Norepinephrine-induced contraction of isolated rabbit bronchial artery: role of alpha 1- and alpha 2-adrenoceptor activation

Zschauer, A. O. A., M. W. Sielczak, D. A. S. Smith, and A. Wanner. Norepinephrine-induced contraction of isolated rabbit bronchial artery: role of ₁-and ₂-adrenoceptor activation. J. Appl. Physiol. 82(6):1918-1925, 1997.The contractile effect of norepinephrine (NE) onisolated rabbit bronchial artery rings (150-300 µm in diameter)and the role of ₁- and₂-adrenoceptors (AR) on smoothmuscle and endothelium were studied. In intact arteries, NE increasedtension in a dose-dependent manner, and the sensitivity for NE wasfurther increased in the absence of endothelium. In intact but not inendothelium-denuded arteries, the response to NE was increased in thepresence of both indomethacin (Indo; cyclooxygenase inhibitor) andN^G-nitro-L-argininemethyl ester [L-NAME;nitric oxide (NO) synthase inhibitor], indicating that twoendothelium-derived factors, NO and a prostanoid, modulate theNE-induced contraction. The₁-AR antagonist prazosinshifted the NE dose-response curve to the right, and phenylephrine(₁-AR agonist) induced adose-dependent contraction that was potentiated byL-NAME or removal of theendothelium. The sensitivity to NE was increased slightly by the₂-AR antagonists yohimbine andidazoxan, and this effect was abolished by Indo or removal of theendothelium. Similarly, contractions induced by UK-14304(₂-AR agonist) were potentiatedby Indo or removal of the endothelium. These results suggest thatNE-induced contraction is mediated through activation of₁- and₂-ARs on both smooth muscle andendothelium. Activation of the₁- and₂-ARs on the smooth musclecauses contraction, whereas activation of the endothelial ₁- and₂-ARs induces relaxationthrough release of NO (₁-ARs) and a prostanoid (₂-ARs).

     

Liposome encapsulation attenuates hemoglobin-induced vasoconstriction in rabbit arterial segments

Rudolph, Alan S., Anthony Sulpizio, Paul Hieble, VictorMacdonald, Mark Chavez, and Giora Feuerstein. Liposomeencapsulation attenuates hemoglobin-induced vasoconstriction in rabbitarterial segments. J. Appl. Physiol.82(6): 1826-1835, 1997.Free hemoglobin (Hb) induces a potentvasoconstrictor response that may limit its therapeutic application asa red blood cell replacement. We have investigated whetherencapsulation of stroma-free Hb (SFHb) or cross-linked Hb (-Hb)in liposomes modulates Hb vasoactivity in isolated blood vessels.Relaxation of rabbit thoracic vessels was measured before and afterexposure to acellular SFHb, -Hb, and liposome-encapsulated SFHbor -Hb. SFHb and -Hb caused significant inhibition ofcarbachol-induced relaxation at 0.5 mg/dl, whereas encapsulationinhibited vessel relaxation at 30- to 60-fold higher Hb concentrations.The contractile response of rabbit ear arterial segments to electricalstimulation in the presence of acellular -Hb resulted in a 150%increase (EC₁₅₀) in contractileamplitude at 0.23 mg/dl, whereas theEC₁₅₀ for encapsulated -Hbwas 13.7 mg/dl. Mechanistic studies of the vasoconstrictor activity ofHb demonstrated that acellular -Hb had no effect onnorepinephrine release in the rabbit ear artery. In addition, neitheracellular nor encapsulated -Hb preparations inhibited endothelialnitric oxide (NO) synthase activity isolated from bovine pulmonaryartery. However, inhibition of vessel relaxation by acellular orencapsulated -Hb was reversed by the NO donor S-nitrosylpenacillamine, implicatingHb-NO binding as a possible mechanism for the vasoconstrictor response.In vitro stopped-flow kinetic studies of Hb-NO binding showed similarrates of reaction for conversion of oxyhemoglobin to methemoglobin(metHb; <2 ms), followed by rapid conversion of metHb to NO-Hb (300 ms) for both acellular and encapsulated -Hb, demonstrating thatliposome encapsulation does not retard NO-Hb binding. The attenuatedvasoactivity of encapsulated Hb may, therefore, result from the limitedaccess of encapsulated Hb to NO imposed by the physical size of theliposome and reduced penetration of Hb across the vascular endothelium.

     

Combined heart rate and activity improve estimates of oxygen consumption and carbon dioxide production rates

Moon, Jon K., and Nancy F. Butte. Combined heart rateand activity improve estimates of oxygen consumption and carbon dioxideproduction rates. J. Appl. Physiol.81(4): 1754-1761, 1996.Oxygen consumption(O₂) andcarbon dioxide production (CO₂) rates were measuredby electronically recording heart rate (HR) and physical activity (PA).Mean daily O₂ andCO₂ measurements by HR andPA were validated in adults (n = 10 women and 10 men) with room calorimeters. Thirteen linear and nonlinear functions of HR alone and HR combined with PA were tested as models of24-h O₂ andCO₂. Mean sleepO₂ andCO₂ were similar to basalmetabolic rates and were accurately estimated from HR alone[respective mean errors were 0.2 ± 0.8 (SD) and0.4 ± 0.6%]. The range of prediction errorsfor 24-h O₂ andCO₂ was smallestfor a model that used PA to assign HR for each minute to separateactive and inactive curves(O₂, 3.3 ± 3.5%; CO₂, 4.6 ± 3%). There were no significant correlations betweenO₂ orCO₂ errors and subject age,weight, fat mass, ratio of daily to basal energy expenditure rate, orfitness. O₂,CO₂, and energy expenditurerecorded for 3 free-living days were 5.6 ± 0.9 ml ^· min^{1 ·} kg¹,4.7 ± 0.8 ml ^· min^{1 ·} kg¹,and 7.8 ± 1.6 kJ/min, respectively. Combined HR and PA measured 24-h O₂ andCO₂ with a precisionsimilar to alternative methods.

     

Association of chest wall motion and tidal volume responses during CO2 rebreathing

Yan, Sheng, Pawel Sliwinski, and Peter T. Macklem.Association of chest wall motion and tidal volume responses during CO₂ rebreathing.J. Appl. Physiol. 81(4):1528-1534, 1996.The purpose of this study is to investigate theeffect of chest wall configuration at end expiration on tidal volume(VT) response duringCO₂ rebreathing. In a group of 11 healthy male subjects, the changes in end-expiratory andend-inspiratory volume of the rib cage (Vrc,E andVrc,I, respectively) and abdomen (Vab,E and Vab,I, respectively) measured by linearizedmagnetometers were expressed as a function of end-tidalPCO₂(PET_CO2). The changes inend-expiratory and end-inspiratory volumes of the chest wall(Vcw,E and Vcw,I,respectively) were calculated as the sum of the respectiverib cage and abdominal volumes. The magnetometer coils were placed atthe level of the nipples and 1-2 cm above the umbilicus andcalibrated during quiet breathing against theVT measured from apneumotachograph. TheVrc,E/PET_CO2 slope was quite variable among subjects. It was significantly positive (P < 0.05) in fivesubjects, significantly negative in four subjects(P < 0.05), and not different fromzero in the remaining two subjects. TheVab,E/PET_CO2slope was significantly negative in all subjects(P < 0.05) with a much smallerintersubject variation, probably suggesting a relatively more uniformrecruitment of abdominal expiratory muscles and a variable recruitmentof rib cage muscles during CO₂rebreathing in different subjects. As a group, the meanVrc,E/PET_CO2,Vab,E/PET_CO2, andVcw,E/PET_CO2slopes were 0.010 ± 0.034, 0.030 ± 0.007, and0.020 ± 0.032 l / Torr, respectively;only theVab,E/PET_CO2 slope was significantly different from zero. More interestingly, theindividualVT/PET_CO2slope was negatively associated with theVrc,E/PET_CO2(r = 0.68,P = 0.021) and Vcw,E/PET_CO2slopes (r = 0.63,P = 0.037) but was not associated withtheVab,E/PET_CO2slope (r = 0.40, P = 0.223). There was no correlation oftheVrc,E/PET_CO2 andVcw,E/PET_CO2slopes with age, body size, forced expiratory volume in 1 s, orexpiratory time. The groupVab,I/PET_CO2 slope (0.004 ± 0.014 l / Torr) was not significantlydifferent from zero despite theVT nearly being tripled at theend of CO₂ rebreathing. Inconclusion, the individual VTresponse to CO₂, althoughindependent of Vab,E, is a function ofVrc,E to the extent that as theVrc,E/PET_CO2slope increases (more positive) among subjects, theVT response toCO₂ decreases. These results maybe explained on the basis of the respiratory muscle actions andinteractions on the rib cage.

     

Tumor necrosis factor-alpha in ischemia and reperfusion injury in rat lungs

The effects ofboth recombinant rat tumor necrosis factor- (TNF-) and ananti-TNF- antibody were studied in isolated buffer-perfused ratlungs subjected to either 45 min of nonventilated[ischemia-reperfusion (I/R)] or air-ventilated(/R) ischemia followed by 90 min of reperfusion and ventilation. In the I/R group, the vascularpermeability, as measured by the filtration coefficient(K_fc),increased three- and fivefold above baseline after 30 and 90 min ofreperfusion, respectively (P < 0.001). Over the same time intervals, theK_fc for the/R group increased five- and tenfold above baseline values, respectively (P < 0.001).TNF- measured in the perfusates of both ischemic modelssignificantly increased after 30 min of reperfusion. Recombinant ratTNF- (50,000 U), placed into perfusate after baseline measurements,produced no measurable change in microvascular permeability in controllungs perfused over the same time period (135 min), but I/R injury wassignificantly enhanced in the presence of TNF-. An anti-TNF-antibody (10 mg/rat) injected intraperitoneally into rats 2 h beforethe lung was isolated prevented the microvascular damage in lungsexposed to both I/R and /R (P < 0.001). These results indicatethat TNF- is an essential component at the cascade of events thatcause lung endothelial injury in short-term I/R and/R models of lung ischemia.

     

Mitochondrial redox state as a potential detector of liver dysoxia in vivo

Dysoxia canbe defined as ATP flux decreasing in proportion toO₂ availability with preserved ATPdemand. Hepatic venous -hydroxybutyrate-to-acetoacetate ratio(-OHB/AcAc) estimates liver mitochondrial NADH/NAD and may detectthe onset of dysoxia. During partial dysoxia (as opposed to anoxia),however, flow may be adequate in some liver regions, diluting effluentfrom dysoxic regions, thereby rendering venous -OHB/AcAc unreliable.To address this concern, we estimated tissue ATP whilegradually reducing liver blood flow of swine to zero in a nuclearmagnetic resonance spectrometer. ATP flux decreasing withO₂ availability was taken asO₂ uptake(O₂) decreasing inproportion to O₂ delivery(O₂);and preserved ATP demand was taken as increasingP_i/ATP.O₂, tissueP_i/ATP, and venous -OHB/AcAcwere plotted againstO₂to identify critical inflection points. Tissue dysoxia required meanO₂for the group to be critical for bothO₂ and forP_i/ATP. CriticalO₂values for O₂ andP_i/ATP of 4.07 ± 1.07 and 2.39 ± 1.18 (SE) ml · 100 g¹ · min¹,respectively, were not statistically significantly different but notclearly the same, suggesting the possibility that dysoxia might havecommenced after O₂ begandecreasing, i.e., that there could have been"O₂ conformity." CriticalO₂for venous -OHB/AcAc was 2.44 ± 0.46 ml · 100 g¹ · min¹(P = NS), nearly the same as that forP_i/ATP, supporting venous -OHB/AcAc as a detector of dysoxia. All issues considered, tissue mitochondrial redox state seems to be an appropriate detector ofdysoxia in liver.

     

Exercise attenuates {alpha}-adrenergic-receptor responsiveness in skeletal muscle vasculature

Attenuation of sympathetic vasoconstriction(sympatholysis) in working muscles during dynamic exercise iscontroversial. A potential mechanism is a reduction in-adrenergic-receptor responsiveness. The purpose of this study wasto examine ₁- and ₂-adrenergic-receptor-mediated vasoconstriction inresting and exercising skeletal muscle using intra-arterial infusionsof selective agonists. Thirteen mongrel dogs were instrumentedchronically with flow probes on the external iliac arteries of bothhindlimbs and a catheter in one femoral artery. The selective₁-adrenergic agonist (phenylephrine) or the selective₂-adrenergic agonist (clonidine) was infused as a bolusinto the femoral artery catheter at rest and during mild and heavyexercise. Intra-arterial infusions of phenylephrine elicited reductionsin vascular conductance of 76 ± 4, 71 ± 5, and 31 ± 2% at rest, 3 miles/h, and 6 miles/h and 10% grade, respectively.Intra-arterial clonidine reduced vascular conductance by 81 ± 5, 49 ± 4, and 14 ± 2%, respectively. The response tointra-arterial infusion of clonidine was unaffected by surgicalsympathetic denervation. Agonist infusion did not affect eithersystemic blood pressure, heart rate, or blood flow in the contralateraliliac artery. ₁-Adrenergic-receptor responsiveness wasattenuated during heavy exercise. In contrast,₂-adrenergic-receptor responsiveness was attenuated evenat a mild exercise intensity. These results suggest that the mechanismof exercise sympatholysis may involve reductions in postsynaptic-adrenergic-receptor responsiveness.

     

Contributions of pulmonary perfusion and ventilation to heterogeneity in VA/Q measured by PET

Treppo, Steven, Srboljub M. Mijailovich, and José G. Venegas. Contributions of pulmonary perfusion and ventilation toheterogeneity in A/measured by PET. J. Appl. Physiol. 82(4): 1163-1176, 1997. To estimate the contributions of the heterogeneity in regionalperfusion () and alveolar ventilation(A) to that of ventilation-perfusionratio (A/), we haverefined positron emission tomography (PET) techniques to image localdistributions of andA per unit of gas volume content(s and sA,respectively) and VA/ indogs. sA was assessed in two ways:1) the washout of ¹³NN tracer after equilibrationby rebreathing (sA_i), and2) the ratio of an apneic image after a bolus intravenousinfusion of ¹³NN-saline solution to an image collectedduring a steady-state intravenous infusion of the same solution(sA_p).sA_p was systematically higher than sA_i in allanimals, and there was a high spatial correlation betweens andsA_p in both body positions(mean correlation was 0.69 prone and 0.81 supine) suggesting thatventilation to well-perfused units was higher than to those poorlyperfused. In the prone position, the spatial distributions ofs, sA_p, and A/ were fairlyuniform with no significant gravitational gradients; however, in thesupine position, these variables were significantly more heterogeneous,mostly because of significant gravitational gradients (15, 5.5, and10%/cm, respectively) accounting for 73, 33, and 66% of thecorresponding coefficient of variation (CV)² values. Weconclude that, in the prone position, gravitational forces in blood andlung tissues are largely balanced out by dorsoventral differences inlung structure. In the supine position, effects of gravity andstructure become additive, resulting in substantial gravitationalgradients in s andsA_p, with the higherheterogeneity inA/ caused by agravitational gradient in s, only partially compensated by that in sA.

     

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 .

     

Effects of hyperthermia on contraction and dilatation of rabbit femoral arteries

To analyze the effect of hyperthermia on thevascular response, the isometric response of isolated rabbit femoralartery segments was recorded at 37°C and hyperthermia (41 and44°C). Contraction to potassium (5 × 10³-5 × 10² M) was significantlygreater at 41 and 44 than at 37°C and increased by inhibition ofnitric oxide (NO) synthesis withN-nitro-L-arginine(L-NNA;10⁴ M) or endotheliumremoval at 37°C but not at 41 or 44°C. Norepinephrine (10⁹-10⁴M) produced a concentration-dependent contraction greater at 41 or 44 than at 37°C and not modified by endothelium removal orL-NNA at either temperature.Phenylephrine(10⁹-10⁴M) produced a contraction increased by warming to 44°C but not to41°C. The specific₂-adrenoceptor agonist BHT-920produced a weak contraction, reduced by the₁-adrenoceptor antagonist prazosin (10⁶ M) andincreased at 44°C but not at 41°C. The concentration-dependent contraction to endothelin-1 (ET-1;10¹¹-10⁷M) was increased by warming to 41 and 44°C and by endothelium removal or L-NNA at 37°C butnot at 41 or 44°C. Response to ET-1 was reduced by endothelinET_A-receptor antagonist BQ-123(10⁵ M) andET_B-receptor antagonist BQ-788(10⁵ M). In arteriesprecontracted with ET-1(10⁸-3 × 10⁸ M), relaxation tosodium nitroprusside(10⁸-10⁴M) was increased at 41 and 44°C vs. at 37°C, but that of ACh (10⁸-10⁴M) or adenosine(10⁸-10⁴M) was not different at all temperatures studied. Relaxation to ACh,but not adenosine, was reduced similarly byL-NNA at all temperaturesstudied. These results suggest hyperthermia in muscular arteries mayinhibit production of, and increase dilatation to, NO, resulting inunchanged relaxation to ACh and increased constriction to KCl and ET-1,and may increase constriction to stimulation of₁-adrenoceptors byNO-independent mechanisms.

     

Muscle capillarization, O2 diffusion distance, and VO2 kinetics in old and young individuals

Chilibeck, P. D., D. H. Paterson, D. A. Cunningham, A. W. Taylor, and E. G. Noble. Muscle capillarization,O₂ diffusion distance, andO₂ kinetics in old andyoung individuals. J. Appl. Physiol.82(1): 63-69, 1997.The relationships between muscle capillarization, estimated O₂diffusion distance from capillary to mitochondria, andO₂ uptake(O₂) kineticswere studied in 11 young (mean age, 25.9 yr) and 9 old (mean age, 66.0 yr) adults. O₂kinetics were determined by calculating the time constants () forthe phase 2 O₂ adjustment to andrecovery from the average of 12 repeats of a 6-min, moderate-intensityplantar flexion exercise. Muscle capillarization was determined fromcross sections of biopsy material taken from lateral gastrocnemius.Young and old groups had similarO₂ kinetics(O₂-on = 44 vs. 48 s;O₂-off = 33 vs. 44 s, for young and old, respectively), muscle capillarization, andestimated O₂ diffusion distances.Muscle capillarization, expressed as capillary density or averagenumber of capillary contacts per fiber/average fiber area, and theestimates of diffusion distance were significantly correlated toO₂-off kinetics in theyoung (r = 0.68 to 0.83;P < 0.05). We conclude that1) capillarization andO₂ kinetics during exerciseof a muscle group accustomed to everyday activity (e.g., walking) arewell maintained in old individuals, and2) in the young, recovery of O₂ after exercise isfaster, with a greater capillary supply over a given muscle fiber areaor shorter O₂ diffusion distances.

     

Role for anions in pulmonary endothelial permeability

Griffin, M. Pamela. Role for anions in pulmonaryendothelial permeability. J. Appl.Physiol. 83(2): 615-622, 1997.-Adrenergic stimulation reduces albumin permeation across pulmonary artery endothelial monolayers and induces changes in cell morphology that aremediated by Cl flux. Wetested the hypothesis that anion-mediated changes in endothelial cellsresult in changes in endothelial permeability. We measured permeationof radiolabeled albumin across bovine pulmonary arterial endothelialmonolayers when the extracellular anion was Cl,Br,I,F, acetate(Ac), gluconate(G), and propionate(Pr). Permeability toalbumin (P_albumin)was calculated before and after addition of 0.2 mM of thephosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), whichreduces permeability. InCl, theP_albumin was 3.05 ± 0.86 × 10⁶ cm/s andfell by 70% with the addition of IBMX. The initialP_albumin was lowest forPr andAc. InitialP_albumin was higher inBr,I,G, andF than inCl. A permeability ratiowas calculated to examine the IBMX effect. The greatest IBMX effect wasseen when Cl was theextracellular anion, and the order among halide anions wasCl > Br > I > F. Although the level ofextracellular Ca²⁺ concentration([Ca²⁺]_o)varied over a wide range in the anion solutions,[Ca²⁺]_odid not systematically affect endothelial permeability in this system.When Cl was theextracellular anion, varying[Ca²⁺]_ofrom 0.2 to 2.8 mM caused a change in initialP_albumin but no changein the IBMX effect. The anion channel blockers4-acetamido-4-isothiocyanotostilbene-2,2-disulfonic acid(0.25 mM) and anthracene-9-carboxylic acid (0.5 mM) significantly altered initialP_albumin and the IBMXeffect. The anion transport blockers bumetanide (0.2 mM) and furosemide(1 mM) had no such effects. We conclude that extracellular anionsinfluence bovine pulmonary arterial endothelial permeability and thatthe pharmacological profile fits better with the activity of anionchannels than with other anion transport processes.

     

Urethan anesthesia protects rats against lethal endotoxemia and reduces TNF-alpha release

Kotanidou, Anastasia, Augustine M. K. Choi, Richard A. Winchurch, Leo Otterbein, and Henry E. Fessler. Urethan anesthesia protects rats against lethal endotoxemia and reduces TNF- release. J. Appl. Physiol. 81(5):2304-2311, 1996.Urethan is a commonly used animalanesthetic for nonrecovery laboratory surgery. However, urethan hasdiverse biological effects that may complicate the interpretation ofexperimental findings. This study examined the effect of urethan on theresponse to an intravenous bolus of lipopolysaccharide (LPS; 30 mg/kg)in rats. In instrumented rats, urethan (1.2 gm/kg ip) completelyprevented the fall in arterial pressure immediately after LPSadministration but did not prevent late cardiovascular collapse. Inuninstrumented rats, urethan also attenuated indexes of organ injurymeasured 4 h after LPS administration, including mural bowelhemorrhage, hemoconcentration, hypoglycemia, metabolic acidosis, andlung myeloperoxidase activity, a measure of neutrophil sequestration.The peak increase in tumor necrosis factor- (TNF-) 90 min afterLPS administration was reduced 88% by urethan (2,060 ± 316 vs.16,934 ± 847 pg/ml; P < 0.001).In uninstrumented animals, urethan at 1.2 gm/kg reduced the 90%mortality rate of a lethal dose of LPS to 0-10% whengiven up to 24 h before LPS administration but did not reduce mortalitywhen given 2 h after LPS. Urethan neither directly bound LPS byLimulus assay nor inhibitedLPS-stimulated TNF- mRNA expression in cultured mouse peritonealmacrophages, but TNF- mRNA expression was suppressed by serum from aurethan-treated rat. Moreover, rauwolscine, which shares₂-adrenoceptor-blocking activity with urethan, also prevented death from a subsequent 90% lethal dose LPS bolus. We conclude that urethan or its metabolites protect against LPS, in part, by reducing TNF- release andspeculate that this may be mediated by₂-adrenoceptors. These actionsof urethan make it an undesirable anesthetic agent for in vivo studies of sepsis or LPS.

     

Influence of age and gender on cardiac output-VO2 relationships during submaximal cycle ergometry

Proctor, David N., Kenneth C. Beck, Peter H. Shen, Tamara J. Eickhoff, John R. Halliwill, and Michael J. Joyner. Influence ofage and gender on cardiacoutput-O₂ relationshipsduring submaximal cycle ergometry. J. Appl.Physiol. 84(2): 599-605, 1998.It is presentlyunclear how gender, aging, and physical activity status interact todetermine the magnitude of the rise in cardiac output(c) during dynamic exercise. To clarify this issue,the present study examined thec-O₂ uptake(O₂) relationship duringgraded leg cycle ergometry in 30 chronically endurance-trained subjects from four groups (n = 6-8/group): younger men (20-30 yr), older men (56-72yr), younger women (24-31 yr), and older women(51-72 yr). c (acetylene rebreathing), strokevolume (c/heart rate), and whole bodyO₂ were measured at restand during submaximal exercise intensities (40, 70, and ~90% of peakO₂). Baseline restinglevels of c were 0.6-1.2 l/min less in theolder groups. However, the slopes of thec-O₂relationship across submaximal levels of cycling were similar among allfour groups (5.4-5.9 l/l). The absolute cassociated with a given O₂(1.0-2.0 l/min) was also similar among groups. Resting andexercise stroke volumes (ml/beat) were lower in women than in men butdid not differ among age groups. However, older men and women showed areduced ability, relative to their younger counterparts, to maintainstroke volume at exercise intensities above 70% of peakO₂. This latter effect wasmost prominent in the oldest women. These findings suggest that neitherage nor gender has a significant impact on thec-O₂ relationships during submaximal cycle ergometry among chronically endurance-trained individuals.

     

O2 uptake kinetics after acetazolamide administration during moderate- and heavy-intensity exercise

Inhibition of carbonic anhydrase (CA) isassociated with a lower plasma lactate concentration([La]_pl)during fatiguing exercise. We hypothesized that a lower[La]_plmay be associated with faster O₂uptake (O₂) kinetics during constant-load exercise. Seven men performed cycle ergometer exercise during control (Con) and acute CA inhibition with acetazolamide (Acz,10 mg/kg body wt iv). On 6 separate days, each subject performed 6-minstep transitions in work rate from 0 to 100 W (below ventilatory threshold,<ET)or to a O₂ corresponding to~50% of the difference between the work rate atET and peakO₂(>ET).Gas exchange was measured breath by breath. Trials were interpolated at1-s intervals and ensemble averaged to yield a single response. The mean response time (MRT, i.e., time to 63% of total exponential increase) for on- and off-transients was determined using a two- (<ET) or athree-component exponential model(>ET).Arterialized venous blood was sampled from a dorsal hand vein andanalyzed for[La]_pl.MRT was similar during Con (31.2 ± 2.6 and 32.7 ± 1.2 s for onand off, respectively) and Acz (30.9 ± 3.0 and 31.4 ± 1.5 s for on and off, respectively) for work rates<ET. Atwork rates >ET, MRTwas similar between Con (69.1 ± 6.1 and 50.4 ± 3.5 s for on andoff, respectively) and Acz (69.7 ± 5.9 and 53.8 ± 3.8 s for on and off, respectively). On- and off-MRTs were slower for>ET thanfor <ETexercise.[La]_plincreased above 0-W cycling values during<ET and>ET exercise but was lower at the end of the transition during Acz (1.4 ± 0.2 and 7.1 ± 0.5 mmol/l for<ET and>ET,respectively) than during Con (2.0 ± 0.2 and 9.8 ± 0.9 mmol/lfor <ETand >ET,respectively). CA inhibition does not affectO₂ utilization at the onset of<ET or>ETexercise, suggesting that the contribution of oxidative phosphorylationto the energy demand is not affected by acute CA inhibition with Acz.

     

Kinetics of oxygen uptake at the onset of exercise in boys and men

The objective of this study was to compare theO₂ uptake(O₂) kinetics at the onsetof heavy exercise in boys and men. Nine boys, aged 9-12 yr, and 8 men, aged 19-27 yr, performed a continuous incremental cyclingtask to determine peak O₂(O_{2 peak}).On 2 other days, subjects performed each day four cycling tasks at 80 rpm, each consisting of 2 min of unloaded cycling followed twice bycycling at 50%O_{2 peak} for 3.5 min,once by cycling at 100%O_{2 peak} for 2 min,and once by cycling at 130%O_{2 peak} for 75 s.O₂ deficit was not significantlydifferent between boys and men (respectively, 50%O_{2 peak} task: 6.6 ± 11.1 vs. 5.5 ± 7.3 ml · min¹ · kg¹;100% O_{2 peak} task:28.5 ± 8.1 vs. 31.8 ± 6.3 ml · min¹ · kg¹;and 130%O_{2 peak}task: 30.1 ± 5.7 vs. 35.8 ± 5.3 ml · min¹ · kg¹).To assess the kinetics, phase I was excluded from analysis. Phase IIO₂ kinetics could bedescribed in all cases by a monoexponential function. ANOVA revealed nodifferences in time constants between boys and men (respectively, 50%O_{2 peak}task: 22.8 ± 5.1 vs. 26.4 ± 4.1 s; 100%O_{2 peak} task: 28.0 ± 6.0 vs. 28.1 ± 4.4 s; and 130%O_{2 peak} task: 19.8 ± 4.1 vs. 20.7 ± 5.7 s). In conclusion, O₂ deficit and fast-componentO₂ on-transientsare similar in boys and men, even at high exercise intensities, whichis in contrast to the findings of other studies employing simplermethods of analysis. The previous interpretation that children relyless on nonoxidative energy pathways at the onset of heavy exercise isnot supported by our findings.

     

Faster adjustment of O2 delivery does not affect VO2 on-kinetics in isolated in situ canine muscle

The mechanism(s)limiting muscle O₂ uptake(O₂) kinetics wasinvestigated in isolated canine gastrocnemius muscles(n = 7) during transitions from restto 3 min of electrically stimulated isometric tetanic contractions(200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% of peakO₂). Two conditions weremainly compared: 1) spontaneousadjustment of blood flow () [control, spontaneous (C Spont)]; and2) pump-perfused, adjusted ~15 s before contractions at aconstant level corresponding to the steady-state value duringcontractions in C Spont [faster adjustment ofO₂ delivery (FastO₂ Delivery)]. During FastO₂ Delivery, 1-2 ml/min of10² M adenosine wereinfused intra-arterially to prevent inordinate pressure increases withthe elevated . The purpose of the study was todetermine whether a faster adjustment ofO₂ delivery would affectO₂ kinetics. was measured continuously; arterial(Ca_O2) and popliteal venous(Cv_O2)O₂ contents were determined atrest and at 5- to 7-s intervals during contractions;O₂ delivery was calculated as · Ca_O2,and O₂ was calculated as · arteriovenous O₂ content difference. Times toreach 63% of the difference between baseline and steady-stateO₂ during contractions were23.8 ± 2.0 (SE) s in C Spont and 21.8 ± 0.9 s in FastO₂ Delivery (not significant). Inthe present experimental model, elimination of any delay inO₂ delivery during therest-to-contraction transition did not affect muscleO₂ kinetics, which suggeststhat this kinetics was mainly set by an intrinsic inertia of oxidativemetabolism.

     

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.

     

Vascular resistance and the efficacy of red cell substitutes in a rat hemorrhage model

We have comparedpolyethylene glycol-modified bovine hemoglobin (PEG-Hb; highO₂ affinity, high viscosity, highoncotic pressure) and human hemoglobin cross-linked between the-chains (-Hb; low O₂affinity, low viscosity, low oncotic pressure) with anon-O₂-carrying plasma expander(pentastarch, high viscosity and oncotic pressure) after a 50% (byvolume) exchange transfusion followed by a severe (60% of bloodvolume) hemorrhage. Mean arterial pressure and systemic vascularresistance rose significantly in the -Hb but not in the PEG-Hbanimals. Two-hour survival was greater in the PEG-Hb animals (93%)than in control (35%), pentastarch (8%), or -Hb (6%) animals.In the PEG-Hb animals, there was no disturbance of acid-base balance,significantly less accumulation of lactic acid, and higher cardiacoutput than in the other groups. The data suggest that the rise invascular resistance that follows -Hb exchange transfusion offsetsthe additional O₂ transport provided by the cell-free hemoglobin. When resistance does not rise, aswith PEG-Hb, even relatively small amounts of cell-free hemoglobinappear to be a very effective blood replacement.

     

Interferon-gamma has immunomodulatory effects with minor endocrine and metabolic effects in humans

To evaluatewhether interferon- (IFN-) is involved in the interaction betweenthe immune and endocrine systems in vivo, we studied six healthysubjects twice in a placebo-controlled trial: once after administrationof recombinant human IFN- and, on another occasion, afteradministration of saline. The rate of appearance of glucose wasdetermined by infusion of[6,6-²H₂]glucoseand resting energy expenditure by indirect calorimetry. Human leukocyteantigen-DR gene expression on monocytes and serum neopterin increased after administration of IFN-(P < 0.05 vs. control). IFN-increased serum interleukin-6 levels significantly. Levels of tumornecrosis factor- remained below detection limits. IFN- increasedplasma concentrations of ACTH and cortisol(P < 0.05 vs. control), IFN- didnot alter concentrations of growth hormone,(nor)epinephrine, insulin, C peptide, glucagon, or insulin-like growthfactor I. IFN- did not alter plasma concentrations of glucose andfree fatty acids nor the rate of appearance of glucose. IFN-increased resting energy expenditure significantly. We conclude thatIFN- is a minor stimulator of the endocrine and metabolic pathways.Therefore, IFN- by itself is probably not a major mediator in theinteraction between the immune and the endocrine and metabolic systems.