Important role of carotid afferents in control of breathing

The purpose of the present study was todetermine the effect on breathing in the awake state of carotid bodydenervation (CBD) over 1-2 wk after denervation. Studies werecompleted on adult goats repeatedly before and1) for 15 days after bilateral CBD (n = 8),2) for 7 days after unilateral CBD(n = 5), and3) for 15 days after sham CBD(n = 3). Absence of ventilatorystimulation when NaCN was injected directly into a common carotidartery confirmed CBD. There was a significant(P < 0.01) hypoventilation during the breathing of room air after unilateral and bilateral CBD. Themaximum Pa_CO2 increase (8 Torr forunilateral and 11 Torr for bilateral) occurred ~4 days afterCBD. This maximum was transient because by 7 (unilateral)to 15 (bilateral) days after CBD, Pa_CO2 was only 3-4 Torr above control.CO₂ sensitivity was attenuated from control by 60% on day 4 afterbilateral CBD and by 35% on day 4 after unilateral CBD. This attenuation was transient, because CO₂ sensitivity returned tocontrol temporally similar to the return ofPa_CO2 during the breathing of room air.During mild and moderate treadmill exercise 1-8 days afterbilateral CBD, Pa_CO2 was unchanged fromits elevated level at rest, but, 10-15 days after CBD,Pa_CO2 decreased slightly from restduring exercise. These data indicate that1) carotid afferents are animportant determinant of rest and exercise breathing and ventilatoryCO₂ sensitivity, and2) apparent plasticity within theventilatory control system eventually provides compensation for chronicloss of these afferents.

     

Effect of prior O2 breathing on ventilatory response to sustained isocapnic hypoxia in adult humans

Honda, Y., H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama. Effect of priorO₂ breathing on ventilatoryresponse to sustained isocapnic hypoxia in adult humans.J. Appl. Physiol. 81(4):1627-1632, 1996.Sixteen healthy volunteers breathed 100%O₂ or room air for 10 min in random order, then their ventilatory response to sustained normocapnic hypoxia (80% arterial O₂saturation, as measured with a pulse oximeter) was studied for 20 min.In addition, to detect agents possibly responsible for the respiratorychanges, blood plasma of 10 of the 16 subjects was chemically analyzed.1) Preliminary O₂ breathing uniformly andsubstantially augmented hypoxic ventilatory responses.2) However, the profile ofventilatory response in terms of relative magnitude, i.e., biphasichypoxic ventilatory depression, remained nearly unchanged.3) Augmented ventilatory incrementby prior O₂ breathing wassignificantly correlated with increment in the plasma glutamine level.We conclude that preliminary O₂administration enhances hypoxic ventilatory response without affectingthe biphasic response pattern and speculate that the excitatory aminoacid neurotransmitter glutamate, possibly derived from augmentedglutamine, may, at least in part, play a role in this ventilatoryenhancement.

     

Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea

Xie, Ailiang, Fiona Rankin, Ruth Rutherford, and T. DouglasBradley. Effects of inhaledCO₂ and added dead space on idiopathic central sleep apnea. J. Appl.Physiol. 82(3): 918-926, 1997.We hypothesizedthat reductions in arterial PCO₂ (Pa_CO2) below the apnea threshold play akey role in the pathogenesis of idiopathic central sleep apnea syndrome(ICSAS). If so, we reasoned that raisingPa_CO2 would abolish apneas in thesepatients. Accordingly, patients with ICSAS were studied overnight onfour occasions during which the fraction of end-tidalCO₂ and transcutaneous PCO₂ were measured: during room airbreathing (N1), alternating room airand CO₂ breathing(N2),CO₂ breathing all night(N3), and addition of dead space viaa face mask all night (N4).Central apneas were invariably preceded by reductions infraction of end-tidal CO₂. Bothadministration of a CO₂-enrichedgas mixture and addition of dead space induced 1- to 3-Torr increasesin transcutaneous PCO₂, whichvirtually eliminated apneas and hypopneas; they decreased from43.7 ± 7.3 apneas and hypopneas/h onN1 to 5.8 ± 0.9 apneas andhypopneas/h during N3(P < 0.005), from 43.8 ± 6.9 apneas and hypopneas/h during room air breathing to 5.9 ± 2.5 apneas and hypopneas/h of sleep duringCO₂ inhalation during N2 (P < 0.01), and to 11.6% of the room air level while the patients werebreathing through added dead space duringN4 (P < 0.005). Because raisingPa_CO2 through two different meansvirtually eliminated central sleep apneas, we conclude that centralapneas during sleep in ICSA are due to reductions inPa_CO2 below the apnea threshold.

     

Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI)

Gelfand, R., C. J. Lambertsen, J. M. Clark, and E. Hopkin.Hypoxic ventilatory sensitivity in men is not reduced by prolongedhyperoxia (Predictive Studies V and VI). J. Appl.Physiol. 84(1): 292-302, 1998.Potential adverseeffects on the O₂-sensing functionof the carotid body when its cells are exposed to toxic O₂ pressures were assessed duringinvestigations of human organ tolerance to prolonged continuous andintermittent hyperoxia (Predictive Studies V and VI). Isocapnic hypoxicventilatory responses (HVR) were determined at 1.0 ATA before and aftersevere hyperoxic exposures: 1)continuous O₂ breathing at 1.5, 2.0, and 2.5 ATA for 17.7, 9.0, and 5.7 h and2) intermittentO₂ breathing at 2.0 ATA (30 minO₂-30 min normoxia) for 14.3 O₂ h within 30-h total time. Postexposure curvature of HVR hyperbolas was not reduced compared withpreexposure controls. The hyperbolas were temporarily elevated tohigher ventilations than controls due to increments in respiratory frequency that were proportional toO₂ exposure time, notO₂ pressure. In humans, prolongedhyperoxia does not attenuate the hypoxia-sensing function of theperipheral chemoreceptors, even after exposures that approach limits ofhuman pulmonary and central nervous system O₂ tolerance. Current applicationsof hyperoxia in hyperbaric O₂therapy and in subsea- and aerospace-related operations are guided byand are well within these exposure limits.

     

Task failure with lack of diaphragm fatigue during inspiratory resistive loading in human subjects

McKenzie, D. K., G. M. Allen, J. E. Butler, and S. C. Gandevia. Task failure with lack of diaphragm fatigue during inspiratory resistive loading in human subjects. J. Appl. Physiol. 82(6): 2011-2019, 1997.Taskfailure during inspiratory resistive loading is thought to beaccompanied by substantial peripheral fatigue of the inspiratorymuscles. Six healthy subjects performed eight resistive breathingtrials with loads of 35, 50, 75 and 90% of maximal inspiratorypressure (MIP) with and without supplemental oxygen. MIP measuredbefore, after, and at every minute during the trial increased slightlyduring the trials, even when corrected for lung volume (e.g., for 24 trials breathing air, 12.5% increase, P < 0.05). In some trials, taskfailure occurred before 20 min (end point of trial), and in thesetrials there was an increase in end-tidalPCO₂(P < 0.01), despite the absence of peripheral muscle fatigue. In four subjects (6 trials with task failure), there was no decline in twitch amplitude with bilateral phrenic stimulation or in voluntary activation of the diaphragm, eventhough end-tidal PCO₂ rose by 1.6 ± 0.9%. These results suggest that hypoventilation,CO₂ retention, and ultimate taskfailure during resistive breathing are not simply dependent on impairedforce-generating capacity of the diaphragm or impaired voluntaryactivation of the diaphragm.

     

Zone of apposition in the passive diaphragm of the dog

Boriek, Aladin M., Joseph R. Rodarte, and Susan S. Margulies. Zone of apposition in the passive diaphragm of thedog. J. Appl. Physiol. 81(5): 1929-1940, 1996.Wedetermined the regional area of the diaphragmatic zone of apposition(ZAP) as well as the regional craniocaudal extent of the ZAP(ZAP_ht) of the passive diaphragm in six paralyzedanesthetized beagle dogs (8-12 kg) at residual lung volume (RV),functional residual capacity (FRC), FRC + 0.25 and FRC + 0.5 inspiratory capacity, and total lung capacity (TLC) in prone and supinepostures. To identify the caudal boundary of the ZAP, 17 lead markers(1 mm) were sutured to the abdominal side of the costal and cruraldiaphragms around the diaphragm insertion on the chest wall. Two weekslater, the dogs' caudal thoraces were scanned by the use of thedynamic spatial reconstructor (DSR), a prototype fast volumetric X-raycomputer tomographic scanner, developed at the Mayo Clinic. Thethree-dimensional spatial coordinates of the markers were identified(±1.4 mm), and the cranial boundary of the ZAP was determined from30-40 1.4-mm-thick sagittal and coronal slices in each DSR image.We interpolated the DSR data to find the position of the cranial andcaudal boundaries of the ZAP every 5° around the thorax and computedthe distribution of regional variation of area of the ZAP andZAP_ht as well as the total area of ZAP. TheZAP_ht and area of ZAP increased as lung volume decreasedand were largest near the lateral extremes of the rib cage. We measuredthe surface area of the rib cage cephaled to the ZAP(A_L) in both postures in another six beagle dogs(12-16 kg) of similar stature, scanned previously in the DSR. Weestimated the entire rib cage surface area(A_rc = A_ZAP +A_L). The A_ZAP as a percentageof A_rc increased more than threefold as lung volumedecreased from TLC to RV, from ~9 to 29% of A_rc.

     

Brain stem lesion size determined by DEAD red or conjugation of neurotoxin to fluorescent beads

Neurotoxinmicroinjected into the retrotrapezoid nucleus of anesthetized ratsdecreases phrenic activity and eliminates the response toCO₂. In unanesthetized rats, suchtreatment has no effect on awake, resting breathing and decreasesCO₂ sensitivity by 40% (M. Akilesh, M. Kamper, A. Li, and E. E. Nattie. J. Appl. Physiol. 82: 469-479, 1997). One important factorin explaining these disparate results is the actual size of theanatomic lesion. In the present study, we injected ibotenic acid intothe retrotrapezoid nucleus of anesthetized rats and evaluated lesionsize by using two new approaches: 1)DEAD red, a fluorescent probe that enters impaired cells through leakymembranes and binds to nucleic acids, and2) conjugation of toxin tofluorescent beads. With the use of DEAD red, the region containinglabeled dying cells was 313 ± 104 nl(n = 4), six times larger than theinitial injected volume, and the physiological effects on phrenicamplitude, the CO₂ response, andblood pressure began within minutes and were substantial. Withconjugated toxin, in theory, neuronal damage would be limited to theregion of detectable fluorescence (49 ± 10 nl;n = 4). Effects on phrenicamplitude, CO₂ sensitivity, andblood pressure were absent until ~2 h postinjection. Controlexperiments, with 2 h of in vitro incubation of theneurotoxin-microbead conjugate and injection of the supernatant aftercentrifugation, showed similar results that suggest release ofconjugated neurotoxin. We conclude that DEAD red provides a usefulmeans to monitor neuronal impairment in acute studies in vivo.Conjugation of neurotoxin to microbeads may be less reliable in this regard.

     

Phrenic motoneuron discharge during sustained inspiratory resistive loading

Iscoe, Steve. Phrenic motoneuron discharge duringsustained inspiratory resistive loading. J. Appl.Physiol. 81(5): 2260-2266, 1996.I determinedwhether prolonged inspiratory resistive loading (IRL) affects phrenicmotoneuron discharge, independent of changes in chemical drive. Inseven decerebrate spontaneously breathing cats, the discharge patternsof eight phrenic motoneurons from filaments of one phrenic nerve weremonitored, along with the global activity of the contralateral phrenicnerve, transdiaphragmatic pressure, and fractional end-tidalCO₂ levels. Discharge patterns during hyperoxic CO₂ rebreathingand breathing against an IRL (2,500-4,000cmH₂O ^· l^{1 ·} s)were compared. During IRL, transdiaphragmatic pressure increased andthen either plateaued or decreased. At the highest fractional end-tidalCO₂ common to both runs,instantaneous discharge frequencies in six motoneurons were greaterduring sustained IRL than during rebreathing, when compared at the sametime after the onset of inspiration. These increased dischargefrequencies suggest the presence of a load-induced nonchemical drive tophrenic motoneurons from unidentified source(s).

     

Effects of training duration on substrate turnover and oxidation during exercise

Phillips, S. M., H. J. Green, M. A. Tarnopolsky, G. J. F. Heigenhauser, R. E. Hill, and S. M. Grant. Effects of training duration on substrate turnover and oxidation during exercise. J. Appl. Physiol. 81(5):2182-2191, 1996.Adaptations in fat and carbohydrate metabolismafter a prolonged endurance training program were examined using stableisotope tracers of glucose([6,6-²H₂]glucose),glycerol([²H₅]glycerol),and palmitate([²H₂]palmitate).Active, but untrained, males exercised on a cycle for 2 h/day[60% pretraining peak O₂consumption (O_{2 peak}) = 44.3 ± 2.4 ml ^· kg^{1 ·} min¹]for a total of 31 days. Three cycle tests (90 min at 60% pretraining O_{2 peak}) wereadministered before training (PRE) and after 5 (5D) and 31 (31D) daysof training. Exercise increased the rate of glucose production(R_a) and utilization(R_d) as well as the rate oflipolysis (glycerol R_a) and freefatty acid turnover (FFA R_a/R_d).At 5D, training induced a 10% (P < 0.05) increase in total fat oxidation because of an increase inintramuscular triglyceride oxidation (+63%,P < 0.05) and a decreased glycogenoxidation (16%, P < 0.05).At 31D, total fat oxidation during exercise increased a further 58%(P < 0.01). The pattern of fatutilization during exercise at 31D showed a reduced reliance on plasmaFFA oxidation (FFA R_d) and agreater dependence on oxidation of intramuscular triglyceride, whichincreased more than twofold (P < 0.001). In addition, glucose R_aand R_d were reduced at all timepoints during exercise at 31D compared with PRE and 5D. We concludethat long-term training induces a progressive increase in fatutilization mediated by a greater oxidation of fats from intramuscularsources and a reduction in glucose oxidation. Initial changes arepresent as early as 5D and occur before increases in muscle maximalmitochondrial enzyme activity [S. M. Phillips, H. J. Green, M. A. Tarnopolsky, G. J. F. Heigenhauser, and S. M. Grant.Am. J. Physiol. 270 (Endocrinol. Metab. 33):E265-E272, 1996].

     

Recovery of diaphragmatic function in awake sheep after two approaches to thoracic surgery

Imanaka, Hideaki, William R. Kimball, John C. Wain, MasajiNishimura, Kenichi Okubo, Dean Hess, and Robert M. Kacmarek. Recovery of diaphragmatic function in awake sheep after two approaches to thoracic surgery. J. Appl.Physiol. 83(5): 1733-1740, 1997.Video-assistedthoracoscopic surgery (VATS) is replacing thoracotomy, but no study hasaddressed the extent or duration of VATS-induced diaphragmaticalteration. We hypothesized that VATS would impair diaphragmaticfunction less and return diaphragmatic function faster thanthoracotomy. In eight sheep, sonomicrometers were randomly implanted onthe right costal diaphragm via VATS or thoracotomy. Diaphragmaticresting length, shortening fraction, and respiratory function weremeasured weekly during quiet breathing (QB) andCO₂ rebreathing for 4 wk. ForVATS, shortening fraction was smallest onpostoperative days 1 (POD 1) (6.4 ± 3.4 and12.9 ± 8.7% during QB and 10%CO₂ rebreathing, respectively) and7 (6.3 ± 3.4 and 16.9 ± 4.0%during QB and 10% CO₂rebreathing, respectively) and recovered by 3 wk (13.2 ± 1.8 and28.9 ± 8.0% during QB and 10%CO₂ rebreathing, respectively).For thoracotomy, shortening fraction at 10%CO₂ rebreathing was smaller onPODs 1, 7, 14 (15.9 ± 7.1, 13.6 ± 5.4, and 19.0 ± 6.9%) than onPOD 28 (29.9 ± 8.2%), but notduring QB on POD 1 or7 (7.5 ± 3.8 and 3.4 ± 2.6%)compared with POD 28 (10.7 ± 8.7%). Shortening fraction did not differ between surgeries. There wasno group difference in minute ventilation, respiratory rate,transdiaphragmatic pressure, or esophageal and gastric pressures. Inconclusion, although shortening fraction recovered faster for VATS,this translated into insignificant functional differences.

     

Effect of ingested sodium bicarbonate on muscle force, fatigue, and recovery

Verbitsky, O., J. Mizrahi, M. Levin, and E. Isakov.Effect of ingested sodium bicarbonate on muscle force, fatigue, and recovery. J. Appl. Physiol. 83(2):333-337, 1997.The influence of acute ingestion ofNaHCO₃ on fatigue and recovery ofthe quadriceps femoris muscle after exercise was studied in six healthymale subjects. A bicycle ergometer was used for exercising under three loading conditions: test A, loadcorresponding to maximal oxygen consumption; testB, load in test A + 17%; test C, load intest B but performed 1 h after acuteingestion of NaHCO₃.Functional electrical stimulation (FES) was applied to provokeisometric contraction of the quadriceps femoris. The resulting kneetorque was monitored during fatigue (2-min chronic FES) and recovery (10-s FES every 10 min, for 40 min). Quadriceps torques were higher inthe presence of NaHCO₃(P < 0.05): withNaHCO₃ the peak, residual, andrecovery (after 40 min) normalized torques were, respectively, 0.68 ± 0.05 (SD), 0.58 ± 0.05, and 0.73 ± 0.05; withoutNaHCO₃ the values were 0.45 ± 0.04, 0.30 ± 0.06, and 0.63 ± 0.06. The increasedtorques obtained after acute ingestion ofNaHCO₃ indicate the possibleexistence of improved nonoxidative glycolysis in isometric contraction,resulting in reduced fatigue and enhanced recovery.

     

Isoproterenol attenuates high vascular pressure-induced permeability increases in isolated rat lungs

Parker, James C., and Claire L. Ivey.Isoproterenol attenuates high vascular pressure-inducedpermeability increases in isolated rat lungs. J. Appl.Physiol. 83(6): 1962-1967, 1997.To separate thecontributions of cellular and basement membrane components of thealveolar capillary barrier to the increased microvascular permeabilityinduced by high pulmonary venous pressures (Ppv), we subjected isolatedrat lungs to increases in Ppv, which increased capillary filtrationcoefficient(K_fc) withoutsignificant hemorrhage (31 cmH₂O)and with obvious extravasation of red blood cells (43 cmH₂O). Isoproterenol (20 µM)was infused in one group (Iso) to identify a reversible cellularcomponent of injury, and residual blood volumes were measured to assessextravasation of red blood cells through ruptured basement membranes.In untreated lungs (High Ppv group),K_fc increased 6.2 ± 1.3 and 38.3 ± 15.2 times baseline during the 31 and 43 cmH₂O Ppv states. In Iso lungs, K_fc was 36.2%(P < 0.05) and 64.3% of that in theHigh Ppv group at these Ppv states. Residual blood volumes calculatedfrom tissue hemoglobin contents were significantly increased by53-66% in the high Ppv groups, compared with low vascularpressure controls, but there was no significant difference between HighPpv and Iso groups. Thus isoproterenol significantly attenuatedvascular pressure-induced K_fc increases atmoderate Ppv, possibly because of an endothelial effect, but it did notaffect red cell extravasation at higher vascular pressures.

     

Ventilatory response to exercise in subjects breathing CO2 or HeO2

Babb, T. G. Ventilatory response to exercise insubjects breathing CO₂ orHeO₂.J. Appl. Physiol. 82(3): 746-754, 1997.To investigate the effects of mechanical ventilatory limitationon the ventilatory response to exercise, eight older subjects with normal lung function were studied. Each subject performed graded cycleergometry to exhaustion once while breathing room air; once whilebreathing 3% CO₂-21%O₂-balanceN₂; and once while breathing HeO₂ (79% He and 21%O₂). Minute ventilation(E) and respiratory mechanics weremeasured continuously during each 1-min increment in work rate (10 or20 W). Data were analyzed at rest, at ventilatory threshold (VTh),and at maximal exercise. When the subjects were breathing 3%CO₂, there was an increase(P < 0.001) inE at rest and at VTh but not duringmaximal exercise. When the subjects were breathingHeO₂,E was increased(P < 0.05) only during maximalexercise (24 ± 11%). The ventilatory response to exercise belowVTh was greater only when the subjects were breathing 3% CO₂(P < 0.05). Above VTh, theventilatory response when the subjects were breathingHeO₂ was greater than whenbreathing 3% CO₂(P < 0.01). Flow limitation, aspercent of tidal volume, during maximal exercise was greater(P < 0.01) when the subjects werebreathing CO₂ (22 ± 12%) thanwhen breathing room air (12 ± 9%) or when breathingHeO₂ (10 ± 7%)(n = 7). End-expiratory lung volumeduring maximal exercise was lower when the subjects were breathingHeO₂ than when breathing room airor when breathing CO₂(P < 0.01). These data indicate thatolder subjects have little reserve for accommodating an increase inventilatory demand and suggest that mechanical ventilatory constraintsinfluence both the magnitude of Eduring maximal exercise and the regulation ofE and respiratory mechanics duringheavy-to-maximal exercise.

     

Ozone enhances excitabilities of pulmonary C fibers to chemical and mechanical stimuli in anesthetized rats

Acute exposureto ozone (O₃) enhances pulmonarychemoreflex response to capsaicin, and an increased sensitivity ofbronchopulmonary C-fiber afferent endings may be involved. The presentstudy was aimed at determining the effect ofO₃ on the responses of pulmonary Cfibers to chemical and mechanical stimuli. A total of 31 C fibers werestudied in anesthetized, open-chest, and vagotomized rats. Duringcontrol, right atrial injection of a low dose of capsaicin abruptlyevoked a short and mild burst of discharge [0.77 ± 0.28 impulses (imp)/s, 2-s average]. After acute exposure toO₃ (3 parts/million for 30 min),there was no significant change in arterial blood pressure, trachealpressure, or baseline activity of C fibers. However, the stimulatoryeffect of the same dose of capsaicin on these fibers was markedlyenhanced (6.05 ± 0.88 impulses/s;P < 0.01) and prolonged immediatelyafter O₃ exposure, and returnedtoward control in 54 ± 6 min. Similarly, the pulmonary C-fiberresponse to injection of a low dose of lactic acid was also elevatedafter O₃ exposure. Furthermore,O₃ exposure significantly potentiated the C-fiber response to constant-pressure (tracheal pressure = 30 cmH₂O) lunginflation (control: 0.19 ± 0.07 imp/s; afterO₃: 1.12 ± 0.26 imp/s;P < 0.01). In summary, these results show that the excitabilities of pulmonary C-fiber afferents to lunginflation and injections of chemical stimulants are markedly potentiated after acute exposure toO₃, suggesting a possible involvement of these afferents in theO₃-induced changes in breathing pattern and chest discomfort in humans.

     

Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia

Dwinell, M. R., P. L. Janssen, J. Pizarro, and G. E. Bisgard. Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia. J. Appl.Physiol. 82(1): 118-124, 1997.Hypoxicventilatory sensitivity is increased during ventilatory acclimatizationto hypoxia (VAH) in awake goats, resulting in a time-dependent increasein expired ventilation (E). Theobjectives of this study were to determine whether the increasedcarotid body (CB) hypoxic sensitivity is dependent on the level of CB CO₂ and whether the CBCO₂ gain is changed during VAH.Studies were carried out in adult goats with CB blood gases controlled by an extracorporeal circuit while systemic (central nervous system) blood gases were regulated independently by the level of inhaled gases. Acute E responsesto CB hypoxia (CB PO₂ 40 Torr) and CBhypercapnia (CB PCO₂ 50 and 60 Torr)were measured while systemic normoxia and isocapnia were maintained. CBPO₂ was then lowered to 40 Torr for 4 h while the systemic blood gases were kept normoxic and normocapnic.During the 4-h CB hypoxia, E increasedin a time-dependent manner. Thirty minutes after return to normoxia,the ventilatory response to CB hypoxia was significantly increasedcompared with the initial response. The slope of the CBCO₂ response was also elevatedafter VAH. An additional group of goats(n = 7) was studied with asimilar protocol, except that CB PCO₂was lowered throughout the 4-h hypoxic exposure to prevent reflexhyperventilation. CB PCO₂ wasprogressively lowered throughout the 4-h CB hypoxic period to maintainE at the control level. After the 4-hCB hypoxic exposure, the ventilatory response to hypoxia was alsosignificantly elevated. However, the slope of the CBCO₂ response was not elevatedafter the 4-h hypoxic exposure. These results suggest that CBsensitivity to both O₂ andCO₂ is increased after 4 h of CBhypoxia with systemic isocapnia. The increase in CB hypoxic sensitivityis not dependent on the level of CBCO₂ maintained during the 4-hhypoxic period.

     

Effects of supplemental oxygen on forearm vasodilation in humans

Crawford, Paul, Peter A. Good, Eric Gutierrez, Joshua H. Feinberg, John P. Boehmer, David H. Silber, and Lawrence I. Sinoway. Effects of supplemental oxygen on forearm vasodilation in humans.J. Appl. Physiol. 82(5):1601-1606, 1997.Supplemental O₂ reduces cardiac output andraises systemic vascular resistance in congestive heart failure. Inthis study, 100% O₂ was given tonormal subjects and peak forearm flow was measured. Inexperiment 1, 100%O₂ reduced blood flow andincreased resistance after 10 min of forearm ischemia (flow 56.7 ± 7.9 vs. 47.8 ± 6.7 ml · min¹ · 100 ml¹;P < 0.02; vascular resistance 1.7 ± 0.2 vs. 2.4 ± 0.4 mmHg · min · 100 ml · ml¹;P < 0.03). Inexperiment 2, lower body negativepressure (LBNP; 30 mmHg) and venous congestion (VC) simulatedthe high sympathetic tone and edema of congestive heart failure.Postischemic forearm flow and resistance were measured under fourconditions: room air breathing (RA); LBNP+RA; RA+LBNP+VC; and 100%O₂+LBNP+VC. LBNP and VC did notlower peak flow. However, O₂raised minimal resistance (2.3 ± 0.4 RA; 2.8 ± 0.5 O₂+LBNP+VC,P < 0.04). When O₂ alone(experiment 1) was compared withO₂+LBNP+VC(experiment 2), no effect of LBNP+VCon peak flow or minimum resistance was noted, although the return rateof flow and resistance toward baseline was increased.O₂ reduces peak forearm flow evenin the presence of LBNP and VC.

     

A model for phosphocreatine resynthesis

Nevill, Alan M., David A. Jones, David McIntyre, Gregory C. Bogdanis, and Mary E. Nevill. A model forphosphocreatine resynthesis. J. Appl.Physiol. 82(1): 329-335, 1997.A model for phosphocreatine (PCr) resynthesis is proposed based on a simple electric circuit, where the PCr store in muscle is likened to thestored charge on the capacitor. The solution to the second-order differential equation that describes the potential around the circuitsuggests the model for PCr resynthesis is given byPCr(t) = R  [d₁ ^· exp(k₁ ^· t) ± d₂ ^· exp(k₂ ^· t)],where R is PCr concentration at rest,d₁,d₂, k₁, andk₂ are constants, andt is time. By using nonlinear leastsquares regression, this double-exponential model was shown to fit thePCr recovery data taken from two studies involving maximal exerciseaccurately. In study 1, when themuscle was electrically stimulated while occluded, PCr concentrations rose during the recovery phase to a level above that observed at rest.In study 2, after intensive dynamicexercise, PCr recovered monotonically to resting concentrations. Thesecond exponential term in the double-exponential model was found tomake a significant additional contribution to the quality of fit inboth study 1 (P < 0.05) andstudy 2 (P < 0.01).

     

Effects of N2O narcosis on breathing and effort sensations during exercise and inspiratory resistive loading

Fothergill, D. M., and N. A. Carlson. Effects ofN₂O narcosis on breathing andeffort sensations during exercise and inspiratory resistive loading.J. Appl. Physiol. 81(4):1562-1571, 1996.The influence of nitrous oxide(N₂O) narcosis on the responses toexercise and inspiratory resistive loading was studied in thirteen maleUS Navy divers. Each diver performed an incremental bicycle exercisetest at 1 ATA to volitional exhaustion while breathing a 23%N₂O gas mixture and a nonnarcoticgas of the same PO₂, density, andviscosity. The same gas mixtures were used during four subsequent30-min steady-state submaximal exercise trials in which the subjectsbreathed the mixtures both with and without an inspiratory resistance(5.5 vs. 1.1 cmH₂O ^· s ^· l¹at 1 l/s). Throughout each test, subjective ratings of respiratory effort (RE), leg exertion, and narcosis were obtained with acategory-ratio scale. The level of narcosis was rated between slightand moderate for the N₂O mixturebut showed great individual variation. Perceived leg exertion and thetime to exhaustion were not significantly different with the twobreathing mixtures. Heart rate was unaffected by the gas mixture andinspiratory resistance at rest and during steady-state exercise but wassignificantly lower with the N₂O mixture during incremental exercise (P < 0.05). Despite significant increases in inspiratory occlusionpressure (13%; P < 0.05),esophageal pressure (12%; P < 0.001), expired minute ventilation (4%;P < 0.01), and the work rate ofbreathing (15%; P < 0.001) when the subjects breathed the N₂O mixture,RE during both steady-state and incremental exercise was 25% lowerwith the narcotic gas than with the nonnarcotic mixture(P < 0.05). We conclude that the narcotic-mediated changes in ventilation, heart rate, and RE induced by23% N₂O are not of sufficientmagnitude to influence exercise tolerance at surface pressure.Furthermore, the load-compensating respiratory reflexes responsible formaintaining ventilation during resistive breathing are not depressed byN₂O narcosis.

     

Neuronal swelling and surface area regulation: elevated intracellular calcium is not a requirement

Neurons aremechanically robust. During prolonged swelling, molluscan neurons cantriple their apparent membrane area. They gain surface area andcapacitance independent of extracellular Ca concentration([Ca]_e), but it isunknown if an increase in intracellular Ca concentration([Ca]_i) isnecessary. If Ca for stimulating exocytosis is unnecessary, it ispossible that swelling-induced membrane tension changes directlytrigger surface area readjustments. If, however, Ca-mediated but nottension-mediated membrane recruitment is responsible for surface areaincreases, swelling neurons should sustain elevated levels of[Ca]_i. The purpose ofthis investigation is to determine if the[Ca]_i in swellingneurons attains levels high enough to promote exocytosis and if anysuch increase is required. Lymnaeaneurons were loaded with the Ca concentration indicator fura 2. Calibration was performed in situ using 4-bromo-A-23187 and Ca-ethyleneglycol-bis(-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), with free Ca concentration ranging from 0 to 5 µM. Swelling perturbations (medium osmolarity reduced to 25% for 5 min)were done at either a standard[Ca]_e or very low[Ca]_e level (0.9 mM or0.13 µM, respectively). In neither case did the[Ca]_i increase tolevels that drive exocytosis. We also monitored osmomechanically drivenmembrane dynamics [swelling, then formation and reversal ofvacuole-like dilations (VLDs)] with the[Ca]_i clamped below 40 nM via1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). [Ca]_idid not change with swelling, and VLD behavior was unaffected,consistent with tension-driven,[Ca]_i-independent surface area adjustments. In addition, neurons with[Ca]_i clamped at 0.1 µM via an ionophore could produce VLDs. We conclude that, undermechanical stress, neuronal membranes are compliant by virtue ofsurface area regulatory adjustments that operate independent of[Ca]_i. The findingssupport the hypothesis that plasma membrane area is regulated in partby membrane tension.

     

Nucleus raphe obscurus modulates hypoglossal output of neonatal rat in vitro transverse brain stem slices

Nucleus raphéobscurus (NRo) modulates hypoglossal (XII) nerve motor output in the invitro transverse brain stem slice of neonatal rats (1-5 days old);chemical ablation of NRo and its focal CO₂ acidificationmodulated the bursting rhythm of XII nerves. We microinjected a 4.5 mMsolution of kainic acid into the NRo to disrupt cellular activity andobserved that XII nerve activity was temporarily abolished(n = 10). We also microinjected CO₂-acidified (pH = 6.00 ± 0.01) artificialcerebrospinal fluid (aCSF) into the NRo (n = 6), thepre-Bötzinger complex (PBC) (n = 6), as well as acontrol region in the lateral tegmental field equidistant to NRo, PBC,and the XII motor nuclei (n = 12). CO₂acidification of the control region had no effect on XII motor output.CO₂ acidification of the NRo significantly(P < 0.05) increased the burst discharge frequency ofXII nerves by 77%; integrated burst amplitude and burst durationincreased by 64% and 52%, respectively. CO₂ acidificationof the PBC significantly (P < 0.05) increased theburst discharge frequency of XII nerves by 65%, but neither integratedburst amplitude nor burst duration changed. These results demonstratethat chemical ablation of the NRo can abolish XII nerve bursting rhythmand that stimulation of the NRo with CO₂-acidified aCSF canexcite XII nerve bursting activity. From these observations, weconclude that, in transverse brain stem slices, the NRo containspH/CO₂-sensitive cells that modulate XII motor output.