effect in rats, suggesting that part of the evoked stimulation is mediated by effects at the level of the carotid body. BK (or Maxi K) channels, which consist of a pore‐forming α‐subunit (slo1) and various â regulatory subunits, are present in the carotid body and have been implicated in oxygen sensing. Hypoxia reportedly decreases BK potassium current and increases carotid sinus nerve activity. In preliminary studies using GH3 cells we demonstrated that GAL‐021 exerts modest inhibition of BK channels (56%I at 10 μM). To test the hypothesis that GAL‐021 may stimulate breathing via inhibition of BK channels, we administered GAL‐021 (0.03 ‐ 3 mg/kg, IV) as bolus injections to isoflurane anesthetized, wild‐type and BK á‐subunit knockout (Slo1−/−) mice. In wild‐type mice, GAL‐021 dose‐dependently increased Vmin (maximum response 143 ± 34 % above baseline; ED50 0.5 mg/kg) consistent with prior studies in rats and monkeys. In Slo1−/− mice the effects of GAL‐021 on Vmin (maximum response 64 ± 24 % above baseline; ED50 2.1 mg/kg) were significantly attenuated (but not abolished) in comparison to the wild‐type. These data suggest that BK channels contribute to the effects of GAL‐021 on ventilation but that non‐BK‐dependent mechanisms are also involved.

The accessory role of the diaphragmaticus muscle in lung ventilation in the estuarine crocodile Crocodylus porosus

Crocodilians use a combination of three muscular mechanisms to effect lung ventilation: the intercostal muscles producing thoracic movement, the abdominal muscles producing pelvic rotation and gastralial translation, and the diaphragmaticus muscle producing visceral displacement. Earlier studies suggested that the diaphragmaticus is a primary muscle of inspiration in crocodilians, but direct measurements of the diaphragmatic contribution to lung ventilation and gas exchange have not been made to date. In this study, ventilation, metabolic rate and arterial blood gases were measured from juvenile estuarine crocodiles under three conditions: (i) while resting at 30°C and 20°C; (ii) while breathing hypercapnic gases; and (iii) during immediate recovery from treadmill exercise. The relative contribution of the diaphragmaticus was then determined by obtaining measurements before and after transection of the muscle. The diaphragmaticus was found to make only a limited contribution to lung ventilation while crocodiles were resting at 30°C and 20°C, and during increased respiratory drive induced by hypercapnic gas. However, the diaphragmaticus muscle was found to play a significant role in facilitating a higher rate of inspiratory airflow in response to exercise. Transection of the diaphragmaticus decreased the exercise-induced increase in the rate of inspiration (with no compensatory increases in the duration of inspiration), thus compromising the exercise-induced increases in tidal volume and minute ventilation. These results suggest that, in C. porosus, costal ventilation alone is able to support metabolic demands at rest, and the diaphragmaticus is largely an accessory muscle used at times of elevated metabolic demand.

Gestation increases the energetic cost of breathing in the lizard, Tiliqua rugosa

High gestational loads result in fetuses that occupy a large proportion of the body cavity and may compress maternal organs. Compression of the lungs results in alterations in breathing patterns during gestation, which may affect the energetic cost of breathing. In this study, the energetic cost of breathing during gestation was determined in the viviparous skink Tiliqua rugosa. Radiographic imaging showed progressive lung compression during gestation and a 30% reduction in the lung inflation index (rib number at which the caudal margin of the lung was imaged divided by total rib number). Pneumotachography and open flow respirometry were used to measure breathing patterns and metabolic rates. Gestation induced a twofold increase in minute ventilation via increases in breathing frequency, but no change in inspired tidal volume. The rates of O(2) consumption and CO(2) production did not change significantly during gestation. Together, these results suggest that a relative hyperventilation occurs during gestation in T. rugosa, which in turn suggests that diffusion and/or perfusion limitations may exist at the lung during gestation. The energetic cost of breathing was estimated as a percentage of resting metabolic rate using hypercapnia to stimulate ventilation at different stages of pregnancy. The energetic cost of breathing in non-pregnant lizards was 19.96±3.85% of resting metabolic rate and increased threefold to 62.80±10.11% during late gestation. This significant increase in the energetic cost of breathing may have significant consequences for energy budgets during gestation.

Disodium Cromoglycate Attenuates Hypoxia Induced Enlargement of End-Expiratory Lung Volume in Rats

Mechanism responsible for the enlargement of end-expiratory lung volume (EELV) induced by chronic hypoxia remains unclear. The fact that the increase in EELV persists after return to normoxia suggests involvement of morphological changes. Because hypoxia has been also shown to activate lung mast cells, we speculated that they could play in the mechanism increasing EELV similar role as in vessel remodeling in hypoxic pulmonary hypertension (HPH). We, therefore, tested an effect of mast cells degranulation blocker disodium cromoglycate (DSCG) on hypoxia induced EELV enlargement. Ventilatory parameters, EELV and right to left heart weight ratio (RV/LV+S) were measured in male Wistar rats. The experimental group (H+DSCG) was exposed to 3 weeks of normobaric hypoxia and treated with DSCG during the first four days of hypoxia, control group was exposed to hypoxia only (H), two others were kept in normoxia as non-treated (N) and treated (N+DSCG) groups. DSCG treatment significantly attenuated the EELV enlargement (H+DSCG = 6.1+/-0.8; H = 9.2+/-0.9; ml +/-SE) together with the increase in minute ventilation (H + DSCG = 190+/-8; H = 273 +/- 10; ml/min +/- SE) and RV/LV + S (H + DSCG = 0.39 +/- 0.03; H = 0.50 +/- 0.06).