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

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

     

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.

     

Protein kinase C modulation of ventilatory response to hypoxia in nucleus tractus solitarii of conscious rats

This study aimedto determine the role of protein kinase C (PKC) in signal transductionmechanisms underlying ventilatory regulation in the nucleus tractussolitarii (NTS). Microinjection of phorbol 12-myristate 13-acetate intothe commissural NTS of nine chronically instrumented, unrestrained ratselicited significant cardiorespiratory enhancements that lasted for atleast 4 h, whereas administration of vehicle(n = 15) or the inactive phorbol ester 4-phorbol 12,13-didecanoate (n = 7)did not elicit minute ventilation (E)changes. Peak hypoxic Eresponses (10% O₂-balanceN₂) were measured in 19 additional animals after NTS microinjection of bisindolylmaleimide(BIM) I, a selective PKC inhibitor (n = 12), BIM V (inactive analog; n = 7),or vehicle (Con; n = 19). In Con,E increased from 139 ± 9 to 285 ± 26 ml/min in room air and hypoxia, respectively, and similarresponses occurred after BIM V. BIM I did not affect room airE but markedly attenuated hypoxia-induced E increases (128 ± 12 to 167 ± 18 ml/min; P < 0.02 vs. Con and BIM V). When BIM I was microinjected into the cerebellum(n = 4), cortex(n = 4), or spinal cord(n = 4),E responses were similar to Con.Western blots of subcellular fractions of dorsocaudal brain stemlysates revealed translocation of PKC, , , , , and  isoenzymes during acute hypoxia, and enhanced overall PKC activity wasconfirmed in the particulate fraction of dorsocaudal brain stem lysatesharvested after acute hypoxia. These studies suggest that, in the adultrat, PKC activation in the NTS mediates essential components of theacute hypoxic ventilatory response.

     

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.

     

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).

     

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.

     

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.

     

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.

     

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.     

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.

     

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.

     

Blood volume and cardiac index in rats after exchange transfusion with hemoglobin-based oxygen carriers

Migita, Russell, Armando Gonzales, Maria L. Gonzales, Kim D. Vandegriff, and Robert M. Winslow. Blood volume and cardiac indexin rats after exchange transfusion with hemoglobin-based oxygencarriers. J. Appl. Physiol. 82(6):1995-2002, 1997.We have measured plasma volume and cardiac indexin rats after 50% isovolemic exchange transfusion with humanhemoglobin cross-linked between the -chains withbis(3,5-dibromosalicyl)fumarate (Hb) and with bovine hemoglobinmodified with polyethylene glycol (PEGHb). Hb and PEGHb differ incolloid osmotic pressure (23.4 and 118.0 Torr, respectively), oxygenaffinity (oxygen half-saturation pressure of hemoglobin = 30.0 and 10.2 Torr, respectively), viscosity (1.00 and 3.39 cP, respectively), andmolecular weight (64,400 and 105,000, respectively). Plasma volume wasmeasured by Evans blue dye dilution modified for interference by plasmahemoglobin. Blood volumes in PEGHb-treated animals were significantlyelevated (74.0 ± 3.5 ml/kg) compared with animals treated withHb (49.0 ± 1.2 ml/kg) or Ringer lactate (48.0 ± 2.0 ml/kg) or with controls (58.2 ± 1.9 ml/kg). Heart rate reductionafter Hb exchange is opposite to that expected with blood volumecontraction, suggesting that Hb may have a direct myocardialdepressant action. The apparently slow elimination of PEGHb during the2 h after its injection is a consequence of plasma volume expansion:when absolute hemoglobin (concentration × plasma volume) iscompared for PEGHb and Hb, no difference in their eliminationrates is found. These studies emphasize the need to understand bloodvolume regulation when the effects of cell-free hemoglobin onhemodynamic measurements are evaluated.

     

Airway thermal volume in humans and its relation to body size

Serikov, Vladimir B., E. Heidi Jerome, Neal W. Fleming,Peter G. Moore, Frederick A. Stawitcke, and Norman C. Staub.Airway thermal volume in humans and its relation to body size.J. Appl. Physiol. 83(2): 668-676, 1997.The objective of this study was to investigate the influence ofvolume ventilation(E) andcardiac output () on the temperature of the expiredgas at the distal end of the endotracheal tube in anesthetized humans.In 63 mechanically ventilated adults, we used a step decrease in thehumidity of inspired gas to cool the lungs. After change from humid todry gas ventilation, the temperature of the expired gas decreased. Weevaluated the relationship between the inverse monoexponential timeconstant of the temperature fall (1/) and eitherE or . WhenE wasincreased from 5.67 ± 1.28 to 7.14 ± 1.60 (SD) l/min(P = 0.02), 1/ did not changesignificantly [from 1.25 ± 0.38 to 1.21 ± 0.51 min¹,P = 0.81]. In the 11 patients in whom changed during the study period(from 5.07 ± 1.81 to 7.38 ± 2.45 l/min,P = 0.02), 1/ increasedcorrespondingly from 0.89 ± 0.22 to 1.52 ± 0.44 min¹(P = 0.003). We calculated the airwaythermal volume (ATV) as the ratio of the measured values to 1/ and related it to the body height (BH):ATV (liters) = 0.086 BH (cm)  9.55 (r = 0.90).

     

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.

     

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.

     

Absence of myofibrillar creatine kinase and diaphragm isometric function during repetitive activation

Creatine kinase(CK) provides ATP buffering in skeletal muscle and is expressed as1) cytosolic myofibrillar CK (M-CK)and 2) sarcomeric mitochondrial CK(ScCKmit) isoforms that differ in their subcellular localization. Wecompared the isometric contractile and fatigue properties of1) control CK-sufficient (Ctl),2) M-CK-deficient (M-CK[/]), and3) combined M-CK/ScCKmit-deficientnull mutant (CK[/]) diaphragm (Dia) todetermine the effect of the absence of M-CK activity on Dia performancein vitro. Baseline contractile properties were comparable across groupsexcept for specific force, which was ~16% lower inCK[/] Dia compared withM-CK[/] and Ctl Dia. During repetitiveactivation (40 Hz, duty cycle), force declined in all threegroups. This decline was significantly greater inCK[/] Dia compared with Ctl and M-CK[/] Dia. The pattern of forcedecline did not differ between M-CK[/] andCtl Dia. We conclude that Dia isometric muscle function is notabsolutely dependent on the presence of M-CK, whereas the completeabsence of CK acutely impairs isometric force generation duringrepetitive activation.

     

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.

     

Activity of respiratory pump and upper airway muscles during sleep onset

Ventilationdecreases at sleep onset. This change is initiated abruptly at -electroencephalographic transitions. The aim of this study was todetermine the contributions of reduced activity in respiratory pumpmuscles and upper airway dilator muscles to this change. Surfaceelectromyograms over the diaphragm (Di) and intercostal muscles andfine-wire intramuscular electrodes in genioglossus (GG) and tensorpalatini (TP) muscles were recorded in nine healthy young men. It wasshown that phasic Di and both phasic and tonic TP activities were lowerduring  than during  activity. Breath-by-breath analysis of thechanges at - transitions during the sleep-onset period showed anumber of changes. At - transitions, phasic activity of Di,intercostal, and GG muscles fell and rose again, and phasic and tonicactivities of TP fell and remained at low levels during . With astate transition from  to , the phasic and tonic activities ofthe Di, GG, and TP increased dramatically. It is now clear that thefall in ventilation that occurs with sleep is related to a fall inactivities of both upper airway dilator muscles and respiratory pumpmuscles.

     

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.

     

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.