Hyperventilation-induced airway injury and vascular leakage in dogs: effects of alpha 1-adrenergic agonists

Freed, Arthur N., Varsha Taskar, Brian Schofield, andChiharu Omori. Hyperventilation-induced airway injury and vascular leakage in dogs: effects of₁-adrenergic agonists.J. Appl. Physiol. 83(6):1884-1889, 1997.₁-Adrenergic agonistsinhibit hyperventilation-induced bronchoconstriction (HIB) in dogs. Wetested the hypothesis that -agonists inhibit HIB byreducing bronchovascular leakage and edema that theoretically couldcause airway obstruction. Peripheral airways were isolated by using abronchoscope; pretreated with either methoxamine (Mx), norepinephrine(NE), or saline aerosol; and then exposed to a 2,000 ml/min dry-airchallenge (DAC) for 2 min. Colloidal carbon was injected before DAC andused to quantify bronchovascular permeability. Mx-, NE-, andvehicle-treated airways were prepared for morphometric analysis within1 h after DAC. Light microscopy revealed that the 2-min DAC producedminimal bronchovascular leakage and little epithelial damage. However, pretreatment with either Mx or NE significantly enhanced dryair-induced bronchovascular hyperpermeability and mucosal injury. Theincreased damage associated with these₁-agonists implicates aprotective role for the bronchial circulation. The factthat ₁-agonists inhibit HIBsuggests that neither dry air-induced leakage nor injury directlycontributes to the development of airway obstruction. In addition,our data suggest that-agonists attenuate HIB in part byaugmenting hyperventilation-induced bronchovascular leakage and byreplacing airway water lost during a DAC.

     

Reduction of allergic airway responses in P-selectin-deficient mice

De Sanctis, George T., Walter W. Wolyniec, Francis H. Y. Green, Shixin Qin, Aiping Jiao, Patricia W. Finn, Thomas Noonan, Anthony A. Joetham, Erwin Gelfand, Claire M. Doerschuk, and Jeffrey M. Drazen. Reduction of allergic airway responses inP-selectin-deficient mice. J. Appl.Physiol. 83(3): 681-687, 1997.P-selectin is an adhesion receptor that has been shown to be important in therecruitment of eosinophils and lymphocytes in a variety of inflammatoryconditions. Because cellular recruitment is thought to be a criticalevent in allergen-induced changes in airway responsiveness, we reasoned that P-selectin-deficient mice would exhibit reduced airwayresponsiveness and cellular trafficking noted in wild-type (+/+) mice.Both (+/+) and P-selectin-deficient (/) micesensitized and challenged with ovalbumin (OVA/OVA) exhibited thesame capacity to produce increased titers of total and OVA-specificimmunoglobulin E. Airway responsiveness to methacholine wassignificantly greater in the (+/+) (OVA/OVA) animals than it was in therespective (/) (OVA/OVA) group or control groups(P = 0.0016). Bronchoalveolarlavage fluid from (/) (OVA/OVA) mice contained significantlyfewer eosinophils and lymphocytes compared with the (+/+) (OVA/OVA)mice (P < 0.05). These resultssuggest that the predominant role of P-selectin in OVA-inducedairway hyperresponsiveness is to promote the airway inflammatoryresponse to allergen inhalation.

     

Supraglottic airway pressure-flow relationships during oronasal airflow partitioning in dogs

Amis, T. C., N. O'Neill, T. Van der Touw, A. Tully, and A. Brancatisano. Supraglottic airway pressure-flow relationships during oronasal airflow partitioning in dogs. J. Appl.Physiol. 81(5): 1958-1964, 1996.We studiedpressure-flow relationships in the supraglottic airway of eight pronemouth-open anesthetized (intravenous chloralose or pentobarbitalsodium) crossbred dogs (weight 15-26 kg) during increasingrespiratory drive (CO₂administration; n = 4) and duringgraded-voltage electrical stimulation (SV;n = 4) of the soft palate muscles.During increased respiratory drive, inspiratory airflow occurred viaboth the nose (n) and mouth(m), with the ratio of n tom[%(n/m)]decreasing maximally from 16.0 ± 7.0 (SD) to 2.4 ± 1.6%(P < 0.05). Simultaneously, oralairway resistance at peak inspiratory flow decreased from 2.1 ± 1.0 to 0.4 ± 0.4 cmH₂O(P < 0.05), whereas nasal airway resistance did not change (14.4 ± 7.2 to 13.1 ± 5.4 cmH₂O;P = 0.29). Inspiratory pressure-flowplots of the oral airway were inversely curvilinear or more complex innature. Nasal pathway plots, however, demonstrated a positive linearrelationship in all animals (r = 0.87 ± 0.11; all P < 0.001). Duringelectrical stimulation of soft palate muscle contraction accompanied bygraded constant-inspiratory airflows of 45-385 ml/s through anisolated upper airway, %(n/m)decreased from 69 ± 50 to 10 ± 13% at a SV of 84 ± 3% ofmaximal SV (P < 0.001). At a SV of85 ± 1% of maximum, normalized oral airway resistance (expressedas percent baseline) fell to 5 ± 3%, whereas normalized nasalresistance was 80 ± 9% (both P < 0.03). Thus control of oronasal airflow partitioning in dogsappears mediated more by alterations in oral route geometry than byclosure of the nasopharyngeal airway.

     

Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. II. Morphometric analysis

Welty-Wolf, Karen E., Steven G. Simonson, Yuh-Chin T. Huang,Stephen P. Kantrow, Martha S. Carraway, Ling-Yi Chang, James D. Crapo, and Claude A. Piantadosi. Aerosolizedmanganese SOD decreases hyperoxic pulmonary injury in primates. II.Morphometric analysis. J. Appl.Physiol. 83(2): 559-568, 1997.Hyperoxia damages lung parenchyma via increased cellular production of reactive oxygenspecies that exceeds antioxidant defenses. We hypothesized thataerosolized human recombinant manganese superoxide dismutase (rhMnSOD)would augment extracellular antioxidant defenses and attenuateepithelial injury in the lung during hyperoxia in primates. Twenty-fouradult male baboons were anesthetized and mechanically ventilated with100% oxygen for 96 h. The baboons were divided equally into fourgroups. Oxygen alone and oxygen plus rhMnSOD given at 3 mg · kg¹ · day¹were compared to assess efficacy of the drug. Subsequently, aerosolized rhMnSOD was given at 1 or 10 mg · kg¹ · day¹to study dose effects and toxicity. Quantitative morphometry showedprotection of alveolar epithelium from hyperoxia by 3 mg · kg¹ · day¹rhMnSOD (P < 0.05). In addition,interstitial fibroblast volumes were increased in the treatment group(P = 0.06). This effect appearedgreater at the two higher doses of the rhMnSOD. The aerosolized drugwas localized to the surface of airways and air spaces and macrophagesby immunolabeling studies, suggesting efficacy via physicochemicalproperties that localize it to cell surfaces or by effects on alveolarmacrophage function.

     

Effect of alae nasi activation on maximal nasal inspiratory airflow in humans

The upper airway is a complicatedstructure that is usually widely patent during inspiration. However, oninspiration during certain physiological and pathophysiological states,the nares, pharynx, and larynx may collapse. Collapse at theselocations occurs when the transmural pressure (Ptm) at a flow-limitingsite (FLS) falls below a critical level (Ptm'). On airwaycollapse, inspiratory airflow is limited to a maximal level(I_max)determined by (Ptm')/Rus, where Rus is the resistanceupstream to the FLS. The airflow dynamics of the upper airway areaffected by the activity of its associated muscles. In this study, weexamine the modulation ofI_maxby muscle activity in the nasal airway under conditions of inspiratoryairflow limitation. Each of six subjects performed sniffs through onepatent nostril (pretreated with an alpha agonist) while flaring thenostril at varying levels of dilator muscle (alae nasi) EMG activity(EMGan). For each sniff, we located the nasal FLS with an airwaycatheter and determinedI_max,Ptm', and Rus. Activation of the alae nasi from the lowest to thehighest values of EMGan increasedI_maxfrom 422 ± 156 to 753 ± 291 ml/s (P < 0.01) and decreasedPtm' from 3.6 ± 3.0 to 6.0 ± 4.7 cmH₂O (P < 0.05). Activation of the alaenasi had no consistent effect on Rus.I_maxwas positively correlated with EMGan, and Ptm' was negativelycorrelated with EMGan in all subjects. Our findings demonstrate thatalae nasi activation increasesI_maxthrough the nasal airway by decreasing airway collapsibility.

     

Airway smooth muscle orientation in intraparenchymal airways

Lei, M., H. Ghezzo, M. F. Chen, and D. H. Eidelman.Airway smooth muscle orientation in intraparenchymal airways.J. Appl. Physiol. 82(1): 70-77, 1997.Airway smooth muscle (ASM) shortening is the central eventleading to bronchoconstriction. The degree to which airway narrowingoccurs as a consequence of shortening is a function of both themechanical properties of the airway wall as well as the orientation ofthe muscle fibers. Although the latter is theoretically important, ithas not been systematically measured to date. The purpose of this studywas to determine the angle of orientation of ASM () in normal lungs by using a morphometric approach. We analyzed the airway tree of theleft lower lobes of four cats and one human. All material was fixedwith 10% buffered Formalin at a pressure of 25 cmH₂O for 48 h. The fixed materialwas dissected along the airway tree to permit isolation ofgenerations 4-18 in the cats andgenerations 5-22 in the humanspecimen. Each airway generation was individually embedded in paraffin.Five-micrometer-thick serial sections were cut parallel to the airwaylong axis and stained with hematoxylin-phloxine-saffron. Each blockyielded three to five sections containing ASM. To determine , wemeasured the orientation of ASM nuclei relative to the transverse axisof the airway by using a digitizing tablet and a light microscope (×250) equipped with a drawing tube attachment. Inspection of thesections revealed extensive ASM crisscrossing without a homogeneous orientation. The  was clustered between 20° and 20°in all airway generations and did not vary much between generations inany of the cats or in the human specimen. When  was expressedwithout regard to sign, the mean values were 13.2° in the cats and13.1° in the human. This magnitude of obliquity is not likely toresult in physiologically important changes in airway length duringbronchoconstriction.

     

Mechanical and metabolic determination of VO2 and fatigue during repetitive isometric contractions in situ

Repetitiveisometric tetanic contractions (1/s) of the caninegastrocnemius-plantaris muscle were studied either at optimal length(L_o) or shortlength (L_s;~0.9 · L_o),to determine the effects of initial length on mechanical and metabolicperformance in situ. Respective averages of mechanical and metabolicvariables were(L_o vs.L_s, allP < 0.05) passive tension (preload) = 55 vs. 6 g/g, maximal active tetanic tension(P_o) = 544 vs. 174 (0.38 · P_o)g/g, maximal blood flow () = 2.0 vs. 1.4 ml · min¹ · g¹,and maximal oxygen uptake(O₂) = 12 vs. 9 µmol · min¹ · g¹.Tension at L_odecreased to0.64 · P_o over20 min of repetitive contractions, demonstrating fatigue; there were nosignificant changes in tension atL_s. In separatemuscles contracting atL_o, was set to that measured atL_s (1.1 ml · min¹ · g¹),resulting in decreased O₂(7 µmol · min¹ · g¹),and rapid fatigue, to0.44 · P_o. Thesedata demonstrate that 1)muscles at L_ohave higher andO₂ values than those at L_s;2) fatigue occurs atL_o with highO₂, adjusting metabolic demand (tension output) to match supply; and3) the lack of fatigue atL_s with lowertension, , andO₂ suggestsadequate matching of metabolic demand, set low by shortmuscle length, with supply optimized by low preload. Thesedifferences in tension andO₂ betweenL_o andL_s groupsindicate that muscles contracting isometrically at initial lengthsshorter than L_oare working under submaximal conditions.

     

Determination of production of nitric oxide by lower airways of humans---theory

Hyde, Richard W., Edgar J. Geigel, Albert J. Olszowka, JohnA. Krasney, Robert E. Forster II, Mark J. Utell, and Mark W. Frampton.Determination of production of nitric oxide by the lower airwaysof humanstheory. J. Appl. Physiol.82(4): 1290-1296, 1997.Exercise and inflammatory lung disorderssuch as asthma and acute lung injury increase exhaled nitric oxide(NO). This finding is interpreted as a rise in production of NO by thelungs (NO)but fails to take into account the diffusing capacity for NO(DNO) that carries NO into thepulmonary capillary blood. We have derived equations to measureNO from thefollowing rates, which determine NO tension in the lungs(PL) at any moment from 1) production(NO);2) diffusion, whereDNO(PL) = rate of removal by lung capillary blood; and3) ventilation, whereA(PL)/(PB  47) = the rate of NO removal by alveolar ventilation(A) and PB is barometric pressure. During open-circuit breathingwhen PL is not in equilibrium,d/dtPL[V_L/(PB  47)] (where V_L is volumeof NO in the lower airways) = NO  DNO(PL)  A(PL)/(PB  47). When PL reaches asteady state so that d/dt = 0 andA iseliminated by rebreathing or breath holding, then PL = NO/DNO.PL can be interpreted as NOproduction per unit of DNO. Thisequation predicts that diseases that diminishDNO but do not alterNO willincrease expired NO levels. These equations permit precise measurementsof NO thatcan be applied to determining factors controlling NO production by thelungs.

     

Aerosolized manganese SOD decreases hyperoxic pulmonary injury in primates. I.Physiology and biochemistry

Simonson, Steven G., Karen E. Welty-Wolf, Yuh-Chin T. Huang,David E. Taylor, Stephen P. Kantrow, Martha S. Carraway, James D. Crapo, and Claude A. Piantadosi. Aerosolizedmanganese SOD decreases hyperoxic pulmonary injury in primates. I. Physiology and biochemistry. J. Appl.Physiol. 83(2): 550-558, 1997.Prolonged hyperoxia causes lung injury andrespiratory failure secondary to oxidative tissue damage mediated, inpart, by the superoxide anion. We hypothesized that aerosol treatmentwith recombinant human manganese superoxide dismutase (rhMnSOD) wouldattenuate hyperoxic lung damage in primates. Adult baboons wereanesthetized and ventilated with 100% oxygen for 96 h or until death.Six animals were treated with aerosolized rhMnSOD (3 mg · kg¹ · day¹in divided doses), and six control animals did not receive enzyme therapy. Physiological variables were recorded every 12 h, and ventilation-perfusion ratio relationships were evaluated by using themultiple inert-gas elimination technique. After the experiments, surfactant composition and lung edema were measured. We found thatrhMnSOD significantly decreased pulmonary shunt fraction (P < 0.01) and preserved arterialoxygenation (P < 0.01) during hyperoxia. The rhMnSOD increased lung phospholipids,phosphatidylcholine and disaturated phosphatidylcholine, and decreasedlung edema in this model. Testing of higher and lower doses of MnSOD (1 and 10 mg · kg¹ · day¹)in two other groups of baboons produced variable physiological protection, suggesting a "window" of effective dosage. Weconclude that aerosolized MnSOD (3 mg · kg¹ · day¹)affords significant preservation of pulmonary gas exchange during hyperoxic lung injury.

     

Effects of dopamine and domperidone on ventilatory sensitivity to hypoxia after 8h of isocapnic hypoxia

Acclimatization to altitude involves an increase in the acutehypoxic ventilatory response (AHVR). Because low-dose dopamine decreases AHVR and domperidone increases AHVR, the increase in AHVR ataltitude may be generated by a decrease in peripheral dopaminergicactivity. The AHVR of nine subjects was determined with and without aprior period of 8 h of isocapnic hypoxia under each of threepharmacological conditions: 1)control, with no drug administered;2) dopamine (3 µg · min¹ · kg¹);and 3) domperidone (Motilin, 40 mg).AHVR increased after hypoxia (P  0.001). Dopaminedecreased (P  0.01), and domperidone increased (P  0.005) AHVR. The effect of both drugs on AHVR appearedlarger after hypoxia, an observation supported by a significantinteraction between prior hypoxia and drug in the analysis of variance(P  0.05). Although the increasedeffect of domperidone after hypoxia of 0.40 l · min¹ · %saturation¹[95% confidence interval (CI) 0.11 to 0.92 l · min¹ · %¹]did not reach significance, the lower limit for this confidence interval suggests that little of the increase in AHVR after sustained hypoxia was brought about by a decrease in peripheral dopaminergic inhibition.

     

Diffusional permeability of rabbit mesothelium

Diffusional permeability (P) to sucrose(P_suc) andNa⁺(P_Na⁺)was determined in specimens of rabbit sternal parietal pericardium,which may be obtained without stripping. Specimens were mounted in anUssing apparatus with ³H-labeledsucrose and²²Na⁺in a luminal (L) or interstitial (I) chamber.P_suc was 2.16 ± 0.44 for LI and 2.63 ± 0.45 (SE) × 10⁵ cm/s for IL,i.e., ~10 times smaller than that previously obtained in strippedspecimens of pleura despite the similarity of intercellular junctionsin pericardium and pleural mesothelium of various species. Thesefindings suggest that previousP_suc wasoverestimated because stripping damages the mesothelium.P_Na⁺ (×10⁵ cm/s) was 7.07 ± 0.71 for LI and 7.37 ± 0.69 × 10⁵ cm/s for IL.Measurements were also done with phospholipids, which are adsorbed onthe luminal side of mesothelium in vivo. With phospholipids in L,P_suc was 0.75 ± 0.10 and 0.65 ± 0.08 andP_Na⁺was 3.80 ± 0.32 and 3.76 ± 0.15 × 10⁵ cm/s for LI andIL, respectively, i.e., smaller than without phospholipids.With phospholipids in I (where they are not adsorbed), P_suc (2.33 ± 0.42 × 10⁵ cm/s) andP_Na⁺(7.01 ± 0.45 × 10⁵ cm/s) were similar tothose values without phospholipids. Hence, adsorbed phospholipidsdecrease P of mesothelium. If themesothelium were scraped away from the specimen,P_suc of theconnective tissue would be 13.2 ± 0.76 × 10⁵ cm/s.P_suc of themesothelium, computed fromP_suc of theunscraped and scraped specimens, corrected for the effect of unstirredlayers (2.54 and 19.4 × 10⁵ cm/s, respectively),was 2.92 and 0.74 × 10⁵ cm/s without and withphospholipids, respectively. Hence, most of the resistance to diffusionof the pericardium is provided by the mesothelium.

     

Ventilatory response to exercise in diabetic subjects with autonomic neuropathy

Tantucci, C., P. Bottini, M. L. Dottorini, E. Puxeddu, G. Casucci, L. Scionti, and C. A. Sorbini. Ventilatory response toexercise in diabetic subjects with autonomic neuropathy.J. Appl. Physiol. 81(5):1978-1986, 1996.We have used diabetic autonomic neuropathy as amodel of chronic pulmonary denervation to study the ventilatoryresponse to incremental exercise in 20 diabetic subjects, 10 with(Dan+) and 10 without (Dan) autonomic dysfunction, and in 10 normal control subjects. Although both Dan+ and Dan subjectsachieved lower O₂ consumption andCO₂ production(CO₂) thancontrol subjects at peak of exercise, they attained similar values ofeither minute ventilation(E) oradjusted ventilation (E/maximalvoluntary ventilation). The increment of respiratory rate withincreasing adjusted ventilation was much higher in Dan+ than inDan and control subjects (P < 0.05). The slope of the linearE/CO₂relationship was 0.032 ± 0.002, 0.027 ± 0.001 (P < 0.05), and 0.025 ± 0.001 (P < 0.001) ml/min inDan+, Dan, and control subjects, respectively. Bothneuromuscular and ventilatory outputs in relation to increasingCO₂ were progressivelyhigher in Dan+ than in Dan and control subjects. At peak ofexercise, end-tidal PCO₂ was muchlower in Dan+ (35.9 ± 1.6 Torr) than in Dan (42.1 ± 1.7 Torr; P < 0.02) and control (42.1 ± 0.9 Torr; P < 0.005) subjects.We conclude that pulmonary autonomic denervation affects ventilatoryresponse to stressful exercise by excessively increasing respiratoryrate and alveolar ventilation. Reduced neural inhibitory modulationfrom sympathetic pulmonary afferents and/or increasedchemosensitivity may be responsible for the higher inspiratoryoutput.

     

Greater rate of decline in maximal aerobic capacity with age in physically active vs. sedentary healthy women

Tanaka, Hirofumi, Christopher A. DeSouza, Pamela P. Jones,Edith T. Stevenson, Kevin P. Davy, and Douglas R. Seals. Greater rate of decline in maximal aerobic capacity with age in physically active vs. sedentary healthy women. J. Appl.Physiol. 83(6): 1947-1953, 1997.Using ameta-analytic approach, we recently reported that the rate of declinein maximal oxygen uptake(O_{2 max}) with age inhealthy women is greatest in the most physically active and smallest inthe least active when expressed in milliliters per kilogram per minuteper decade. We tested this hypothesis prospectively underwell-controlled laboratory conditions by studying 156 healthy, nonobesewomen (age 20-75 yr): 84 endurance-trained runners (ET) and 72 sedentary subjects (S). ET were matched across the age range forage-adjusted 10-km running performance. Body mass was positivelyrelated with age in S but not in ET. Fat-free mass was not differentwith age in ET or S. Maximal respiratory exchange ratio and rating ofperceived exertion were similar across age in ET and S, suggestingequivalent voluntary maximal efforts. There was a significant butmodest decline in running mileage, frequency, and speed with advancingage in ET.O_{2 max}(ml · kg¹ · min¹)was inversely related to age (P < 0.001) in ET (r = 0.82) and S(r = 0.71) and was higher atany age in ET. Consistent with our meta-analysic findings,the absolute rate of decline inO_{2 max} was greater inET (5.7ml · kg¹ · min¹ · decade¹)compared with S (3.2 ml · kg¹ · min¹ · decade¹;P < 0.01), but the relative (%)rate of decline was similar (9.7 vs 9.1%/decade; notsignificant). The greater absolute rate of decline inO_{2 max} in ET comparedwith S was not associated with a greater rate of decline in maximalheart rate (5.6 vs. 6.2beats · min¹ · decade¹),nor was it related to training factors. The present cross-sectional findings provide additional evidence that the absolute, but not therelative, rate of decline in maximal aerobic capacity with age may begreater in highly physically active women compared with theirsedentary healthy peers. This difference does not appear to be relatedto age-associated changes in maximal heart rate, bodycomposition, or training factors.

     

Chest wall mechanics in sustained microgravity

We assessed theeffects of sustained weightlessness on chest wall mechanics in fiveastronauts who were studied before, during, and after the 10-daySpacelab D-2 mission (n = 3)and the 180-day Euromir-95 mission (n = 2). We measured flow and pressure at the mouth and rib cage andabdominal volumes during resting breathing and during a relaxationmaneuver from midinspiratory capacity to functional residual capacity.Microgravity produced marked and consistent changes () in thecontribution of the abdomen to tidal volume [Vab/(Vab + Vrc), where Vab is abdominal volume and Vrc is rib cagevolume], which increased from 30.7 ± 3.5 (SE)% at1 G head-to-foot acceleration to 58.3 ± 5.7% at 0 G head-to-foot acceleration (P < 0.005). Values ofVab/(Vab + Vrc) did not change significantly during the 180 days of the Euromir mission, but in the two subjects Vab/(Vab + Vrc) was greater on postflight day1 than on subsequent postflight days or preflight. Inthe two subjects who produced satisfactory relaxation maneuvers, the slope of the Konno-Mead plot decreased in microgravity; this decrease was entirely accounted for by an increase in abdominal compliance because rib cage compliance did not change. These alterations aresimilar to those previously reported during short periods ofweightlessness inside aircrafts flying parabolic trajectories. They arealso qualitatively similar to those observed on going from upright tosupine posture; however, in contrast to microgravity, such posturalchange reduces rib cage compliance.

     

Respiratory muscle work compromises leg blood flow during maximal exercise

Harms, Craig A., Mark A. Babcock, Steven R. McClaran, DavidF. Pegelow, Glenn A. Nickele, William B. Nelson, and Jerome A. Dempsey.Respiratory muscle work compromises leg blood flow during maximalexercise. J. Appl. Physiol.82(5): 1573-1583, 1997.We hypothesized that duringexercise at maximal O₂ consumption (O_{2 max}),high demand for respiratory muscle blood flow() would elicit locomotor muscle vasoconstrictionand compromise limb . Seven male cyclists(O_{2 max} 64 ± 6 ml · kg¹ · min¹)each completed 14 exercise bouts of 2.5-min duration atO_{2 max} on a cycleergometer during two testing sessions. Inspiratory muscle work waseither 1) reduced via aproportional-assist ventilator, 2)increased via graded resistive loads, or3) was not manipulated (control).Arterial (brachial) and venous (femoral) blood samples, arterial bloodpressure, leg (legs;thermodilution), esophageal pressure, andO₂ consumption(O₂) weremeasured. Within each subject and across all subjects, at constantmaximal work rate, significant correlations existed(r = 0.74-0.90;P < 0.05) between work of breathing(Wb) and legs (inverse), leg vascular resistance (LVR), and leg O₂(O_{2 legs};inverse), and between LVR and norepinephrine spillover. Mean arterialpressure did not change with changes in Wb nor did tidal volume orminute ventilation. For a ±50% change from control in Wb,legs changed 2 l/min or 11% of control, LVRchanged 13% of control, and O₂extraction did not change; thusO_{2 legs}changed 0.4 l/min or 10% of control. TotalO_{2 max} was unchangedwith loading but fell 9.3% with unloading; thusO_{2 legs}as a percentage of totalO_{2 max} was 81% incontrol, increased to 89% with respiratory muscle unloading, anddecreased to 71% with respiratory muscle loading. We conclude that Wbnormally incurred during maximal exercise causes vasoconstriction inlocomotor muscles and compromises locomotor muscle perfusion andO₂.

     

Scaling of submaximal oxygen uptake with body mass and combined mass during uphill treadmill bicycling

This study examined the scaling relationships ofnet O₂ uptake [O_2(net) = O₂  restingO₂] to body mass(M_B) andcombined mass (M_C = M_B + bicycle)during uphill treadmill bicycling. It was hypothesized thatO_2(net)(l/min) would scale proportionally withM_C [i.e.,O_2(net)  M^1.0_C] and less than proportionally withM_B [i.e.,O_2(net)  M_B].Twenty-five competitive cyclists [73.9 ± 8.8 and 85.0 ± 9.0 (SD) kg forM_B andM_C,respectively] rode their bicycles on a treadmill at 3.46 m/s andgrades of 1.7, 3.5, 5.2, and 7.0% whileO₂ was measured. Multiplelog-linear regression procedures were applied to the pooledO_2(net)data to determine the exponents forM_C andM_B afterstatistically controlling for differences in treadmill grade anddynamic friction. The regression models were highly significant (R² = 0.95, P < 0.001). Exponents forM_C (0.99, 95%confidence interval = 0.80-1.18) andM_B (0.89, 95%confidence interval = 0.72-1.07) did not differ significantly fromeach other or 1.0. It was concluded that the 0.99 M_C exponent wasdue to gravitational resistance, whereas theM_B exponent was<1.0 because the bicycles were relatively lighter for heaviercyclists.

     

Effect of cardiogenic and noncardiogenic pulmonary edema on histamine responsiveness in sheep

We compared the effects of cardiogenic pulmonaryedema, brief pulmonary vascular congestion without frank edema, andnoncardiogenic pulmonary edema on responsiveness to inhaled histaminein chronically instrumented awake sheep. Histamine responsiveness wasmeasured before and after 1)cardiogenic pulmonary edema induced by raising left atrial pressure to35 cmH₂O(Pla) for 3.5 h by partial obstruction of flowacross the mitral valve, 2) briefcardiogenic congestion via Pla for 0.5 h,3) noncardiogenic pulmonary edemainduced by 25 mg/kg intravenous perilla ketone (PK), and4) 3.5 h of monitoring withoutPla or PK (controls). Treatment for 3.5 h with Pla(n = 9) and PK(n = 11) each significantly lessenedthe histamine dose required to cause a fall to 65% of baseline dynamiclung compliance (ED₆₅Cdyn), i.e.,increased responsiveness. Sheep treated for 0.5 h with Pla(n = 7) and controls(n = 5) showed no significant changein ED₆₅Cdyn. Intravenous atropine(0.1 mg/kg) before the second histamine challenge altered neither thereduction of ED₆₅Cdyn inPla (n = 8) and PK(n = 9) sheep nor theED₆₅Cdyn level of controls(n = 9). These data imply that thelocal effects of edema, rather than bronchial vascular hemodynamics,cholinergic reflexes, and permeability changes, are germane to lunghyperresponsiveness during pulmonary edema in sheep.

     

Reductions in visceral fat during weight loss and walking are associated with improvements in {V}O2 max

The accumulation ofvisceral fat is independently associated with an increased risk forcardiovascular disease. The aim of this study was to determine whetherthe loss of visceral adipose tissue area (VAT; computed tomography) isrelated to improvements in maximal O₂ uptake(O_2 max) during a weight loss(250-350 kcal/day deficit) and walking (3 days/wk, 30-40 min)intervention. Forty obese [body fat 47 ± 1 (SE) %], sedentary(O_2 max 19 ± 1 ml · kg¹ · min¹)postmenopausal women (age 62 ± 1 yr) participated in the study. The intervention resulted in significant declines in body weight (8%), total fat mass (dual-energy X-ray absorptiometry; 17%), VAT(17%), and subcutaneous adipose tissue area (17%) with no changein lean body mass (all P < 0.001). Women with anaverage 10% increase in O_2 max reducedVAT by an average of 20%, whereas those who did not increaseO_2 max decreased VAT by only 10%,despite comparable reductions in body fat, fat mass, and subcutaneousadipose tissue area. The decrease in VAT was independently related tothe change in O_2 max(r² = 0.22; P < 0.01) andfat mass (r² = 0.08; P = 0.05). These data indicate that greater improvements inO_2 max with weight loss and walking areassociated with greater reductions in visceral adiposity in obesepostmenopausal women.

     

Combined myofibrillar and mitochondrial creatine kinase deficiency impairs mouse diaphragm isotonic function

Watchko, Jon F., Monica J. Daood, Gary C. Sieck, John J. LaBella, Bill T. Ameredes, Alan P. Koretsky, and BeWieringa. Combined myofibrillar and mitochondrialcreatine kinase deficiency impairs mouse diaphragm isotonic function.J. Appl. Physiol. 82(5): 1416-1423, 1997.Creatine kinase (CK) is an enzyme central to cellular high-energy phosphate metabolism in muscle. To characterize the physiological role of CK in respiratory muscle during dynamic contractions, we compared the force-velocity relationships, power, andwork output characteristics of the diaphragm (Dia) from mice withcombined myofibrillar and sarcomeric mitochondrial CK deficiency (CK[/]) with CK-sufficient controls (Ctl).Maximum velocity of shortening was significantly lower inCK[/] Dia (14.1 ± 0.9 L_o/s,where L_o isoptimal fiber length) compared with Ctl Dia (17.5 ± 1.1 L_o/s)(P < 0.01). Maximum power wasobtained at 0.4-0.5 tetanic force in both groups; absolute maximumpower (2,293 ± 138 W/m²) andwork (201 ± 9 J/m²) werelower in CK[/] Dia compared with Ctl Dia(2,744 ± 146 W/m² and 284 ± 26 J/m², respectively)(P < 0.05). The ability ofCK[/] Dia to sustain shortening duringrepetitive isotonic activation (75 Hz, 330-ms duration repeated eachsecond at 0.4 tetanic force load) was markedly impaired, withCK[/] Dia power and work declining to zero by 37 ± 4 s, compared with 61 ± 5 s in Ctl Dia. We conclude that combined myofibrillar and sarcomeric mitochondrial CK deficiency profoundly impairs Dia power and work output, underscoring the functional importance of CK during dynamic contractions in skeletal muscle.

     

Pulmonary blood flow redistribution by increased gravitational force

This study was undertaken to assess theinfluence of gravity on the distribution of pulmonary blood flow (PBF)using increased inertial force as a perturbation. PBF was studied inunanesthetized swine exposed toG_x (dorsal-to-ventraldirection, prone position), where G is the magnitude of the force ofgravity at the surface of the Earth, on the Armstrong LaboratoryCentrifuge at Brooks Air Force Base. PBF was measured using 15-µmfluorescent microspheres, a method with markedly enhanced spatialresolution. Each animal was exposed randomly to 1, 2, and3 G_x. Pulmonary vascularpressures, cardiac output, heart rate, arterial blood gases, and PBFdistribution were measured at each G level. Heterogeneity of PBFdistribution as measured by the coefficient of variation of PBFdistribution increased from 0.38 ± 0.05 to 0.55 ± 0.11 to0.72 ± 0.16 at 1, 2, and 3G_x, respectively. At 1G_x, PBF was greatest in theventral and cranial and lowest in the dorsal and caudal regions of thelung. With increased G_x,this gradient was augmented in both directions. Extrapolation of thesevalues to 0 G predicts a slight dorsal (nondependent) region dominanceof PBF and a coefficient of variation of 0.22 in microgravity. Analysisof variance revealed that a fixed component (vascular structure)accounted for 81% and nonstructure components (including gravity)accounted for the remaining 19% of the PBF variance across the entireexperiment (all 3 gravitational levels). The results are inconsistentwith the predictions of the zone model.