Protective effects of intravascular pressure and nitric oxide in ischemic lung injury

Cessation of bloodflow during ischemia will decrease both distending and shearforces exerted on endothelium and may worsen ischemic lung injury bydecreasing production of nitric oxide (NO), which influences vascularbarrier function. We hypothesized that increased intravascular pressure(Piv) during ventilated ischemia might maintain NO productionby increasing endothelial stretch or shear forces, thereby attenuatingischemic lung injury. Injury was assessed by measuring the filtrationcoefficient(K_f) and theosmotic reflection coefficient for albumin(_alb) after 3 h of ventilated(95% O₂-5%CO₂; expiratory pressure 3 mmHg) ischemia. Lungs were flushed with physiological salt solution, and then Piv was adjusted to achieve High Piv (mean 6.7 ± 0.4 mmHg, n = 15) or Low Piv (mean0.83 ± 0.4 mmHg, n = 10).N^G-nitro-L-arginine methyl ester(L-NAME;10⁵ M,n = 10),N^G-nitro-D-argininemethyl ester (D-NAME;10⁵ M,n = 11), orL-NAME(10⁵M)+L-arginine (5 × 10⁴ M,n = 6) was added at the start ofischemia in three additional groups of lungs with High Piv.High Piv attenuated ischemic injury compared with Low Piv(_alb 0.67 ± 0.04 vs. 0.35 ± 0.04, P < 0.05). Theprotective effect of High Piv was abolished byL-NAME(_alb 0.37 ± 0.04, P < 0.05) but not byD-NAME(_alb 0.63 ± 0.07). The effects of L-NAME were overcomeby an excess of L-arginine(_alb 0.56 ± 0.05, P < 0.05).K_f did not differsignificantly among groups. These results suggest that Piv modulatesischemia-induced barrier dysfunction in the lung, and theseeffects may be mediated by NO.

     

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.

     

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.

     

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.

     

Training-induced alterations of carbohydrate metabolism in women: women respond differently from men

We examined the hypothesis that glucose flux wasdirectly related to relative exercise intensity both beforeand after a 12-wk cycle ergometer training program [5days/wk, 1-h duration, 75% peakO₂ consumption(O_{2 peak})] inhealthy female subjects (n = 17; age23.8 ± 2.0 yr). Two pretraining trials (45 and 65% of O_{2 peak})and two posttraining trials [same absolute workload (65% of oldO_{2 peak})and same relative workload (65% of new O_{2 peak})] wereperformed on nine subjects by using a primed-continuous infusion of[1-¹³C]- and[6,6-²H]glucose.Eight additional subjects were studied by using[6,6-²H]glucose.Subjects were studied postabsorption for 90 min of rest and 1 h ofcycling exercise. After training, subjects increased O_{2 peak} by 25.2 ± 2.4%. Pretraining, the intensity effect on glucose kinetics wasevident between 45 and 65% ofO_{2 peak} with rates ofappearance (R_a: 4.52 ± 0.25 vs. 5.53 ± 0.33 mg · kg¹ · min¹),disappearance (R_d: 4.46 ± 0.25 vs. 5.54 ± 0.33 mg · kg¹ · min¹),and oxidation (R_ox: 2.45 ± 0.16 vs. 4.35 ± 0.26 mg · kg¹ · min¹)of glucose being significantly greater(P  0.05) in the 65% thanin the 45% trial. Training reducedR_a (4.7 ± 0.30 mg · kg¹ · min¹),R_d (4.69 ± 0.20 mg · kg¹ · min¹),and R_ox (3.54 ± 0.50 mg · kg¹ · min¹)at the same absolute workload (P  0.05). When subjects were tested at the same relative workload,R_a,R_d, andR_ox were not significantlydifferent after training. However, at both workloads after training,there was a significant decrease in total carbohydrate oxidation asdetermined by the respiratory exchange ratio. These results show thefollowing in young women: 1)glucose use is directly related to exercise intensity;2) training decreasesglucose flux for a given power output;3) when expressed asrelative exercise intensity, training does not affect the magnitude ofblood glucose flux during exercise; but4) training does reduce totalcarbohydrate oxidation.

     

Training-induced alterations of glucose flux in men

Friedlander, Anne L., Gretchen A. Casazza, Michael A. Horning, Melvin J. Huie, and George A. Brooks. Training-induced alterations of glucose flux in men. J. Appl.Physiol. 82(4): 1360-1369, 1997.We examined thehypothesis that glucose flux was directly related to relative exerciseintensity both before and after a 10-wk cycle ergometer trainingprogram in 19 healthy male subjects. Two pretraining trials [45and 65% of peak O₂ consumption(O_{2 peak})] andtwo posttraining trials (same absolute and relative intensities as 65%pretraining) were performed for 90 min of rest and 1 h of cyclingexercise. After training, subjects increasedO_{2 peak} by9.4 ± 1.4%. Pretraining, the intensity effect on glucose kinetics was evident with rates of appearance(R_a; 5.84 ± 0.23 vs. 4.73 ± 0.19 mg · kg¹ · min¹),disappearance (R_d; 5.78 ± 0.19 vs. 4.73 ± 0.19 mg · kg¹ · min¹),oxidation (R_ox; 5.36 ± 0.15 vs. 3.41 ± 0.23 mg · kg¹ · min¹),and metabolic clearance (7.03 ± 0.56 vs. 5.20 ± 0.28 ml · kg¹ · min¹)of glucose being significantly greater(P  0.05) in the 65% than the 45%O_{2 peak} trial. WhenR_d was expressed as a percentage of total energy expended per minute(R_{d E}), there was nodifference between the 45 and 65% intensities. Training did reduceR_a (4.63 ± 0.25),R_d (4.65 ± 0.24),R_ox (3.77 ± 0.43), andR_{d E} (15.30 ± 0.40 to12.85 ± 0.81) when subjects were tested at the same absolute workload (P  0.05). However, whenthey were tested at the same relative workload,R_a,R_d, andR_{d E} were not different,although R_ox was lowerposttraining (5.36 ± 0.15 vs. 4.41 ± 0.42, P  0.05). These results show1) glucose use is directly relatedto exercise intensity; 2) trainingdecreases glucose flux for a given power output;3) when expressed as relativeexercise intensity, training does not affect the magnitude of bloodglucose use during exercise; 4)training alters the pathways of glucose disposal.

     

H2O2 increases sheep tracheal blood flow, permeability, and vascular response to luminal capsaicin

Wells, U. M., S. Duneclift, and J. G. Widdicombe.H₂O₂increases sheep tracheal blood flow, permeability, and vascular response to luminal capsaicin. J. Appl.Physiol. 82(2): 621-631, 1997.Exogenous hydrogenperoxide(H₂O₂)causes airway epithelial damage in vitro. We have studied the effectsof luminalH₂O₂in the sheep trachea in vivo on tracheal permeability tolow-molecular-weight hydrophilic (technetium-99m-labeleddiethylenetriamine pentaacetic acid;^99mTc-DTPA) and lipophilic([¹⁴C]antipyrine;[¹⁴C]AP) tracers andon the tracheal vascular response to luminal capsaicin, whichstimulates afferent nerve endings. A tracheal artery was perfused, andtracheal venous blood was collected. H₂O₂exposure (10 mM) reduced tracheal potential difference(42.0 ± 6.4 mV) to zero. It increased arterial andvenous flows (56.7 ± 6.1 and 57.3 ± 10.0%,respectively; n = 5, P < 0.01, paired t-test) but not tracheal lymph flow(unstimulated flow 5.0 ± 1.2 µl ^· min^{1 ·} cm¹,n = 4). DuringH₂O₂exposure, permeability to ^99mTc-DTPA increased from2.6 to 89.7 × 10⁷ cm/s(n = 5, P < 0.05), whereas permeability to[¹⁴C]AP (3,312.6 × 10⁷ cm/s,n = 4) was not altered significantly(2,565 × 10⁷cm/s). Luminal capsaicin (10 µM) increased tracheal blood flow (10.1 ± 4.1%, n = 5)and decreased venous ^99mTc-DTPAconcentration (19.7 ± 4.0, P < 0.01), and these effects weresignificantly greater after epithelial damage (28.1 ± 6.0 and45.7 ± 4.3%, respectively,P < 0.05, unpairedt-test). Thus H₂O₂increases the penetration of a hydrophilic tracer into tracheal bloodand lymph but has less effect on a lipophilic tracer. It also enhancesthe effects of luminal capsaicin on blood flow and tracer uptake.

     

Effect of luteal phase elevation in core temperature on forearm blood flow during exercise

Kolka, Margaret A., and Lou A. Stephenson. Effect ofluteal phase elevation in core temperature on forearm blood flow duringexercise. J. Appl. Physiol. 82(4):1079-1083, 1997.Forearm blood flow (FBF) as an index of skinblood flow in the forearm was measured in five healthy women by venousocclusion plethysmography during leg exercise at 80% peak aerobicpower and ambient temperature of 35°C (relative humidity 22%;dew-point temperature 10°C). Resting esophagealtemperature (T_es) was 0.3 ± 0.1°C higher in the midluteal than in the early follicular phase ofthe menstrual cycle (P < 0.05).Resting FBF was not different between menstrual cycle phases. TheT_es threshold for onset of skinvasodilation was higher (37.4 ± 0.2°C) in midluteal than inearly follicular phase (37.0 ± 0.1°C; P < 0.05). The slope of the FBF toT_es relationship was not different between menstrual cycle phases (14.0 ± 4.2 ml · 100 ml¹ · min¹ · °C¹for early follicular and 16.3 ± 3.2 ml · 100 ml¹ · min¹ · °C¹for midluteal phase). Plateau FBF was higher during exercise inmidluteal (14.6 ± 2.2 ml · 100 ml¹ · min¹ · °C¹)compared with early follicular phase (10.9 ± 2.4 ml · 100 ml¹ · min¹ · °C¹;P < 0.05). The attenuation of theincrease in FBF to T_es occurred when T_es was 0.6°C higher andat higher FBF in midluteal than in early follicular experiments(P < 0.05). In summary, the FBF response is different during exercise in the two menstrual cycle phasesstudied. After the attenuation of the increase in FBF and whileT_es was still increasing, thegreater FBF in the midluteal phase may have been due to the effects ofincreased endogenous reproductive endocrines on the cutaneousvasculature.

     

Changes in maximum oxygen uptake during prolonged training, overtraining, and detraining in horses

Tyler, Catherine M., Lorraine C. Golland, David L. Evans,David R. Hodgson, and Reuben J. Rose. Changes in maximum oxygenuptake during prolonged training, overtraining, and detraining inhorses. J. Appl. Physiol. 81(5):2244-2249, 1996.Thirteen standardbred horses were trained asfollows: phase 1 (endurance training, 7 wk),phase 2 (high-intensity training, 9 wk),phase 3 (overload training, 18 wk), andphase 4 (detraining, 12 wk). Inphase 3, the horses were divided intotwo groups: overload training (OLT) and control (C). The OLT groupexercised at greater intensities, frequencies, and durations than groupC. Overtraining occurred after 31 wk of training and was defined as asignificant decrease in treadmill run time in response to astandardized exercise test. In the OLT group, there was a significantdecrease in body weight (P < 0.05).From pretraining values of 117 ± 2 (SE)ml ^· kg^{1 ·} min¹,maximal O₂ uptake(O_{2 max}) increased by15% at the end of phase 1, and when signs of overtraining werefirst seen in the OLT group,O_{2 max} was 29%higher (151 ± 2 ml ^· kg^{1 ·} min¹in both C and OLT groups) than pretraining values. There was nosignificant reduction inO_{2 max} until after 6 wk detraining whenO_{2 max} was 137 ± 2 ml ^· kg^{1 ·} min¹.By 12 wk detraining, meanO_{2 max} was134 ± 2 ml ^· kg^{1 ·} min¹,still 15% above pretraining values. When overtraining developed, O_{2 max} was notdifferent between C and OLT groups, but maximal values forCO₂ production (147 vs. 159 ml ^· kg^{1 ·} min¹)and respiratory exchange ratio (1.04 vs. 1.11) were lower in the OLTgroup. Overtraining was not associated with a decrease inO_{2 max} and, afterprolonged training, decreases inO_{2 max} occurredslowly during detraining.

     

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.

     

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.

     

Effect of ventilation on vascular permeability and cyclic nucleotide concentrations in ischemic sheep lungs

Ventilation during ischemia attenuatesischemia-reperfusion lung injury, but the mechanism is unknown.Increasing tissue cyclic nucleotide levels has been shown to attenuatelung ischemia-reperfusion injury. We hypothesized thatventilation prevented increased pulmonary vascular permeability duringischemia by increasing lung cyclic nucleotide concentrations.To test this hypothesis, we measured vascular permeability and cGMP andcAMP concentrations in ischemic (75 min) sheep lungs that wereventilated (12 ml/kg tidal volume) or statically inflated with the samepositive end-expiratory pressure (5 Torr). The reflection coefficientfor albumin (_alb) was 0.54 ± 0.07 and 0.74 ± 0.02 (SE) in nonventilated and ventilatedlungs, respectively (n = 5, P < 0.05). Filtration coefficientsand capillary blood gas tensions were not different. The effect ofventilation was not mediated by cyclic compression of alveolarcapillaries, because negative-pressure ventilation(n = 4) also was protective (_alb = 0.78 ± 0.09). Thefinal cGMP concentration was less in nonventilated than in ventilatedlungs (0.02 ± 0.02 and 0.49 ± 0.18 nmol/g blood-free dry wt,respectively, n = 5, P < 0.05). cAMP concentrations werenot different between groups or over time. Sodium nitroprussideincreased cGMP (1.97 ± 0.35 nmol/g blood-free dry wt) and_alb (0.81 ± 0.09) innonventilated lungs (n = 5, P < 0.05). Isoproterenol increasedcAMP in nonventilated lungs (n = 4, P < 0.05) but had no effect on_alb. The nitric oxide synthaseinhibitor N^G-nitro-L-arginine methylester had no effect on lung cGMP (n = 9) or _alb(n = 16) in ventilated lungs but didincrease pulmonary vascular resistance threefold(P < 0.05) in perfused sheep lungs (n = 3). These results suggest thatventilation during ischemia prevented an increase in pulmonaryvascular protein permeability, possibly through maintenance of lungcGMP by a nitric oxide-independent mechanism.

     

Magnitude and time course of hemodynamic responses to Mueller maneuvers in patients with congestive heart failure

To simulate theimmediate hemodynamic effect of negative intrathoracic pressure duringobstructive apneas in congestive heart failure (CHF), without inducingconfounding factors such as hypoxia and arousals from sleep, eightawake patients performed, at random, 15-s Mueller maneuvers (MM) attarget intrathoracic pressures of 20 (MM 20) and40 cmH₂O (MM 40),confirmed by esophageal pressure, and 15-s breath holds, as apneic timecontrols. Compared with quiet breathing, at baseline, before theseinterventions, the immediate effects [first 5 cardiac cycles(SD), P values refer to MM 40compared with breath holds] of apnea, MM 20, and MM 40 were, for left ventricular (LV) systolic transmural pressure (Ptm), 1.0 ± 1.9, 7.2 ± 3.5, and 11.3 ± 6.8 mmHg(P < 0.01); for systolic bloodpressure (SBP), 2.9 ± 2.6, 5.5 ± 3.4, and 12.1 ± 6.8 mmHg (P < 0.01); and forstroke volume (SV) index, 0.4 ± 2.8, 4.1 ± 2.8, and6.9 ± 2.3 ml/m²(P < 0.001), respectively.Corresponding values over the last five cardiac cycles were for LVPtm6.4 ± 4.4, 5.4 ± 6.6, and 4.5 ± 9.1 mmHg (P < 0.01); for SBP6.9 ± 4.2, 8.2 ± 7.7, and 24.2 ± 6.9 mmHg (P < 0.01); and for SVindex 0.4 ± 2.1, 5.2 ± 2.8, and 9.2 ± 4.8 ml/m²(P < 0.001), respectively.Thus, in CHF patients, the initial hemodynamic response to thegeneration of negative intrathoracic pressure includes an immediateincrease in LV afterload and an abrupt fall in SV. The magnitude ofresponse is proportional to the intensity of the MM stimulus. By theend of a 15-s MM 40, LVPtm falls below baseline values, yet SVand SBP do not recover. Thus, when 40cmH₂O intrathoracic pressure issustained, additional mechanisms, such as a drop in LV preload due toventricular interaction, are engaged, further reducing SV. The neteffect of MM 40 was a 33% reduction in SV index (from 27 to 18 ml/min²), and a 21% reductionin SBP (from 121 to 96 mmHg). Obstructive apneas can have adverseeffects on systemic and, possibly, coronary perfusion in CHF throughdynamic mechanisms that are both stimulus and timedependent.

     

Age-related declines in maximal aerobic capacity in regularly exercising vs. sedentary women: a meta-analysis

Fitzgerald, Margaret D., Hirofumi Tanaka, Zung V. Tran, andDouglas R. Seals. Age-related declines in maximal aerobic capacityin regularly exercising vs. sedentary women: a meta-analysis. J. Appl. Physiol. 83(1): 160-165, 1997.Our purpose was to determine the relationship between habitualaerobic exercise status and the rate of decline in maximal aerobiccapacity across the adult age range in women. A meta-analytic approachwas used in which mean maximal oxygen consumption(O_{2 max}) values fromfemale subject groups (ages 18-89 yr) were obtained from thepublished literature. A total of 239 subject groups from 109 studiesinvolving 4,884 subjects met the inclusion criteria and werearbitrarily separated into sedentary (groups = 107; subjects = 2,256),active (groups = 69; subjects = 1,717), and endurance-trained (groups = 63; subjects = 911) populations.O_{2 max} averaged 29.7 ± 7.8, 38.7 ± 9.2, and 52.0 ± 10.5 ml · kg¹ · min¹,respectively, and was inversely related to age within each population (r = 0.82 to 0.87, allP < 0.0001). The rate of decline inO_{2 max} withincreasing subject group age was lowest in sedentary women (3.5ml · kg¹ · min¹· decade¹), greater inactive women (4.4ml · kg¹ · min¹· decade¹), andgreatest in endurance-trained women (6.2ml · kg¹ · min¹ · decade¹)(all P < 0.001 vs. each other). Whenexpressed as percent decrease from mean levels at age ~25 yr, therates of decline inO_{2 max} were similarin the three populations (10.0 to 10.9%/decade). Therewas no obvious relationship between aerobic exercise status and therate of decline in maximal heart rate with age. The results of thiscross-sectional study support the hypothesis that, in contrast to theprevailing view, the rate of decline in maximal aerobic capacity withage is greater, not smaller, in endurance-trained vs. sedentary women.The greater rate of decline inO_{2 max} in endurance-trained populations may be related to their higher values asyoung adults (baseline effect) and/or to greater age-related reductions in exercise volume; however, it does not appear to berelated to a greater rate of decline in maximal heart rate with age.

     

Effects of changes in pH and CO2 on pulmonary arterial wall tension are not endothelium dependent

We examined thechanges in isolated pulmonary artery (PA) wall tension on switchingfrom control conditions (pH 7.38 ± 0.01, PCO₂ 32.9 ± 0.4 Torr) toisohydric hypercapnia (pH change 0.00 ± 0.01, PCO₂ change 24.9 ± 1.1 Torr) ornormocapnic acidosis (pH change 0.28 ± 0.01, PCO₂ change 0.3 ± 0.04 Torr) and the role of the endothelium in these responses. In rat PA, submaximally contracted with phenylephrine, isohydric hypercapnia did not cause a significant change in mean (± SE) tension [3.0 ± 1.8% maximal phenylephrine-induced tension(P_o)]. Endothelial removal did not alter this response. In aorticpreparations, isohydric hypercapnia caused significant(P < 0.01) relaxation (27.4 ± 3.2% P_o), which waslargely endothelium dependent. Normocapnic acidosis caused relaxationof PA (20.2 ± 2.6% P_o), which was less(P < 0.01) than that observed in aorticpreparations (35.7 ± 3.4%P_o). Endothelial removal leftthe pulmonary response unchanged while increasing(P < 0.01) the aortic relaxation(53.1 ± 4.4% P_o).These data show that isohydric hypercapnia does not alter PA tone.Reduction of PA tone in normocapnic acidosis is endothelium independentand substantially less than that of systemic vessels.

     

Effect of prolonged, heavy exercise on pulmonary gas exchange in athletes

During maximalexercise, ventilation-perfusion inequality increases, especially inathletes. The mechanism remains speculative. Wehypothesized that, if interstitial pulmonary edema is involved, prolonged exercise would result in increasing ventilation-perfusion inequality over time by exposing the pulmonary vascular bed to highpressures for a long duration. The response to short-term exercise wasfirst characterized in six male athletes [maximal O₂ uptake(O_{2 max}) = 63 ml · kg¹ · min¹] by using 5 minof cycling exercise at 30, 65, and 90%O_{2 max}. Multiple inert-gas, blood-gas, hemodynamic, metabolic rate, and ventilatory data were obtained. Resting log SD of the perfusion distribution (logSD) was normal [0.50 ± 0.03 (SE)] and increased with exercise (logSD = 0.65 ± 0.04, P < 0.005), alveolar-arterialO₂ difference increased (to 24 ± 3 Torr), and end-capillary pulmonary diffusion limitation occurred at 90%O_{2 max}. The subjectsrecovered for 30 min, then, after resting measurements were taken,exercised for 60 min at ~65%O_{2 max}.O₂ uptake, ventilation, cardiacoutput, and alveolar-arterial O₂difference were unchanged after the first 5 min of this test, but logSD increased from0.59 ± 0.03 at 5 min to 0.66 ± 0.05 at 60 min(P < 0.05), without pulmonary diffusion limitation. LogSD was negativelyrelated to total lung capacity normalized for body surface area(r = 0.97,P < 0.005 at 60 min). These data are compatible with interstitial edema as a mechanism and suggest that lungsize is an important determinant of the efficiency of gas exchangeduring exercise.

     

Increased compliance in diaphragm muscle of the cardiomyopathic Syrian hamster

We investigatedthe hypothesis that diaphragm compliance was abnormal incardiomyopathic Syrian hamsters (CSH), an experimental model ofmyopathy. The passive elastic properties of isolated diaphragm muscleswere analyzed at both the muscle and sarcomere levels. We used thefollowing passive exponential relationship between stress () andstrain ():  = (E_o/)(e  1), where E_o is the initialelastic modulus and  is the stiffness constant. Immunocytochemistryprocedures were used to analyze the distribution of two key elasticcomponents of muscle, extracellular collagen and intracellular titinelastic components, as well as the extracellular matrix glycoproteinlaminin. Muscle and sarcomere values of  were nearly twofold lowerin CSH (8.7 ± 1.9 and 8.3 ± 1.4, respectively) than in controlanimals (19.7 ± 1.7 and 16.8 ± 2.1, respectively)(P < 0.01 for each). Compared withcontrols, E_o was higher in CSH.Sarcomere slack length was significantly longer in CSH than in controlanimals (2.1 ± 0.1 vs. 1.9 ± 0.1 µm,P < 0.05). The surface area ofcollagen I was significantly larger in CSH (17.4 ± 1.8%) than incontrol animals (12.4 ± 0.7%, P < 0.05). There was no change in the distribution of titin or lamininlabelings between the groups. These results demonstrate increaseddiaphragm compliance in cardiomyopathic hamsters. The increase in CSHdiaphragm compliance was observed despite an increase in the surfacearea of collagen and was not associated with an abnormal distributionof titin or laminin.

     

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.

     

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.

     

Bioenergetics of contracting skeletal muscle after partial reduction of blood flow

The purpose ofthis study was to examine the bioenergetics and regulation ofO₂ uptake(O₂) and force productionin contracting muscle when blood flow was moderately reduced during asteady-state contractile period. Canine gastrocnemius muscle(n = 5) was isolated, and 3-minstimulation periods of isometric, tetanic contractions were elicitedsequentially at rates of 0.25, 0.33, and 0.5 contractions/s (Hz)immediately followed by a reduction of blood flow [ischemic (I)condition] to 46 ± 3% of the value obtained at 0.5 Hz with normal blood flow. TheO₂ of thecontracting muscle was significantly (P < 0.05) reduced during the Icondition [6.5 ± 0.8 (SE) ml · 100 g¹ · min¹]compared with the same stimulation frequency with normal flow (11.2 ± 1.5 ml · 100 g¹ · min¹),as was the tension-time index (79 ± 12 vs. 123 ± 22 N · g¹ · min¹,respectively). The ratio ofO₂ to tension-time indexremained constant throughout all contraction periods. Musclephosphocreatine concentration, ATP concentration, and lactate effluxwere not significantly different during the I condition compared withthe 0.5-Hz condition with normal blood flow. However, at comparable rates of O₂ andtension-time index, muscle phosphocreatine concentration and ATPconcentration were significantly less during the I condition comparedwith normal-flow conditions. These results demonstrate that, in thishighly oxidative muscle, the normal balance ofO₂ supply to force output wasmaintained during moderate ischemia by downregulation of forceproduction. In addition,1) the minimal disruption inintracellular homeostasis after the initiation of ischemia waslikely a result of steady-state metabolic conditions having alreadybeen activated, and 2) thedifference in intracellular conditions at comparable rates ofO₂ and tension-time index between the normal flow and I condition may have been due to altered intracellular O₂ tension.