Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea

Xie, Ailiang, Fiona Rankin, Ruth Rutherford, and T. DouglasBradley. Effects of inhaledCO₂ and added dead space on idiopathic central sleep apnea. J. Appl.Physiol. 82(3): 918-926, 1997.We hypothesizedthat reductions in arterial PCO₂ (Pa_CO2) below the apnea threshold play akey role in the pathogenesis of idiopathic central sleep apnea syndrome(ICSAS). If so, we reasoned that raisingPa_CO2 would abolish apneas in thesepatients. Accordingly, patients with ICSAS were studied overnight onfour occasions during which the fraction of end-tidalCO₂ and transcutaneous PCO₂ were measured: during room airbreathing (N1), alternating room airand CO₂ breathing(N2),CO₂ breathing all night(N3), and addition of dead space viaa face mask all night (N4).Central apneas were invariably preceded by reductions infraction of end-tidal CO₂. Bothadministration of a CO₂-enrichedgas mixture and addition of dead space induced 1- to 3-Torr increasesin transcutaneous PCO₂, whichvirtually eliminated apneas and hypopneas; they decreased from43.7 ± 7.3 apneas and hypopneas/h onN1 to 5.8 ± 0.9 apneas andhypopneas/h during N3(P < 0.005), from 43.8 ± 6.9 apneas and hypopneas/h during room air breathing to 5.9 ± 2.5 apneas and hypopneas/h of sleep duringCO₂ inhalation during N2 (P < 0.01), and to 11.6% of the room air level while the patients werebreathing through added dead space duringN4 (P < 0.005). Because raisingPa_CO2 through two different meansvirtually eliminated central sleep apneas, we conclude that centralapneas during sleep in ICSA are due to reductions inPa_CO2 below the apnea threshold.

     

Effects of supplemental oxygen on forearm vasodilation in humans

Crawford, Paul, Peter A. Good, Eric Gutierrez, Joshua H. Feinberg, John P. Boehmer, David H. Silber, and Lawrence I. Sinoway. Effects of supplemental oxygen on forearm vasodilation in humans.J. Appl. Physiol. 82(5):1601-1606, 1997.Supplemental O₂ reduces cardiac output andraises systemic vascular resistance in congestive heart failure. Inthis study, 100% O₂ was given tonormal subjects and peak forearm flow was measured. Inexperiment 1, 100%O₂ reduced blood flow andincreased resistance after 10 min of forearm ischemia (flow 56.7 ± 7.9 vs. 47.8 ± 6.7 ml · min¹ · 100 ml¹;P < 0.02; vascular resistance 1.7 ± 0.2 vs. 2.4 ± 0.4 mmHg · min · 100 ml · ml¹;P < 0.03). Inexperiment 2, lower body negativepressure (LBNP; 30 mmHg) and venous congestion (VC) simulatedthe high sympathetic tone and edema of congestive heart failure.Postischemic forearm flow and resistance were measured under fourconditions: room air breathing (RA); LBNP+RA; RA+LBNP+VC; and 100%O₂+LBNP+VC. LBNP and VC did notlower peak flow. However, O₂raised minimal resistance (2.3 ± 0.4 RA; 2.8 ± 0.5 O₂+LBNP+VC,P < 0.04). When O₂ alone(experiment 1) was compared withO₂+LBNP+VC(experiment 2), no effect of LBNP+VCon peak flow or minimum resistance was noted, although the return rateof flow and resistance toward baseline was increased.O₂ reduces peak forearm flow evenin the presence of LBNP and VC.

     

Effect of supplemental oxygen on supramaximal exercise performance and recovery in cystic fibrosis

Shah, Ashish R., Thomas G. Keens, and David Gozal.Effect of supplemental oxygen on supramaximal exercise performance and recovery in cystic fibrosis. J. Appl.Physiol. 83(5): 1641-1647, 1997.The effects ofsupplemental O₂ on recovery fromsupramaximal exercise and subsequent performance remain unknown. Ifrecovery from exercise could be enhanced in individuals with chroniclung disease, subsequent supramaximal exercise performance could also be improved. Recovery from supramaximal exercise and subsequent supramaximal exercise performance were assessed after 10 min of breathing 100% O₂ or room air(RA) in 17 cystic fibrosis (CF) patients [25 ± 10 (SD) yrold, 53% men, forced expired volume in 1 s = 62 ± 21%predicted] and 17 normal subjects (25 ± 8 yr old, 59% men,forced expired volume in 1 s = 112 ± 15% predicted). Supramaximalperformance was assessed as the work of sustained bicycling at a loadof 130% of the maximum load achieved during a graded maximal exercise.Peak minute ventilation(E) andheart rate (HR) were lower in CF patients at the end of eachsupramaximal bout than in controls. In CF patients, single-exponentialtime decay constants indicated faster recovery of HR(_HR = 86 ± 8 and 73 ± 6 s in RA and O₂,respectively, P < 0.01). Similarly, fast and slow time constants of two-exponential equations providing thebest fit for ventilatory recovery were improved in CF patients duringO₂ breathing ( = 132.1 ± 10.5 vs. 82.5 ± 10.4 s; = 880.3 ± 300.1 vs. 368.6 ± 107.1 s,P < 0.01). However, no such improvements occurred in controls. Supramaximal performance after O₂ improved in CF patients (109 ± 6% of the 1st bout after O₂ vs. 94 ± 6% in RA, P < 0.01).O₂ supplementation had no effect on subsequent performance in controls (97 ± 3% inO₂ vs. 93 ± 3% in RA). Weconclude that supplemental O₂after a short bout of supramaximal exercise accelerates recovery andpreserves subsequent supramaximal performance in patients with CF.

     

Ventilatory response to exercise in subjects breathing CO2 or HeO2

Babb, T. G. Ventilatory response to exercise insubjects breathing CO₂ orHeO₂.J. Appl. Physiol. 82(3): 746-754, 1997.To investigate the effects of mechanical ventilatory limitationon the ventilatory response to exercise, eight older subjects with normal lung function were studied. Each subject performed graded cycleergometry to exhaustion once while breathing room air; once whilebreathing 3% CO₂-21%O₂-balanceN₂; and once while breathing HeO₂ (79% He and 21%O₂). Minute ventilation(E) and respiratory mechanics weremeasured continuously during each 1-min increment in work rate (10 or20 W). Data were analyzed at rest, at ventilatory threshold (VTh),and at maximal exercise. When the subjects were breathing 3%CO₂, there was an increase(P < 0.001) inE at rest and at VTh but not duringmaximal exercise. When the subjects were breathingHeO₂,E was increased(P < 0.05) only during maximalexercise (24 ± 11%). The ventilatory response to exercise belowVTh was greater only when the subjects were breathing 3% CO₂(P < 0.05). Above VTh, theventilatory response when the subjects were breathingHeO₂ was greater than whenbreathing 3% CO₂(P < 0.01). Flow limitation, aspercent of tidal volume, during maximal exercise was greater(P < 0.01) when the subjects werebreathing CO₂ (22 ± 12%) thanwhen breathing room air (12 ± 9%) or when breathingHeO₂ (10 ± 7%)(n = 7). End-expiratory lung volumeduring maximal exercise was lower when the subjects were breathingHeO₂ than when breathing room airor when breathing CO₂(P < 0.01). These data indicate thatolder subjects have little reserve for accommodating an increase inventilatory demand and suggest that mechanical ventilatory constraintsinfluence both the magnitude of Eduring maximal exercise and the regulation ofE and respiratory mechanics duringheavy-to-maximal exercise.

     

Within-night variation in respiratory effort preceding apnea termination and EEG delta power in sleep apnea

We studied the within-night variability of themaximum esophageal pressure deflection before apnea termination(DP_max) in nine patients withsevere obstructive sleep apnea as an index of the arousal threshold andthe mean electroencephalogram (EEG) delta power for each 30 s as anindex of the timing of sleep cycles. Periodicity in the time variationof delta power and DP_max was analyzed by determining their power spectral density and their relationship determined by cross correlation.DP_max and delta power variedcyclically and in phase with a major periodicity (major peak in powerspectral density) of 117.6 ± 8.8 (SE) min. The correlation betweenthe values of DP_max and deltapower was significant (P < 0.001) ineach subject (mean r = 0.47 ± 0.03), and the coherence betweenDP_max and delta power at theirdominant frequency was high. Within cycles of non-rapid-eye-movementsleep, DP_max and delta powerincreased, reaching peak values on average at or after midcycle. Thesefindings suggest that the arousal threshold to airway occlusion inpatients with obstructive sleep apnea varies cyclically during thenight synchronous to the underlying cycles of sleep.

     

Respiratory changes associated with rapid eye movements in normo- and hypercapnia during sleep

Rapid eyemovements during rapid-eye-movement (REM) sleep are associated withrapid, shallow breathing. We wanted to know whether thiseffect persisted during increased respiratory drive byCO₂. In eight healthy subjects, werecorded electroencephalographic, electrooculographic, andelectromyographic signals, ventilation, and end-tidalPCO₂ during the night. InspiratoryPCO₂ was changed to increaseend-tidal PCO₂ by 3 and 6 Torr. During normocapnia, rapid eye movements were associated with a decreasein total breath time by 0.71 ± 0.19 (SE) s(P < 0.05) because of shortenedexpiratory time (0.52 ± 0.08 s,P < 0.001) and with a reduced tidalvolume (89 ± 27 ml, P < 0.05) because of decreased rib cage contribution (75 ± 18 ml, P < 0.05). Abdominal (11 ± 16 ml, P = 0.52) and minuteventilation (0.09 ± 0.21 ml/min, P = 0.66) did not change. Inhypercapnia, however, rapid eye movements were associated with afurther shortening of total breath time. Abdominal breathing was alsoinhibited (79 ± 23 ml, P < 0.05), leading to a stronger inhibition of tidal volume and minuteventilation (1.84 ± 0.54 l/min,P < 0.05). We conclude thatREM-associated respiratory changes are even more pronounced duringhypercapnia because of additional inhibition of abdominal breathing.This may contribute to the reduction of the hypercapnic ventilatory response during REM sleep.

     

Systemic and pulmonary hemodynamic responses to normal and obstructed breathing during sleep

Schneider, H., C. D. Schaub, K. A. Andreoni, A. R. Schwartz,R. L. Smith, J. L. Robotham, and C. P. O'Donnell. Systemic andpulmonary hemodynamic responses to normal and obstructed breathing during sleep. J. Appl. Physiol. 83(5):1671-1680, 1997.We examined the hemodynamic responses to normalbreathing and induced upper airway obstructions during sleep in acanine model of obstructive sleep apnea. During normal breathing,cardiac output decreased (12.9 ± 3.5%,P < 0.025) from wakefulness tonon-rapid-eye-movement sleep (NREM) but did not change from NREM torapid-eye-movement (REM) sleep. There was a decrease(P < 0.05) in systemic (7.2 ± 2.1 mmHg) and pulmonary (2.0 ± 0.6 mmHg) arterial pressures fromwakefulness to NREM sleep. In contrast, systemic (8.1 ± 1.0 mmHg,P < 0.025), but not pulmonary,arterial pressures decreased from NREM to REM sleep. During repetitiveairway obstructions (56.0 ± 4.7 events/h) in NREM sleep, cardiacoutput (17.9 ± 3.1%) and heart rate (16.2 ± 2.5%) increased(P < 0.05), without a change instroke volume, compared with normal breathing during NREM sleep. Duringsingle obstructive events, left (7.8 ± 3.0%,P < 0.05) and right (7.1 ± 0.7%, P < 0.01)ventricular outputs decreased during the apneic period. However, left(20.7 ± 1.6%, P < 0.01) andright (24.0 ± 4.2%, P < 0.05)ventricular outputs increased in the postapneic period because of anincrease in heart rate. Thus 1) thesystemic, but not the pulmonary, circulation vasodilates during REMsleep with normal breathing; 2)heart rate, rather than stroke volume, is the dominant factormodulating ventricular output in response to apnea; and3) left and right ventricular outputs oscillate markedly and in phase throughout the apnea cycle.

     

Prostaglandin production contributes to exercise-induced vasodilation in heart failure

Lang, Chim C., Don B. Chomsky, Javed Butler, Shiv Kapoor,and John R. Wilson. Prostaglandin production contributes toexercise-induced vasodilation in heart failure. J. Appl. Physiol. 83(6): 1933-1940, 1997.Endothelial release of prostaglandins may contribute toexercise-induced skeletal muscle arteriolar vasodilation in patientswith heart failure. To test this hypothesis, we examined the effect ofindomethacin on leg circulation and metabolism in eight chronic heartfailure patients, aged 55 ± 4 yr. Central hemodynamics and legblood flow, determined by thermodilution, and leg metabolic parameterswere measured during maximum treadmill exercise before and 2 h afteroral administration of indomethacin (75 mg). Leg release of6-ketoprostaglandin F₁ was alsomeasured. During control exercise, leg blood flow increased from 0.34 ± 0.03 to 1.99 ± 0.19 l/min(P < 0.001), legO₂ consumption from 13.6 ± 1.8 to 164.5 ± 16.2 ml/min (P < 0.001), and leg prostanoid release from 54.1 ± 8.5 to267.4 ± 35.8 pg/min (P < 0.001).Indomethacin suppressed release of prostaglandinF₁(P < 0.001) throughout exercise anddecreased leg blood flow during exercise(P < 0.05). This was associated witha corresponding decrease in leg O₂ consumption (P < 0.05) and a higher level offemoral venous lactate at peak exercise(P < 0.01). These data suggest thatrelease of vasodilatory prostaglandins contributes to skeletal musclearteriolar vasodilation in patients with heart failure.

     

Comparative hemodynamic effects of periodic obstructive and simulated central apneas in sedated pigs

Chen, Ling, and Steven M. Scharf. Comparativehemodynamic effects of periodic obstructive and simulated centralapneas in sedated pigs. J. Appl.Physiol. 83(2): 485-494, 1997.It has beenspeculated that because of increased left ventricular (LV) afterload,decreased intrathoracic pressure (ITP) is responsible for decreasedcardiac output (CO) in obstructive sleep apnea. If this were true, thenobstructive apnea (OA) should have a greater effect on CO than wouldcentral apnea (CA). To assess the importance of decreasedITP during OA, we studied seven preinstrumented sedated pigs with OAand simulated CA that were matched for blood gases and apneaperiodicities (with 15- or 30-s apnea duration). Compared with OA, CAwith 30-s apnea duration produced comparable decreases in heart rate(from baseline to end apnea: OA, 106.6 ± 4.8 to 93.4 ± 4.4 beats/min, P < 0.01; and CA, 111.1 ± 6.2 to 94.0 ± 5.2 beats/min,P < 0.01) and comparable increasesin LV end-diastolic pressure and LV end-diastolic myocardial segmentlength but greater increases in mean arterial pressure (97.1 ± 3.7 to 107.7 ± 4.3 Torr, P < 0.05;and 97.3 ± 4.8 to 119.3 ± 7.4 Torr,P < 0.01) and systemic vascularresistance (2,577 ± 224 to 3,346 ± 400 dyn · s · cm⁵,P < 0.01; and 2,738 ± 294 to5,111 ± 1,181 dyn · s · cm⁵,P < 0.01) and greater decreases inCO (3.18 ± 0.31 to 2.74 ± 0.26 l/min,P < 0.05; and 3.07 ± 0.38 to2.30 ± 0.36 l/min, P < 0.01) andstroke volume (32.2 ± 2.9 to 25.9 ± 2.4 ml,P < 0.05; and 31.5 ± 1.9 to 19.8 ± 3.1 ml, P < 0.01). Only CA increased LV end-systolic myocardialsegment length. Similar findings were observed with 15-s apneaduration. We conclude that CA produced greater depression of CO andgreater changes of afterload-related LV dysfunction than did OA.Therefore, decreased ITP was not the dominant factor determining LVfunction with apneas.

     

Expiratory flow limitation and intrinsic positive end-expiratory pressure in obesity

Breathing at very low lung volumes might beaffected by decreased expiratory airflow and air trapping. Our purposewas to detect expiratory flow limitation (EFL) and, as a consequence, intrinsic positive end-expiratory pressure(PEEP_i) in grossly obesesubjects (OS). Eight OS with a mean body mass index (BMI) of 44 ± 5 kg/m² and six age-matchednormal-weight control subjects (CS) were studied in different bodypositions. Negative expiratory pressure (NEP) was used to determineEFL. In contrast to CS, EFL was found in two of eight OS in the uprightposition and in seven of eight OS in the supine position. DynamicPEEP_i and mean transdiaphragmatic pressure (mean Pdi) were measured in all six CS and in six of eight OS.In OS, PEEP_i increased from 0.14 ± 0.06 (SD) kPa in the upright position to 0.41 ± 0.11 kPa inthe supine position (P < 0.05) anddecreased to 0.20 ± 0.08 kPa in the right lateral position(P < 0.05, compared with supine),whereas, in CS, PEEP_i wassignificantly smaller (<0.05 kPa) in each position. In OS, mean Pdiin each position was significantly larger compared with CS. Mean Pdiincreased from 1.02 ± 0.32 kPa in the upright position to 1.26 ± 0.17 kPa in the supine position (not significant) and decreasedto 1.06 ± 0.26 kPa in the right lateral position(P < 0.05, compared with supine),whereas there were no significant changes in CS. We conclude that in OS1) tidal breathing can be affectedby EFL and PEEP_i;2) EFL andPEEP_i are promoted by the supineposture; and 3) the increaseddiaphragmatic load in the supine position is, in part, related toPEEP_i.

     

Effect of crystalloid administration on oxygen extraction in endotoxemic pigs

We asked whethercrystalloid administration improves tissue oxygen extraction inendotoxicosis. Four groups of anesthetized pigs(n = 8/group) received either normalsaline infusion or no saline and either endotoxin or no endotoxin. Wemeasured whole body (WB) and gut oxygen delivery and consumption duringhemorrhage to determine the critical oxygen extraction ratio(ER_O2 crit). Just after onset of ischemia (critical oxygen delivery rate), gut was removed for determination of area fraction of interstitial edema and capillary hematocrit. Radiolabeled microspheres were used todetermine erythrocyte transit time for the gut. Endotoxin decreased WBER_O2 crit(0.82 ± 0.06 to 0.55 ± 0.08, P < 0.05) and gutER_O2 crit(0.77 ± 0.07 to 0.52 ± 0.06, P < 0.05). Unexpectedly, saline administration also decreased WBER_O2 crit (0.82 ± 0.06 to 0.62 ± 0.08, P < 0.05) and gutER_O2 crit (0.77 ± 0.07 to 0.67 ± 0.06, P < 0.05) in nonendotoxin pigs. Saline administration increased thearea fraction of interstitial space (P < 0.05) and resulted in arterial hemodilution(P < 0.05) but not capillaryhemodilution (P > 0.05). Salineincreased the relative dispersion of erythrocyte transit times from0.33 ± 0.08 to 0.72 ± 0.53 (P < 0.05). Thus saline administration impairs tissue oxygen extractionpossibly by increasing interstitial edema or increasing heterogeneityof microvascular erythrocyte transit times.

     

Cerebral vasomotor reactivity at high altitude in humans

The purpose of this study was twofold:1) to determine whether at highaltitude cerebral blood flow (CBF) as assessed during CO₂ inhalation and duringhyperventilation in subjects with acute mountain sickness (AMS) wasdifferent from that in subjects without AMS and2) to compare the CBF as assessedunder similar conditions in Sherpas at high altitude and in subjects atsea level. Resting control values of blood flow velocity in themiddle cerebral artery (V_MCA), pulseoxygen saturation (Sa_O2), andtranscutaneous PCO₂ were measured at4,243 m in 43 subjects without AMS, 17 subjects with AMS, 20 Sherpas,and 13 subjects at sea level. Responses ofCO₂ inhalation andhyperventilation onV_MCA,Sa_O2, and transcutaneous PCO₂ were measured, and the cerebralvasomotor reactivity (VMR = V_MCA/PCO₂)was calculated as the fractional change ofV_MCA per Torrchange of PCO₂, yielding ahypercapnic VMR and a hypocapnic VMR. AMS subjects showeda significantly higher resting controlV_MCA than didno-AMS subjects (74 ± 22 and 56 ± 14 cm/s, respectively;P < 0.001), andSa_O2 was significantly lower (80 ± 8 and 88 ± 3%, respectively; P < 0.001). Resting control V_MCA values inthe sea-level group (60 ± 15 cm/s), in the no-AMS group, and inSherpas (59 ± 13 cm/s) were not different. Hypercapnic VMR valuesin AMS subjects were 4.0 ± 4.4, in no-AMS subjects were 5.5 ± 4.3, in Sherpas were 5.6 ± 4.1, and in sea-level subjects were 5.6 ± 2.5 (not significant). Hypocapnic VMR values were significantly higher in AMS subjects (5.9 ± 1.5) compared with no-AMS subjects (4.8 ± 1.4; P < 0.005) but werenot significantly different between Sherpas (3.8 ± 1.1) and thesea-level group (2.8 ± 0.7). We conclude that AMS subjects havegreater cerebral hemodynamic responses to hyperventilation, higherV_MCAresting control values, and lower Sa_O2 compared with no-AMSsubjects. Sherpas showed a cerebral hemodynamic patternsimilar to that of normal subjects at sea level.     

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.

     

Effects of load and tone on the mechanics of isolated human bronchial smooth muscle

Isotonic and isometric properties of nine human bronchial smoothmuscles were studied under various loading and tone conditions. Freshlydissected bronchial strips were electrically stimulated successively atbaseline, after precontraction with10⁷ M methacholine (MCh),and after relaxation with10⁵ M albuterol (Alb).Resting tension, i.e., preload determining optimal initial length(L_o) atbaseline, was held constant. Compared with baseline, MCh decreasedmuscle length to 93 ± 1%L_o(P < 0.001) before any electricalstimulation, whereas Alb increased it to 111 ± 3%L_o(P < 0.01). MCh significantlydecreased maximum unloaded shortening velocity (0.045 ± 0.007 vs.0.059 ± 0.007 L_o/s), maximalextent of muscle shortening (8.4 ± 1.2 vs. 13.9 ± 2.4%L_o), and peakisometric tension (6.1 ± 0.8 vs. 7.2 ± 1.0 mN/mm²). Alb restored all thesecontractile indexes to baseline values. These findings suggest that MChreversibly increased the number of active actomyosin cross bridgesunder resting conditions, limiting further muscle shortening and activetension development. After the electrically induced contraction,muscles showed a transient phase of decrease in tension below preload.This decrease in tension was unaffected by afterload levels but wassignificantly increased by MCh and reduced by Alb. These findingssuggest that the cross bridges activated before, but not during, theelectrically elicited contraction may modulate the phase of decrease intension below preload, reflecting the active part of resting tension.     

Ozone enhances excitabilities of pulmonary C fibers to chemical and mechanical stimuli in anesthetized rats

Acute exposureto ozone (O₃) enhances pulmonarychemoreflex response to capsaicin, and an increased sensitivity ofbronchopulmonary C-fiber afferent endings may be involved. The presentstudy was aimed at determining the effect ofO₃ on the responses of pulmonary Cfibers to chemical and mechanical stimuli. A total of 31 C fibers werestudied in anesthetized, open-chest, and vagotomized rats. Duringcontrol, right atrial injection of a low dose of capsaicin abruptlyevoked a short and mild burst of discharge [0.77 ± 0.28 impulses (imp)/s, 2-s average]. After acute exposure toO₃ (3 parts/million for 30 min),there was no significant change in arterial blood pressure, trachealpressure, or baseline activity of C fibers. However, the stimulatoryeffect of the same dose of capsaicin on these fibers was markedlyenhanced (6.05 ± 0.88 impulses/s;P < 0.01) and prolonged immediatelyafter O₃ exposure, and returnedtoward control in 54 ± 6 min. Similarly, the pulmonary C-fiberresponse to injection of a low dose of lactic acid was also elevatedafter O₃ exposure. Furthermore,O₃ exposure significantly potentiated the C-fiber response to constant-pressure (tracheal pressure = 30 cmH₂O) lunginflation (control: 0.19 ± 0.07 imp/s; afterO₃: 1.12 ± 0.26 imp/s;P < 0.01). In summary, these results show that the excitabilities of pulmonary C-fiber afferents to lunginflation and injections of chemical stimulants are markedly potentiated after acute exposure toO₃, suggesting a possible involvement of these afferents in theO₃-induced changes in breathing pattern and chest discomfort in humans.

     

Nitric oxide regulates oxygen uptake and hydrogen peroxide release by the isolated beating rat heart

Isolated rat heart perfused with 1.5-7.5µM NO solutions or bradykinin, which activates endothelial NOsynthase, showed a dose-dependent decrease in myocardial O₂uptake from 3.2 ± 0.3 to 1.6 ± 0.1 (7.5 µM NO, n = 18,P < 0.05) and to 1.2 ± 0.1 µM O₂ · min¹ · gtissue¹ (10 µM bradykinin, n = 10,P < 0.05). Perfused NO concentrations correlated with aninduced release of hydrogen peroxide (H₂O₂) inthe effluent (r = 0.99, P < 0.01). NO markedlydecreased the O₂ uptake of isolated rat heart mitochondria(50% inhibition at 0.4 µM NO, r = 0.99,P < 0.001). Cytochrome spectra in NO-treated submitochondrial particles showed a double inhibition of electron transfer at cytochrome oxidase and between cytochrome b andcytochrome c, which accounts for the effects in O₂uptake and H₂O₂ release. Most NO was bound tomyoglobin; this fact is consistent with NO steady-state concentrationsof 0.1-0.3 µM, which affect mitochondria. In the intact heart,finely adjusted NO concentrations regulate mitochondrial O₂uptake and superoxide anion production (reflected byH₂O₂), which in turn contributes to thephysiological clearance of NO through peroxynitrite formation.

     

Age-dependent response of the electrocardiogram to K(+) channel blockers in mice

Developmental changes in electrocardiogram (ECG) andresponse to selective K⁺ channelblockers were assessed in conscious, unsedated neonatal (days 1, 7, 14) and adult male mice(>60 days of age). Mean sinus R-R interval decreased from 120 ± 3 ms in day 1 to 110 ± 3 ms inday 7, 97 ± 3 ms inday 14, and 81 ± 1 ms in adultmice (P < 0.001 by ANOVA; all 3 groups different from day 1). Inparallel, the mean P-R interval progressively decreased duringdevelopment. Similarly, the mean Q-T interval decreased from 62 ± 2 ms in day 1 to 50 ± 2 ms inday 7, 47 ± 8 ms inday 14 neonatal mice, and 46 ± 2 ms in adult mice (P < 0.001 byANOVA; all 3 groups are significantly different fromday 1).Q-T_c was calculated asQ- interval.Q-T_c significantly shortened from179 ± 4 ms in day 1 to 149 ± 5 ms in day 7 mice(P < 0.001). In addition, the J junction-S-T segment elevation observed in day1 neonatal mice resolved by day14. Dofetilide (0.5 mg/kg), the selective blocker ofthe rapid component of the delayed rectifier(I_Kr) abolished S-T segment elevation and prolonged Q-T andQ-T_c intervals in day 1 neonates but not in adult mice.In contrast, 4-aminopyridine (4-AP, 2.5 mg/kg) had no effect onday 1 neonates but in adults prolongedQ-T and Q-T_c intervals andspecifically decreased the amplitude of a transiently repolarizingwave, which appears as an r' wave at the end of the apparent QRSin adult mice. In conclusion, ECG intervals and configuration changeduring normal postnatal development in the mouse.K⁺ channel blockers affect themouse ECG differently depending on age. These data are consistent withthe previous findings that the dofetilide-sensitiveI_Kr is dominantin day 1 mice, whereas 4-AP-sensitivecurrents, the transiently repolarizingK⁺ current, and the rapidlyactivating, slowly inactivating K⁺current are the dominant K⁺currents in adult mice. This study provides background information useful for assessing abnormal development in transgenic mice.

     

LY-294002-inhibitable PI 3-kinase and regulation of baseline rates of Na(+) transport in A6 epithelia

Blocker-inducednoise analysis of epithelial Na⁺ channels (ENaCs) was usedto investigate how inhibition of an LY-294002-sensitive phosphatidylinositol 3-kinase (PI 3-kinase) alters Na⁺transport in unstimulated and aldosterone-prestimulated A6 epithelia. From baseline Na⁺ transport rates(I_Na) of 4.0 ± 0.1 (unstimulated) and9.1 ± 0.9 µA/cm² (aldosterone), 10 µM LY-294002caused, following a relatively small initial increase of transport, acompletely reversible inhibition of transport within 90 min to 33 ± 6% and 38 ± 2% of respective baseline values. Initialincreases of transport could be attributed to increases of channel openprobability (P_o) within 5 min to 143 ± 17% (unstimulated) and 142 ± 10% of control (aldosterone) frombaseline P_o averaging near 0.5. Inhibition oftransport was due to much slower decreases of functional channeldensities (N_T) to 28 ± 4% (unstimulated)and 35 ± 3% (aldosterone) of control at 90 min. LY-294002 (50 µM) caused larger but completely reversible increases ofP_o (215 ± 38% of control at 5 min) andmore rapid but only slightly larger decreases ofN_T. Basolateral exposure to LY-294002 induced nodetectable effect on transport, P_o or N_T. We conclude that an LY-294002-sensitive PI3-kinase plays an important role in regulation of transport bymodulating N_T and P_o ofENaCs, but only when presented to apical surfaces of the cells.

     

Influence of hydrostatic pressure gradients on regulation of plasma volume after exercise

The impact of posture on the immediate recoveryof intravascular fluid and protein after intense exercise wasdetermined in 14 volunteers. Forces which govern fluid and proteinmovement in muscle interstitial fluid pressure(P_ISF), interstitial colloid osmotic pressure (COP_i), andplasma colloid osmotic pressure(COP_p) were measured before andafter exercise in the supine or upright position. During exercise,plasma volume (PV) decreased by 5.7 ± 0.7 and 7.0 ± 0.5 ml/kgbody weight in the supine and upright posture, respectively. Duringrecovery, PV returned to its baseline value within 30 min regardless ofposture. PV fell below this level by 60 and 120 min in the supine andupright posture, respectively (P < 0.05). Maintenance of PV in the upright position was associated with adecrease in systolic blood pressure, an increase inCOP_p (from 25 ± 1 to 27 ± 1 mmHg; P < 0.05), and an increasein P_ISF (from 5 ± 1 to 6 ± 2 mmHg), whereas COP_i wasunchanged. Increased P_ISFindicates that the hydrostatic pressure gradient favors fluid movementinto the vascular space. However, retention of the recaptured fluid inthe plasma is promoted only in the upright posture because of increasedCOP_p.

     

Training, muscle volume, and energy expenditure in nonobese American girls

Little is known about the relationship among training,energy expenditure, muscle volume, and fitness in prepubertalgirls. Because physical activity is high in prepubertalchildren, we hypothesized that there would be no effect of training.Forty pre- and early pubertal (mean age 9.1 ± 0.1 yr) nonobesegirls enrolled in a 5 day/wk summer school program for 5 wk and were randomized to control (n = 20) or training groups(n = 20; 1.5 h/day, endurance-type exercise). Totalenergy expenditure (TEE) was measured using doubly labeled water, thighmuscle volume using magnetic resonance imaging, and peak O₂uptake (O_2 peak) using cycle ergometry.TEE was significantly greater (17%, P < 0.02) in thetraining girls. Training increased thigh muscle volume (+4.3 ± 0.9%, P < 0.005) andO_2 peak (+9.5 ± 6%,P < 0.05), effects surprisingly similar to thoseobserved in adolescent girls using the same protocol (Eliakim A,Barstow TJ, Brasel JA, Ajie H, Lee W-NP, Renslo R, Berman N, and CooperDM, J Pediatr 129: 537-543, 1996). We furthercompared these two sample populations: thigh muscle volume per weightwas much lower in adolescent compared with prepubertal girls (17.0 ± 0.3 vs. 27.8 ± 0.6 ml/kg body mass; P < 0.001), and allometric analysis revealed remarkably low scaling factorsrelating muscle volume (0.34 ± 0.05, P < 0.0001), TEE (0.24 ± 0.06, P < 0.0004), andO_2 peak (0.28 ± 0.07, P < 0.0001) to body mass in all subjects. Muscle andcardiorespiratory functions were quite responsive to brief training inprepubertal girls. Moreover, a retrospective, cross-sectional analysissuggests that increases in muscle mass andO_2 peak may be depressed in nonobeseAmerican girls as they mature.