Bronchial vasodilatory response to ionic and nonionic contrast media

Baile, Elisabeth M., Lu Wang, Lorraine Verburgt, and PeterD. Paré. Bronchial vasodilatory response to ionic andnonionic contrast media. J. Appl.Physiol. 82(3): 841-845, 1997.It has recentlybeen shown that bronchial arterial injection of conventional contrastmedium causes a significant increase in bronchial blood flow(br) and that this response is partially attenuatedafter infusion ofN-nitro-L-arginine(L-NNA). However, the precisemechanism for this increase in br is unknown. Inthis study we examined the effect of bronchial arterial injection ofconventional ionic as well as nonionic contrast media. We measuredbr in nine anesthetized, ventilated, open-chestsheep. br was recorded before (baseline) and at thepeak response to injection of 0.5 ml of either 0.9% saline (control;isosmolar with plasma), Omnipaque 300 (iohexol; nonionic), Conray 66 (sodium iothalamate; ionic), or 50% dextrose (viscouscontrol).

     

Endothelial cell dilatory pathways link flow and wall shear stress in an intact arteriolar network

Frame, Mary D. S., and Ingrid H. Sarelius. Endothelialcell dilatory pathways link flow and wall shear stress in an intactarteriolar network. J. Appl. Physiol.81(5): 2105-2114, 1996.Our purpose was to determine whether theendothelial cell-dependent dilatory pathways contribute to theregulation of flow distribution in an intact arteriolar network. Cellflow, wall shear stress (T),diameter, and bifurcation angle were determined for four sequentialbranches of a transverse arteriole in the superfused cremaster muscleof pentobaribtal sodium (Nembutal, 70 mg/kg)-anesthetized hamsters(n = 51). Control cell flow wassignificantly greater into upstream than into downstream branches[1,561 ± 315 vs. 971 ± 200 (SE) cells/s,n = 12]. Tissue exposure to 50 µMN-nitro-L-arginine + 50 µM indomethacin (L-NNA + Indo) produced arteriolar constriction of 14 ± 4% and decreasedflow into the transverse arteriole. More of the available cell flow wasdiverted to downstream branches, yet flow distribution remainedunequal. Control T was higherupstream than downstream (31.3 ± 6.8 vs. 9.8 ± 1.5 dyn/cm²).L-NNA + Indo decreasedT upstream and increasedT downstream to become equal inall branches, in contrast to flow. To determine whether constriction ingeneral induced the same changes, 5%O₂ (8 ± 4% constriction) or10⁹ M norepinephrine (NE;4 ± 3% constriction) was added to the tissue (n = 7). WithO₂, flow was redistributed tobecome equal into each branch. With NE, flow decreased progressivelymore into the first three branches. The changes in flow distributionwere thus predictable and dependent on the agonist. WithO₂ or NE, the spatial changes inflow were mirrored by spatial changes inT. Changes in diameter and incell flux were not related forL-NNA + Indo (r = 0.45),O₂(r = 0.07), or NE(r = 0.36). For all agonists, when thebifurcation angle increased, cell flow to the branch decreasedsignificantly, whereas if the angle decreased, flow was relativelypreserved; thus active changes in bifurcation angle may influence redcell distribution at arteriolar bifurcations. Thus, when theendothelial cell dilatory pathways were blocked, the changes in flowand in T were uncoupled; yet when they were intact, flowand T changed together.

     

Non-cAMP-mediated bronchial arterial vasodilation in response to inhaled beta -agonists

Carvalho, Paula, Shane R. Johnson, Nirmal B. Charan.Non-cAMP-mediated bronchial arterial vasodilation in response toinhaled -agonists. J. Appl.Physiol. 84(1): 215-221, 1998.We studied thedose-dependent effects of inhaled isoetharine HCl, a -adrenergicbronchodilator (2.5, 5.0, 10.0, and 20.0 mg), on bronchial blood flow(br) in anesthetized sheep. Isoetharine resulted ina dose-dependent increase in br. With atotal dose of 17.5 mg, br increased from baselinevalues of 22 ± 3.4 (SE) to 60 ± 16 ml/min(P < 0.001), an effect independentof changes in cardiac output and systemic arterial pressure. To furtherstudy whether synthesis of endogenous nitric oxide (NO) affects-agonist-induced increases in br, weadministered isoetharine (20 mg) by inhalation before and after theNO-synthase inhibitorN-nitro-L-argininemethyl ester (L-NAME).Intravenous L-NAME (30 mg/kg) rapidly decreased br by ~80% of baseline,whereas L-NAME via inhalation(10 mg/kg) resulted in a delayed and smaller (~22%) decrease.Pretreatment with L-NAME viaboth routes of administration attenuated bronchial arterialvasodilation after subsequent challenge with isoetharine. We concludethat isoetharine via inhalation increases br in adose-dependent manner and that -agonist-induced relaxation ofvascular smooth muscle in the bronchial vasculature is partiallymediated via synthesis of NO.

     

Endogenous nitric oxide decreases xanthine oxidase-mediated neutrophil adherence: role of P-selectin

Terada, Lance S., John E. Repine, Dale Piermattei, andBrooks M. Hybertson. Endogenous nitric oxide decreases xanthine oxidase-mediated neutrophil adherence: role of P-selectin.J. Appl. Physiol. 82(3): 913-917, 1997.The oxygen radical-producing enzyme xanthine oxidase (XO) canpromote neutrophil adherence to endothelium. Recognizing that a balanceoften exists in inflammatory processes, we sought to determine whetherXO initiates antiadherent pathways. We found that bovine pulmonaryarterial endothelial cells (EC) exposed to XO released increasedamounts of nitrite into the media, reflecting an increased productionof nitric oxide (NO). When EC were subjected to shear stress, treatmentwith XO and/or the NO synthase inhibitorN-nitro-L-arginine(L-NNA) increased neutrophilrolling behavior and firm neutrophil adherence to EC in an additivefashion. Both rolling and adherent interactions were abolished bymonoclonal antibodies directed against P-selectin. In addition,treatment of EC with XO and/orL-NNA increased both surfaceexpression of P-selectin and release of von Willebrand factor intomedia. Finally, treatment of EC with the NO donor sodium nitroprussidedecreased XO-mediated neutrophil rolling and adherence. We concludethat XO stimulates EC to produce NO and that NO decreases theP-selectin-dependent neutrophil adhesion initiated by XO. Suchincreases in endogenous NO may constitute an importantnegative-feedback response to the acute proadhesive effects of XO.

     

Fish oil and vitamin E supplementation in oxidative stress at rest and after physical exercise

Sen, Chandan K., Mustafa Atalay, Jyrki Ågren,David E. Laaksonen, Sashwati Roy, and Osmo Hänninen. Fishoil and vitamin E supplementation in oxidative stress at rest and afterphysical exercise. J. Appl. Physiol.83(1): 189-195, 1997.Fish oil supplementation and physicalexercise may induce oxidative stress. We tested the effects of 8 wk of-tocopherol (vitamin E) and fish oil (FO) supplementation on resting and exercise-induced oxidative stress. Rats(n = 80) were divided into groupssupplemented with FO, FO and vitamin E (FOVE), soy oil (SO), and SO andvitamin E (SOVE), and for FOVE and SOVE they were dividedinto corresponding exercise groups (FOVE-Ex and SOVE-Ex). Lipidperoxidation [thiobarbituric acid-reacting substances(TBARS)] was 33% higher in FO compared with SO in the liver, butoxidative protein damage (carbonyl levels) remained similar in bothliver and red gastrocnemius muscle (RG). Vitamin E supplementation,compared with FO and SO, markedly decreased liver and RG TBARS, butliver TBARS remained 32% higher in FOVE vs. SOVE. Vitamin E alsomarkedly decreased liver and RG protein carbonyl levels, althoughlevels in FOVE and SOVE were similar. Exercise increased liver and RGTBARS and RG protein carbonyl levels markedly, with similar levels inFOVE-Ex and SOVE-Ex. FO increased lipid peroxidation but not proteinoxidation in a tissue-specific manner. Vitamin E markedly decreasedlipid peroxidation and protein oxidation in both FOVE and SOVE,although liver lipid peroxidation remained higher in FOVE. Despitehigher levels of hepatic lipid peroxidation at rest in FOVE comparedwith SOVE, liver appeared to be relatively less susceptible toexercise-induced oxidative stress in FOVE.

     

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.

     

Effect of Nomega -nitro-L-arginine on ventilatory response to hypercapnia in anesthetized cats

Teppema, Luc, Aad Berkenbosch, and Cees Olievier Effectof N-nitro-L-arginine onventilatory response to hypercapnia in anesthetized cats.J. Appl. Physiol. 82(1): 292-297, 1997.The effect of intravenous administration of 40 mg/kgN-nitro-L-arginine(L-NNA), an inhibitor of thesynthesis of nitric oxide (NO), on the ventilatory response toCO₂ was studied in anesthetizedcats. The ventilatory response toCO₂ was assessed during normoxiaby applying square-wave changes in end-tidalPCO₂ of ~1 kPa. EachCO₂ response was separated into afast peripheral and slow central component characterized by aCO₂ sensitivity (S_pand S_c, respectively), time constant, time delay, and anoffset (apneic threshold). L-NNAreduced S_p,S_c, and the apneic threshold significantly by ~30%. However, the ratioS_p/S_cwas not changed. It is argued that the reduction inS_p andS_c,S_p/S_cremaining constant, may be due to a potent inhibitory action ofL-NNA on the brain stemrespiratory-integrating centers and on the neuromechanical link betweenthese centers and respiratory movements. It is concluded that NO playsan important role in the control of breathing.

     

Differential relaxant responses of pulmonary arteries and veins in lung explants of guinea pigs

Shi, Weibin, David H. Eidelman, and René P. Michel.Differential relaxant responses of pulmonary arteries and veins inlung explants of guinea pigs. J. Appl.Physiol. 83(5): 1476-1481, 1997.The endotheliumregulates vascular tone through release of relaxing or contractingfactors, with nitric oxide (NO) being a major endothelium-derivedrelaxing factor. In the present study, we used a lung explant techniqueto determine the differential abilities and mechanisms of pulmonaryarteries and veins of normal guinea pigs to relax after precontraction.Excised lungs of 15 guinea pigs were filled through the airways with1% agarose, cut into 1-mm-thick slices, and cultured overnight.Luminal areas of vascular cross sections were measured with animage-analysis system. Vessels were precontracted with U-46619, andresponses to histamine, acetylcholine (ACh), sodium nitroprusside, andpapaverine were examined. We also determined the effects ofN-nitro-L-arginineand of indomethacin on ACh-induced responses. We found that histaminerelaxed arteries more than veins and that ACh relaxed only arteries.N-nitro-L-arginine pretreatmentabolished ACh-induced relaxation of arteries and caused ACh-inducedcontraction of veins, whereas indomethacin markedly augmentedACh-induced relaxation of arteries (maximal relaxation: 48.5 ± 4.7 vs. 19.2 ± 5.1% without it) and induced a dose-dependentrelaxation of veins (maximal relaxation: 17.0 ± 4.1%). Sodiumnitroprusside induced a significantly greater relaxation of arteriesthan veins, whereas papaverine relaxed them equally. We conclude thatin guinea pigs endothelial NO-mediated relaxation is greater inpulmonary arteries than in veins and that ACh-induced NO-mediatedrelaxation is reduced by the simultaneous production ofcyclooxygenase-derived vasoconstrictors.

     

Nitric oxide and beta -adrenergic agonist-induced bronchial arterial vasodilation

Charan, Nirmal B., Shane R. Johnson, S. Lakshminarayan,William H. Thompson, and Paula Carvalho. Nitric oxide and-adrenergic agonist-induced bronchial arterial vasodilation.J. Appl. Physiol. 82(2): 686-692, 1997.In anesthetized sheep, we measured bronchial blood flow(br) by an ultrasonic flow probe to investigate the interaction between inhaled nitric oxide (NO; 100 parts/million) givenfor 5 min and 5 ml of aerosolized isoetharine (1.49 × 10² M concentration).NO and isoetharine increased br from 26.5 ± 6.5 to 39.1 (SE) ± 10.6 and 39.7 ± 10.7 ml/min,respectively (n = 5).Administration of NO immediately after isoetharine further increasedbr to 57.3 ± 15.1 ml/min. NO synthase inhibitorN-nitro-L-arginine methyl esterhydrochloride (L-NAME; 30 mg/kg, in 20 ml salinegiven iv) decreased br to 14.6 ± 2.6 ml/min. NO given three times alternately with isoetharine progressively increased br from 14.6 ± 2.6 to 74.3 ± 17.0 ml/min, suggesting that NO and isoetharine potentiatevasodilator effects of each other. In three other sheep, afterL-NAME, three sequential doses of isoetharine increased br from 10.2 ± 3.4 to11.5 ± 5.7, 11.7 ± 4.7, and 13.3 ± 5.7 ml/min,respectively, indicating that effects of isoetharine are predominantlymediated through synthesis of NO. When this was followed by threesequential administrations of NO, br increased by146, 172, and 185%, respectively. Thus in the bronchial circulationthere seems to be a close interaction between adenosine3,5-cyclic monophosphate- and guanosine3,5-cyclic monophosphate-mediated vasodilatation.

     

NO does not mediate inhibitory neural responses in sheep airway and bronchial vascular smooth muscle

Endogenous nitric oxide (NO) influences acetylcholine-inducedbronchovascular dilation in sheep and is a mediator of the airway smooth muscle inhibitory nonadrenergic, noncholinergic neural responsein several species. This study was designed to determine the importanceof NO as a neurally derived modulator of ovine airway and bronchialvascular smooth muscle. We measured the response of pulmonaryresistance (RL) and bronchialblood flow (br) to vagal stimulationin 14 anesthetized, ventilated, open-chest sheep duringthe following conditions: 1)control; 2) infusion of the -agonist phenylephrine to reduce baseline br bythe same amount as would be produced by infusion ofN-nitro-L-arginine(L-NNA), a NO synthaseinhibitor; 3) infusion ofL-NNA(10² M); and4) after administration of atropine(1.5 mg/kg). The results showed that vagal stimulation produced anincrease in RL andbr in periods 1, 2, and 3 (P < 0.01) that was not affected byL-NNA. Afteratropine was administered, there was no increase inbr or RL. Invitro experiments on trachealis smooth muscle contracted with carbachol showed no effect ofL-NNA on neural relaxation butshowed a complete blockade with propranolol(P < 0.01). In conclusion, thevagally induced airway smooth muscle contraction and bronchial vasculardilation are not influenced by NO, and the sheep's trachealis muscle,unlike that in several other species, does not have inhibitorynonadrenergic, noncholinergic innervation.

     

Quantitative analysis of transpleural flux in the isolated lung

Li, M. H., J. Hildebrandt, and M. P. Hlastala.Quantitative analysis of transpleural flux in the isolated lung.J. Appl. Physiol. 82(2): 545-551, 1997.In this study, the loss of inert gas through the pleura of anisolated ventilated and perfused rabbit lung was assessed theoreticallyand experimentally. A mathematical model was used to represent an idealhomogeneous lung placed within a box with gas flow(box) surrounding the lung. Thealveoli are assumed to be ventilated with room air(A) andperfused at constant flow () containinginert gases (x) with various perfusate-air partition coefficients(_p,x).The ratio of transpleural flux of gas(pl_x)to its total delivery to the lung via pulmonary artery( ),representing fractional losses across the pleura, can be shown todepend on four dimensionless ratios:1)_p,x,2) the ratio of alveolar ventilation to perfusion(A/), 3) the ratioof the pleural diffusing capacity(Dpl_x) to the conductance ofthe alveolar ventilation (Dpl_x /A_g,where _g is the capacitancecoefficient of gas), and 4) theratio of extrapleural (box) ventilation to alveolar ventilation(box/A).Experiments were performed in isolated perfused and ventilated rabbitlungs. The perfusate was a buffer solution containing six dissolvedinert gases covering the entire 10⁵-fold range of_p,x usedin the multiple inert gas elimination technique. Steady-state inert gasconcentrations were measured in the pulmonary arterial perfusate,pulmonary venous effluent, exhaled gas, and box effluent gas. Theexperimental data could be described satisfactorily by thesingle-compartment model. It is concluded that a simple theoreticalmodel is a useful tool for predicting transpleural flux from isolatedlung preparations, with known ventilation and perfusion, for inertgases within a wide range of .

     

Effect of nitric oxide synthase inhibition on cardiorespiratory responses in the conscious rat

Gozal, David, José E. Torres, Yair M. Gozal, andSanford M. Littwin. Effect of nitric oxide synthase inhibition on cardiorespiratory responses in the conscious rat. J. Appl. Physiol. 81(5): 2068-2077, 1996.Nitricoxide synthase (NOS) blockade was used to test the cardioventilatoryresponses to hypercapnia and hypoxia in freely behaving animals.Chronically instrumented adult Sprague-Dawley rats were studied beforeand after intravenous administration of either 100 mg/kg ofN^G-nitro-L-arginine methylester (L-NAME), a nonspecificNOS blocker, or 10 mg/kg ofS-methyl-L-thiocitrulline(SMTC), a selective neural NOS inhibitor.L-NAME injection inducedsustained blood pressure (BP) elevation with transient tachycardia andincreased minute ventilation (E), whichreturned to baseline within minutes. SMTC elicited similar, althoughtransient, BP increases; however, heart rate andE decreased.L-NAME and SMTC did not modifyoverall steady-state hypercapnic responses. In controlconditions, hypoxia induced early Eincreases with further E enhancementsat 30 min. L-NAME increased theearly E response to 10%O₂ but induced lateE reductions in hypoxia. SMTC did notchange early E responses but inducedmarked reductions in the later Ehypoxic responses. In control animals, hypoxia induced a significantheart rate increase. This increase was absent during the early response after SMTC and was followed in bothL-NAME- and SMTC-treated animals by significant heart rate reductions to values below room air. Similarly, the sustained BP response to hypoxia in control animals wasabsent after administration of NOS inhibitors. These findings suggestthat NOS activity exerts excitatory influences on respiration andcardiac chronotropy and sustained vasomotor tone during hypoxia. Wespeculate that NOS-mediated mechanisms may play an important role inhypoxia-induced ventilatory roll-off during wakefulness.

     

Human ventilatory response to 8h of euoxic hypercapnia

Tansley, John G., Michala E. F. Pedersen, Christine Clar,and Peter A. Robbins. Human ventilatory response to 8 h of euoxic hypercapnia. J. Appl.Physiol. 84(2): 431-434, 1998.Ventilation (E) risesthroughout 40 min of constant elevated end-tidalPCO₂ without reaching steady state(S. Khamnei and P. A. Robbins. Respir. Physiol. 81: 117-134, 1990). The present studyinvestigates 8 h of euoxic hypercapnia to determine whetherE reachessteady state within this time. Two protocols were employed:1) 8-h euoxic hypercapnia (end-tidalPCO₂ = 6.5 Torr above prestudy value,end-tidal PO₂ = 100 Torr) followed by 8-h poikilocapnic euoxia; and2) control, where the inspired gaswas air. Ewas measured over a 5-min period before the experiment and then hourly over a 16-h period. In the hypercapnia protocol,E had notreached a steady state by the first hour(P < 0.001, analysis of variance), but there were no further significant differences inEover hours 2-8 (analysis ofvariance). Efell promptly on return to eucapnic conditions. We conclude that,whereas there is a component of theE responseto hypercapnia that is slow, there is no progressive rise inE throughoutthe 8-h period.

     

Influence of muscle fiber type and pedal frequency on oxygen uptake kinetics of heavy exercise

Barstow, Thomas J., Andrew M. Jones, Paul H. Nguyen, andRichard Casaburi. Influence of muscle fiber type and pedal frequency on oxygen uptake kinetics of heavy exercise.J. Appl. Physiol. 81(4):1642-1650, 1996.We tested the hypothesis that the amplitude ofthe additional slow component ofO₂ uptake(O₂) during heavy exerciseis correlated with the percentage of type II (fast-twitch) fibers inthe contracting muscles. Ten subjects performed transitions to a workrate calculated to require aO₂ equal to 50% betweenthe estimated lactate (Lac) threshold and maximalO₂ (50%).Nine subjects consented to a muscle biopsy of the vastus lateralis. Toenhance the influence of differences in fiber type among subjects,transitions were made while subjects were pedaling at 45, 60, 75, and90 rpm in different trials. Baseline O₂ was designed to besimilar at the different pedal rates by adjusting baseline work ratewhile the absolute increase in work rate above the baseline was thesame. The O₂ response after the onset of exercise was described by a three-exponential model. Therelative magnitude of the slow component at the end of 8-min exercisewas significantly negatively correlated with %type I fibers at everypedal rate (r = 0.64 to 0.83, P < 0.05-0.01). Furthermore,the gain of the fast component forO₂ (asml ^· min^{1 ·} W¹)was positively correlated with the %type I fibers across pedal rates(r = 0.69-0.83). Increase inpedal rate was associated with decreased relative stress of theexercise but did not affect the relationships between%fiber type and O₂parameters. The relative contribution of the slow component was alsosignificantly negatively correlated with maximalO₂(r = 0.65), whereas the gainfor the fast component was positively associated(r = 0.68-0.71 across rpm). Theamplitude of the slow component was significantly correlated with netend-exercise Lac at all four pedal rates(r = 0.64-0.84), but Lac was notcorrelated with %type I (P > 0.05).We conclude that fiber type distribution significantly affects both thefast and slow components ofO₂ during heavy exerciseand that fiber type and fitness may have both codependent andindependent influences on the metabolic and gas-exchange responses toheavy exercise.

     

V/Q distribution and correlation to atelectasis in anesthetized paralyzed humans

Tokics, Leif, Göran Hedenstierna, Leif Svensson, BoBrismar, Torsten Cederlund, Hans Lundquist, and ÅkeStrandberg. / distributionand correlation to atelectasis in anesthetized paralyzed humans.J. Appl. Physiol. 81(4):1822-1833, 1996.Regional ventilation and perfusion were studiedin 10 anesthetized paralyzed supine patients by single-photon emissioncomputerized tomography. Atelectasis was estimated from twotransaxial computerized tomography scans. The ventilation-perfusion(/) distribution was alsoevaluated by multiple inert gas elimination. While the patients wereawake, inert gas / ratio wasnormal, and shunt did not exceed 1% in any patient. Computerizedtomography showed no atelectasis. During anesthesia, shunt ranged from0.4 to 12.2%. Nine patients displayed atelectasis (0.6-7.2% ofthe intrathoracic area), and shunt correlated with the atelectasis(r = 0.91, P < 0.001). Shunt was located independent lung regions corresponding to the atelectatic area. There wasconsiderable / mismatch, withventilation mainly of ventral lung regions and perfusion of dorsalregions. Little perfusion was seen in the most ventral parts (zone 1)of caudal (diaphragmatic) lung regions. In summary, shunt during anesthesia is due to atelectasis in dependent lung regions. The / distributions differ fromthose shown earlier in awake subjects.

     

cAMP production in rabbit carotid body: role of adenosine

Chen, J., B. Dinger, and S. J. Fidone. cAMP productionin rabbit carotid body: role of adenosine. J. Appl.Physiol. 82(6): 1771-1775, 1997.In the presentstudy, we have investigated the possible role of adenosine in thehypoxia-mediated increase in adenosine 3,5-cyclicmonophosphate (cAMP) in the carotid body. cAMP levels in rabbit carotidbodies superfused in vitro for 10 min were increased in the presence ofadenosine (100 µM and 1.0 mM; maximum increase = 127%,P < 0.01). These effects werereduced by the nonspecific adenosine-receptor antagonist 1,3-dipropyl-8[p-sulfophenyl]xanthine(DPSPX; 10 µM). The specific A₂-receptor agonist2-[4(2-carboxymethyl)phenylethylamino]-5-N-ethylcarboxamido adenosine (CGS-21680; 100 nM) also elevated carotid body cAMP levels,an effect that was blocked by the specificA₂-antagonist 3,7-dimethyl-L-propargyl-xanthine(DMPX; 50 µM). Hypoxia-evoked elevations in cAMP were potentiated inthe presence of the adenosine-uptake inhibitor dipyridamole (100 nM)and blocked by exposure to adenosine-receptor antagonists. Our datasuggest that the rabbit carotid body contains specific adenosinereceptors (A₂ subtype) that arepositively coupled to adenylate cyclase and that increases in cAMPassociated with hypoxia are mediated by the release of endogenousadenosine.

     

Analysis of respiratory water---a new method for evaluation of myocardial energy metabolism

Schwanke, Uwe, Harald Strauss, Gunther Arnold, and Jochen D. Schipke. Analysis of respiratory watera new method for evaluation of myocardial energy metabolism. J. Appl.Physiol. 81(5): 2115-2122, 1996.Aerobic ATPsynthesis via oxidative phosphorylation causes a proportionalproduction of respiratory water. Thus the amount of respiratory waterproduced at a given time should be a reliable measure of the currentATP demand of the mammalian myocardium. Respiratory water from isolatedrabbit hearts was labeled by using the stable oxygen isotope¹⁸O. The hearts were perfusedaccording to the method of Langendorff (O. Langendorff.Pfluegers Arch. 61: 291-332,1895) with¹⁸O₂-equilibratedKrebs-Henseleit solution. Control hearts were exclusively perfused withcarbogen-equilibrated Krebs-Henseleit solution. Myocardial tissue wasthen lyophilized; the extracted water and samples from the coronaryvenous effluent were converted toCO₂ by using the guanidinehydrochloride technique. The¹⁸O values within theCO₂ samples were determined bymass spectrometry and related to the standard mean ocean water(SMOW) scale. Compared with controlhearts, the ¹⁸O-labeled heartsexhibited a significant increase of¹⁸O values from tissue water(47.50 ± 0.64 vs. 40.35 ± 2.05SMOW; P < 0.05). The values were alsosignificantly increased in the coronary venous effluent after aperfusion time of only 50 s (47.50 ± 0.64 vs. 43.66 ± 0.91 SMOW;P < 0.05). Thus this firstadaptation of the guanidine hydrochloride technique on microlitersamples of myocardial tissue water and coronary venous effluentdemonstrates that this method can be used to evaluate both respiratoryactivity and the kinetics of cardiac metabolic processes.

     

Chronic beta -blockade increases skeletal muscle beta -adrenergicreceptor density and enhances contractile force

Murphy, René J. L., Phillip F. Gardiner, Guy Rousseau,Michel Bouvier, and Louise Béliveau. Chronic -blockadeincreases skeletal muscle -adrenergic-receptor density and enhancescontractile force. J. Appl. Physiol.83(2): 459-465, 1997.The effects of a chronic 14-dayadministration of a selective₂-adrenergic-receptor antagonist (ICI-118551) on skeletal muscle were evaluated in female Sprague-Dawley rats. Chronic ICI-118551 treatment did not modify musclemass, oxidative potential, or protein concentration of the medialgastrocnemius muscle, suggesting that maintenance of these skeletalmuscle characteristics is not dependent on₂-adrenergic-receptor stimulation. However, the drug treatment increased-adrenergic-receptor density of the lateral gastrocnemius (42%) andcaused an increase in specific (g/g) isometric in situ contractileforces of the medial gastrocnemius [twitch, 56%; tetanic (200 Hz), 28%]. The elevated contractile forces observed after achronic treatment with ICI-118551 were completely abolished when the₂-adrenergic antagonist wasalso administered acutely before measurement of contractile forces,suggesting that this response is₂-adrenergic-receptor dependent. Possible mechanisms for the increased forces were studied. Caffeine administration potentiated twitch forces but had little effecton tetanic force in control animals. Administration of dibutyryladenosine 3,5-cyclic monophosphate in control animals also resulted in small increases of twitch force but did not modify tetanic forces. We conclude that increases in -adrenergic-receptor density and the stimulation of the receptors by endogenouscatecholamines appear to be responsible for increased contractileforces but that the mechanism remains to be demonstrated.

     

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.

     

TNF-alpha in smoke inhalation lung injury

Hales, Charles A., T. H. Elsasser, Peter Ocampo, and OlgaEfimova. TNF- in smoke inhalation lung injury.J. Appl. Physiol. 82(5):1433-1437, 1997.Adult respiratory distress syndrome is a majorcause of morbidity in fire victims. Tumor necrosis factor- (TNF-)is edematogenic and has been associated with the etiology of otherforms of adult respiratory distress syndrome. In the sheep lymphfistula model, we measured TNF- after 48 (n = 7) or 128 (n = 3) breaths of cotton smoke andcompared this with sham controls (n = 5) or controls in which left atrial pressure was elevated to 20 mmHg(n = 5) to increase lymph flow in the absence of inflammation. Smoke induced a rise in lymph flow and pulmonary arterial pressure with either no fall in lymph-to-plasma protein ratio (128 breaths) or a modest fall in lymph-to-plasma proteinratio (48 breaths), consistent with a change in microvascular permeability as well as a rise in microvascular pressure.Lymph concentration of TNF- fell in both groups, although lymph flux (concentration × flow) transiently rose in both. In neither case did TNF- flux exceed that induced by left atrial pressure elevation. TNF- was detectable in only one out of five sheep in alveolar lavage. Thus, by utilizing a sensitive and specific radioimmunoassay, we were unable to demonstrate a role for TNF- in smoke-induced microvascular lung injury in sheep.