Exposing guinea pigs to ozone for 1wk enhances responsiveness of rapidly adapting receptors

Acute exposure to ozone causes changes inbreathing pattern and lung function which may be caused in part bystimulation of rapidly adapting receptors (RARs). The consequences ofrepeated daily ozone exposure on RAR responsiveness are unknown,although ozone-induced changes in pulmonary function diminish withrepeated exposure. Accordingly, we investigated whether repeated daily ozone exposure diminishes the general responsiveness of RARs. Guineapigs (n = 30) were exposed to 0.5 parts/million ozone or filtered air (8 h/day for 7 days). The animalswere then anesthetized, and RAR impulse activity, dynamic compliance(Cdyn), and lung resistance were recorded at baseline and in responseto four stimuli: substance P, methacholine, hyperinflation, and removalof positive end-expiratory pressure. Repeated daily ozone exposureexaggerated RAR responses to substance P, methacholine, andhyperinflation without causing physiologically relevant effects onbaseline or substance P- and methacholine-induced changes in Cdyn andlung resistance. Because agonist-evoked changes in RAR activitypreceded Cdyn changes, the data suggest that repeated daily ozoneexposure enhances RAR responsiveness via a mechanism other than changes in Cdyn.

     

Sidestream smoke exposure enhances rapidly adapting receptor responses to substance P in young guinea pigs

Bonham, A. C., K. S. Kott, and J. P. Joad. Sidestreamsmoke exposure enhances rapidly adapting receptor responses to substance P in young guinea pigs. J. Appl.Physiol. 81(4): 1715-1722, 1996.We determinedthe effect of sidestream tobacco smoke (SS) exposure on responses oflung rapidly adapting receptors (RARs), peak tracheal pressure (Ptr),and arterial blood pressure (ABP) to substance P in young guinea pigs.Guinea pigs were exposed to SS or filtered air fromday 8 to days41-45 of life. They were then anesthetized andgiven three doses of intravenous substance P (1.56-4.94 nmol/kg).SS exposure augmented substance P-evoked increases in RAR activity(P = 0.029 by analysis of variance) but not substance P-evoked increases in peak Ptr or decreases in ABP.Neurokinin 1-receptor blockade (CP-96345, 400 nmol/kg) attenuatedsubstance P-evoked increases in RAR activity(P = 0.001) and ABP(P = 0.009) but not in peak Ptr(P = 0.06). Thus chronic exposure toSS in young guinea pigs exaggerates RAR responsiveness to substance P. The findings may help explain the increased incidence of airwayhyperresponsiveness and cough in children chronically exposed toenvironmental tobacco smoke.

     

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.

     

Atrial distension in humans during microgravity induced by parabolic flights

Videbaek, Regitze, and Peter Norsk. Atrialdistension in humans during microgravity induced by parabolic flights.J. Appl. Physiol. 83(6):1862-1866, 1997.The hypothesis was tested that human cardiacfilling pressures increase and the left atrium is distended during 20-speriods of microgravity (µG) created by parabolic flights, comparedwith values of the 1-G supine position. Left atrial diameter(n = 8, echocardiography) increasedsignificantly during µG from 26.8 ± 1.2 to 30.4 ± 0.7 mm(P < 0.05). Simultaneously, centralvenous pressure (CVP; n = 6, transducer-tipped catheter) decreased from 5.8 ± 1.5 to 4.5 ± 1.1 mmHg (P < 0.05), and esophageal pressure (EP; n = 6) decreased from1.5 ± 1.6 to 4.1 ± 1.7 mmHg (P < 0.05). Thus transmural CVP(TCVP = CVP  EP; n = 4)increased during µG from 6.1 ± 3.2 to 10.4 ± 2.7 mmHg(P < 0.05). It is concluded thatshort periods of µG during parabolic flights induce an increase inTCVP and left atrial diameter in humans, compared with the resultsobtained in the 1-G horizontal supine position, despite a decrease inCVP.

     

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.

     

Sympathetic discharge and vascular resistance after bed rest

Shoemaker, J. Kevin, Cynthia S. Hogeman, Urs A. Leuenberger,Michael D. Herr, Kristen Gray, David H. Silber, and Lawrence I. Sinoway. Sympathetic discharge and vascular resistance after bedrest. J. Appl. Physiol. 84(2):612-617, 1998.The effect of 6° head-down-tilt bedrest (HDBR) for 14 days on supine sympathetic discharge andcardiovascular hemodynamics at rest was assessed. Mean arterialpressure, heart rate (n = 25), musclesympathetic nerve activity (MSNA; n = 16) burst frequency, and forearm blood flow(n = 14) were measured, and forearmvascular resistance (FVR) was calculated. Stroke distance,our index of stroke volume, was derived from measurements of aorticmean blood velocity (Doppler) and R-R interval(n = 7). With these data, an index oftotal peripheral resistance was determined. Heart rate at rest wasgreater in the post (71 ± 2 beats/min)- compared with the pre-HDBRtest (66 ± 2 beats/min; P < 0.003), but mean arterial pressure was unchanged. Aortic strokedistance during post-HDBR (15.5 ± 1.1 cm/beat) was reduced frompre-HDBR levels (20.0 ± 1.5 cm/beat)(P < 0.03). Also, MSNA burstfrequency was reduced in the post (16.7 ± 2.8 beats/min)- comparedwith the pre (25.2 ± 2.6 beats/min)-HDBR condition(P < 0.01). Bed rest did not alterforearm blood flow, FVR, or total peripheral resistance. Thusreductions in MSNA with HDBR were not associated with a decrease inFVR.

     

Progressive decrease of intramyocellular accumulation of H+ and Pi in human skeletal muscle during repeated isotonic exercise

The purpose of this study was to evaluatethe hypotheses that accumulation of hydrogen ions and/or inorganicphosphate (Pi) in skeletal muscle increases with repeated bouts ofisotonic exercise. ³¹P-Magnetic resonance spectroscopy wasused to examine the gastrocnemius muscle of seven highly aerobicallytrained females during four bouts of isotonic plantar flexion. Theexercise bouts (EX1-4) of 3 min and 18 swere separated by 3 min and 54 s of complete rest. Muscle ATP did notchange during the four bouts. Phosphocreatine (PCr) degradation duringEX1 (13.3 ± 2.4 mmol/kg wet weight) was higher(P < 0.01) compared with EX3-4(9.7 ± 1.6 and 9.6 ± 1.8 mmol/kg wet weight, respectively).The intramyocellular pH at the end of EX1 (6.87 ± 0.05) was significantly lower (P < 0.001) than thoseof EX2 (6.97 ± 0.02), EX3 (7.02 ± 0.01), and EX4 (7.02 ± 0.02). Total Pi anddiprotonated Pi were significantly higher (P < 0.001)at the end of EX1 (17.3 ± 2.7 and 7.8 ± 1.6 mmol/kg wet weight, respectively) compared with the values at the end of EX3 and EX4. The monoprotonated Pi at the endof EX1 (9.5 ± 1.2 mmol/kg wet weight) was alsosignificantly higher (P < 0.001) than that afterEX4 (7.5 ± 1.1 mmol/kg wet weight). Subjects' ratingof perceived exertion increased (P < 0.001) towardexhaustion as the number of exercises progressed (7.1 ± 0.4, EX1; 8.0 ± 0.3, EX2; 8.5 ± 0.3, EX3; and 9.0 ± 0.4, EX4; scale from 0 to10). The present results indicate that human muscle fatigue during repeated intense isotonic exercise is not due to progressive depletion of high energy phosphates nor to intracellular accumulation of hydrogenions, total, mono-, or diprotonated Pi.

     

Neck afferents and muscle sympathetic activity in humans: implications for the vestibulosympathetic reflex

Ray, Chester A., and Keith M. Hume. Neck afferents andmuscle sympathetic activity in humans: implications for the vestibulosympathetic reflex. J. Appl.Physiol. 84(2): 450-453, 1998.We have shownpreviously that head-down neck flexion (HDNF) in humans elicitsincreases in muscle sympathetic nerve activity (MSNA). The purpose ofthis study was to determine the effect of neck muscle afferents onMSNA. We studied this question by measuring MSNA before and after headrotation that would activate neck muscle afferents but not thevestibular system (i.e., no stimulation of the otolith organs orsemicircular canals). After a 3-min baseline period with the head inthe normal erect position, subjects rotated their head to the side(~90°) and maintained this position for 3 min. Head rotation wasperformed by the subjects in both the prone(n = 5) and sitting(n = 6) positions. Head rotation did not elicit changes in MSNA. Average MSNA, expressed asburst frequency and total activity, was 13 ± 1 and 13 ± 1 bursts/min and 146 ± 34 and 132 ± 27 units/min during baselineand head rotation, respectively. There were no significant changes incalf blood flow (2.6 ± 0.3 to 2.5 ± 0.3 ml · 100 ml¹ · min¹;n = 8) and calf vascular resistance(39 ± 4 to 41 ± 4 units; n = 8). Heart rate (64 ± 3 to 66 ± 3 beats/min;P = 0.058) and mean arterial pressure(90 ± 3 to 93 ± 3; P < 0.05)increased slightly during head rotation. Additional neck flexionstudies were performed with subjects lying on their side(n = 5). MSNA, heart rate, and meanarterial pressure were unchanged during this maneuver, which also doesnot engage the vestibular system. HDNF was tested in 9 of the 13 subjects. MSNA was significantly increased by 79 ± 12% (P < 0.001) during HDNF. Thesefindings indicate that neck afferents activated by horizontal neckrotation or flexion in the absence of significant force development donot elicit changes in MSNA. These findings support the concept thatHDNF increases MSNA by the activation of the vestibular system.

     

Effects of hindlimb contraction on pressor and muscle interstitial metabolite responses in the cat

We used the microdialysis technique to measurethe interstitial concentration of several putative metabolic stimulantsof the exercise pressor reflex during 3- and 5-Hz twitch contractions in the decerebrate cat. The peak increases in heart rate and mean arterial pressure during contraction were 20 ± 5 beats/min and 21 ± 8 mmHg and 27 ± 9 beats/min and 37 ± 12 mmHg for the 3- and 5-Hz stimulation protocols, respectively. All variables returned tobaseline after 10 min of recovery. Interstitial lactate rose (P < 0.05) by 0.41 ± 0.15 and0.56 ± 0.16 mM for the 3- and 5-Hz stimulation protocols,respectively, and were not statistically different from one another.Interstitial lactate levels remained above(P < 0.05) baseline during recoveryin the 5-Hz group. Dialysate phosphate concentrations (corrected forshifts in probe recovery) rose with stimulation(P < 0.05) by 0.19 ± 0.08 and0.11 ± 0.03 mM for the 3- and 5-Hz protocols. There were nodifferences between groups. The resting dialysateK⁺ concentrations for the 3- and5-Hz conditions were 4.0 ± 0.1 and 3.9 ± 0.1 meq/l,respectively. During stimulation the dialysate K⁺ concentrations rose steadilyfor both conditions, and the increase from rest to stimulation(P < 0.05) was 0.57 ± 0.19 and0.81 ± 0.06 meq/l for the 3- and 5-Hz conditions, respectively,with no differences between groups. Resting dialysate pH was6.915 ± 0.055 and 6.981 ± 0.032 and rose to 7.013 (P < 0.05) and 7.053 (P < 0.05) for the 3- and 5-Hzconditions, respectively, and then became acidotic (6.905, P < 0.05) during recovery (5 Hzonly). This study represents the first time simultaneous measurements of multiple skeletal muscle interstitial metabolites and pressor responses to twitch contractions have been made in the cat. These datasuggest that interstitial K⁺ andphosphate, but not lactate and H⁺,may contribute to the stimulation of thin fiber muscle afferents duringcontraction.

     

Effects of HCl-pepsin laryngeal instillations on upper airway patency-maintaining mechanisms

Gastroesophageal reflux has been indicated as anetiopathological factor in disorders of the upper airway. Upper airwaycollapsing pressure stimulates pressure-responsive laryngeal receptorsthat reflexly increase the activity of upper airway abductor muscles. We studied, in anesthetized dogs, the effects of repeated laryngeal instillations of HCl-pepsin (HCl-P; pH = 2) on the response of laryngeal afferent endings and the posterior cricoarytenoid muscle (PCA) to negative pressure. The effect of negative pressure on receptordischarge or PCA activity was evaluated by comparing their response toupper airway (UAO) and tracheal occlusions (TO). It is only during UAO,but not during TO, that the larynx is subjected to negative transmuralpressure. HCl-P instillation decreased the rate of discharge during UAOof the 10 laryngeal receptors studied from 56.4 ± 10.9 (SE) to 38.2 ± 9.2 impulses/s (P < 0.05). With UAO, the peak PCA moving time average, normalized by dividing itby the peak values of esophageal pressure, decreased after six HCl-Ptrials from 4.29 ± 0.31 to 2.23 ± 0.18 (n = 6;P < 0.05). The responses to TO ofeither receptors or PCA remained unaltered. We conclude that exposureof the laryngeal mucosa to HCl-P solutions, as it may occur withgastroesophageal reflux, impairs the patency-maintaining mechanismsprovided by laryngeal sensory feedback. Inflammatory and necroticalterations of the laryngeal mucosa are likely responsible for theseeffects.

     

Effect of prostaglandin F2α on pulmonary rapidly-adapting-receptors in the guinea pig

Pulmonary rapidly-adapting-receptors (RARs) are sensory nerve endings whose afferent fibers can be recorded in the vagus nerve. RARs may play a role in reflex bronchoconstriction as seen in anaphylaxis. They can be stimulated by chemical mediators of anaphylaxis, such as prostaglandin F_2α (PGF_2α). PGF_2α aerosol was administered to saline and bovine serum albumin (BSA)-treated guinea pigs while recording the activity of RARs. PGF_2α (250 μg/ml) given for 7–13 minutes increased both tracheal pressure and nerve activity over that produced by saline exposure in untreated guinea pigs. PGF_2α administered for three minutes (5–100 μg/ml) increased RAR nerve activity in a dose-related manner in the first five minutes of the experiment only in the BSA treated guinea pigs. Since changes in tracheal pressure did not show a significant dose-response relationship, the RARs responding to PGF_2α seemed to be stimulated by a direct mechanism. No correlation was shown between tracheal pressure and RAR nerve activity during PGF_2α treatment. Whereas, a significant correlation was found between tracheal pressure and RAR nerve activity during histamine aerosol treatment (r=0.985). Histamine aerosol (1 to 1000 μg/ml, 3 min.) increased intratracheal pressure for 3 out of 4 doses. RAR nerve activity increased significantly only at the highest dose. Therefore, a possible direct effect of PGF_2α upon RARs exists while the effect of histamine seems dependent upon changes in airway pressure in the guinea pig.     

Femoral arterial injection of adenosine in humans elevates MSNA via central but not peripheral mechanisms

MacLean, D. A., B. Saltin, G. Rådegran, and L. Sinoway. Femoral arterial injection of adenosine in humanselevates MSNA via central but not peripheral mechanisms.J. Appl. Physiol. 83(4):1045-1053, 1997.The purpose of the present study was to examinethe effects of femoral arterial injections of adenosine on musclesympathetic nerve activity (MSNA) under three different conditions.These conditions were adenosine injection alone, adenosine injectionafter phenylephrine infusion, and adenosine injection distal to a thighcuff inflated to arrest the circulation. The arterial injection ofadenosine alone resulted in a fourfold (255 ± 18 U/min) increaseabove baseline (73 ± 12 U/min; P < 0.05) in MSNA with an onset latency of 15.8 ± 0.8 s from thetime of injection. The systemic infusion of phenylephrine resulted in an increase (P < 0.05) in meanarterial pressure of ~10 mmHg and a decrease(P < 0.05) in heart rate of8-10 beats/min compared with baseline values before phenylephrineinfusion. After adenosine injection, the onset latency for the increasein MSNA was delayed to 19.2 ± 2.1 s and the magnitude of increasewas attenuated by ~50% (123 ± 20 U/min) compared with adenosineinjection alone (P < 0.05). When acuff was inflated to 220 mmHg to arrest the circulation and adenosinewas injected into the leg distal to the inflated cuff, there were nosignificant changes in MSNA or any of the other measured variables.However, on deflation of the cuff, there was a rapid increase(P < 0.05) in MSNA, with an onsetlatency of 9.1 ± 0.9 s, and the magnitude of increase (276 ± 28 U/min) was similar to that observed for adenosine alone. These datasuggest that ~50% of the effects of exogenously administered adenosine are a result of baroreceptor unloading due to a drop in bloodpressure. Furthermore, the finding that adenosine did not directlyresult in an increase in MSNA while it was trapped in the leg but thatit needed to be released into the circulation suggests that adenosinedoes not directly stimulate thin fiber muscle afferents in the leg ofhumans. In contrast, it would appear that adenosine exerts its effectsvia some other chemically sensitive pool of afferents.

     

Enhanced brain natriuretic peptide response to peak exercise in heart transplant recipients

We investigatedthe atrial (ANP) and brain natriuretic peptides (BNP), catecholamines,heart rate, and blood pressure responses to graded upright maximalcycling exercise of eight matched healthy subjects andcardiac-denervated heart transplant recipients (HTR). Baseline heart rate and diastolic blood pressure, together with ANP(15.2 ± 3.7 vs. 4.4 ± 0.8 pmol/l;P < 0.01) and BNP (14.3 ± 2.6 vs. 7.4 ± 0.6 pmol/l; P < 0.01), were elevated in HTR, but catecholamine levels were similarin both groups. Peak exercise O₂uptake and heart rate were lower in HTR. Exercise-inducedmaximal ANP increase was similar in both groups (167 ± 34 vs. 216 ± 47%). Enhanced BNP increase was significant only in HTR (37 ± 8 vs. 16 ± 8%; P < 0.05).Similar norepinephrine but lower peak epinephrine levels were observedin HTR. ANP and heart rate changes from rest to 75% peak exercise werenegatively correlated (r = 0.76, P < 0.05),and BNP increase was correlated with left ventricular mass index(r = 0.83, P < 0.01) after hearttransplantation. Although ANP increase was notexaggerated, these data support the idea that the chronotropiclimitation secondary to sinus node denervation might stimulate ANPrelease during early exercise in HTR. Furthermore, the BNPresponse to maximal exercise, which is related to the left ventricularmass index of HTR, is enhanced after heart transplantation.

     

Contribution of abdomen and legs to central blood volume expansion in humans during immersion

Johansen, Lars Bo, Thomas Ulrik Skram Jensen, Bettina Pump,and Peter Norsk. Contribution of abdomen and legs to central bloodvolume expansion in humans during immersion. J. Appl.Physiol. 83(3): 695-699, 1997.The hypothesis wastested that the abdominal area constitutes an important reservoir forcentral blood volume expansion (CBVE) during water immersion inhumans. Six men underwent 1) water immersion for 30 min (WI),2) water immersion for 30 min withthigh cuff inflation (250 mmHg) during initial 15 min to exclude legsfrom contributing to CBVE (WI+Occl), and3) a seated nonimmersed control with15 min of thigh cuff inflation (Occl). Plasma protein concentration andhematocrit decreased from 68 ± 1 to 64 ± 1 g/l and from 46.7 ± 0.3 to 45.5 ± 0.4%(P < 0.05), respectively, during WIbut were unchanged during WI+Occl. Left atrial diameter increased from27 ± 2 to 36 ± 1 mm (P < 0.05) during WI and increased similarly during WI+Occl from 27 ± 2 to 35 ± 1 mm (P < 0.05). Centralvenous pressure increased from 3.7 ± 1.0 to 10.4 ± 0.8 mmHg during WI (P < 0.05) butonly increased to 7.0 ± 0.8 mmHg during WI+Occl(P < 0.05). In conclusion, the dilution of blood induced by WI to the neck is caused by fluid from thelegs, whereas the CBVE is caused mainly by blood from theabdomen.

     

Bronchial airway deposition and retention of particles in inhaled boluses: effect of anatomic dead space

The fractionaldeposition of particles in boluses delivered to shallow lung depths andtheir subsequent retention in the airways may depend on the relativevolume and size of an individual's airways. To evaluate the effect ofvariable anatomic dead space (ADS) on aerosol bolus delivery we hadhealthy subjects inhale radiolabeled, monodisperse aerosol(^99mTc-iron oxide, 3.5 µm meanmondispersed aerosol diameter) boluses (40 ml) to a volumetric frontdepth of 70 ml into the lung at a lung volume of 70% total lungcapacity end inhalation. By using filter techniques, aerosolphotometry, and gamma camera analysis, we estimated the fraction of theinhaled boluses deposited in intrathoracic airways (IDF). ADS bysingle-breath N₂ washout was alsomeasured from 70% total lung capacity. Results showed that among allsubjects IDF was variable (range = 0.04-0.43, coefficient ofvariation = 0.54) and increased with decreasing ADS(r = 0.76, P = 0.001, n = 16). We found significantlygreater deposition in the left (L) vs. right (R) lungs; mean L/R (ratioof deposition in L lung to R lung, normalized to ratio of L-to-R lungvolume) was 1.58 ± 0.42 (SD; P < 0.001 for comparison with 1.0). Retention of deposited particles at 2 hwas independent of ADS or IDF. There was significant retention ofparticles at 24 h postdeposition (0.27 ± 0.05) andslow clearance of these particles continued through 48 hpostdeposition. Finally, analysis of central-to-peripheral ratios ofinitial deposition and 24-h-retention gamma-camera images suggestsignificant retention of insoluble particles in large bronchial airwaysat 24 h postdeposition (i.e., 24 h central-to-peripheral ratio = 1.40 ± 0.44 and 1.82 ± 0.54 in the R and L lung, respectively; P < 0.02 for comparison with 1.0).These data may prove useful for 1)designing aerosol delivery techniques to target bronchial airways and2) understanding airway retention ofinhaled particles.

     

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.

     

Systemic and myocardial hemodynamics during periodic obstructive apneas in sedated pigs

The effects of periodic obstructive apneas onsystemic and myocardial hemodynamics were studied in ninepreinstrumented sedated pigs under four conditions: breathing room air(RA), breathing 100% O₂,breathing RA after critical coronary stenosis (CS) of the left anteriordescending coronary artery, and breathing RA after autonomic blockadewith hexamethonium (Hex). Apneas with RA increased mean arterialpressure (MAP; from baseline 103.0 ± 3.5 to late apnea 123.6 ± 7.0 Torr, P < 0.001) and coronary blood flow (CBF; late apnea 193.9 ± 22.9% of baseline,P < 0.001) but decreased cardiacoutput (CO; from baseline 2.97 ± 0.15 to late apnea 2.39 ± 0.19 l/min, P < 0.001). Apneas withO₂ increased MAP (from baseline105.1 ± 4.6 to late apnea 110.7 ± 4.8 Torr, P < 0.001). Apneas with CS producedsimilar increases in MAP as apneas with RA but greater decreases in CO(from baseline 3.03 ± 0.19 to late apnea 2.1 ± 0.15 l/min,P < 0.001). In LAD-perfused myocardium, there was decreased segmental shortening (baseline 11.0 ± 1.5 to late apnea 7.6 ± 2.0%,P < 0.01) and regionalintramyocardial pH (baseline 7.05 ± 0.03 to late apnea 6.72 ± 0.11, P < 0.001) during apneas withCS but under no other conditions. Apneas with Hex increased to the sameextent as apneas with RA. Myocardial O₂ demand remained unchangedduring apnea relative to baseline. We conclude that obstructiveapnea-induced changes in left ventricular afterload and CO aresecondary to autonomic-mediated responses to hypoxemia. Increased CBFduring apneas is related to regional metabolic effects of hypoxia andnot to autonomic factors. In the presence of limited coronary flowreserve, decreased O₂ supply during apneas can lead to myocardial ischemia, which in turnadversely affects left ventricular function.

     

Almitrine and doxapram decrease fatigue and increase subsequent recovery in isolated rat diaphragm

McGuire, Michelle, Michael F. Carey, and John J. O'Connor.Almitrine and doxapram decrease fatigue and increase subsequent recovery in isolated rat diaphragm. J. Appl.Physiol. 83(1): 52-58, 1997.The effects ofalmitrine bimesylate and doxapram HCl on isometric force produced by invitro rat diaphragm were studied during direct muscle activation at37°C. Doxapram and almitrine ameliorate respiratory failureclinically by indirectly increasing phrenic nerve activity. This studywas carried out to investigate possible direct actions of these agentson the diaphragm before and after fatigue of the fibers. Two age groupsof animals were chosen [6-14 wk (group1) and 50-55 wk (group2)] because it is known that increasing agedecreases a muscle fiber's resistance to fatigue. Muscle strips wereisolated from both group 1 and group 2 and directly stimulated (2-mspulse duration, 5-15 V) to produce twitch tensions of 1.3 and 2.1 N/cm², respectively. At lowconcentrations, doxapram (20 µg/ml) and almitrine (12 µg/ml)had no effect on twitch contraction or 100-Hz tetanic tension. However,40 µg/ml doxapram and 30 µg/ml almitrine increased twitch tensionby 9.0 ± 1.4 and 11.6 ± 1.9%, respectively, in animals ofgroup 2 (n = 5). A fatigue protocol consistingof low-frequency stimulation (30-Hz trains, 250-ms duration every 2 sfor 5 min) caused a reduction of twitch tension in animals ofgroup 1 (48 ± 4% ofcontrol) and group 2 (28 ± 4% ofcontrol). At 90 min postfatigue, the twitch tension recovered to 72 ± 3 and 42 ± 2% of control values ingroup 1 and group2, respectively. In the presence of doxapram (20 µg/ml), there was a significant increase in the recovery of twitchtension at 90 min in group 1 andgroup 2 (84.5 ± 3.2 and 80.1 ± 2.8%, respectively) compared with controls at 90 min postfatigue. Inthe presence of almitrine (12 µg/ml), there was a full recovery fromfatigue in group 1 animals (100% ofcontrol) and a recovery to 95.6 ± 2.1% of control ingroup 2 animals at 90 min. Theseresults demonstrate a significant improvement in the rapidity andmagnitude of recovery from fatigue in the rat diaphragm muscle in thepresence of both doxapram and, especially, almitrine. These effects maybe due to changes in intracellular calcium, ADP/ATP ratios, or oxygenfree radical scavenging.

     

Brain natriuretic peptide inhibits hypoxic pulmonary hypertension in rats

Brainnatriuretic peptide (BNP) is a pulmonary vasodilator that is elevatedin the right heart and plasma of hypoxia-adapted rats. To test thehypothesis that BNP protects against hypoxic pulmonary hypertension, wemeasured right ventricular systolic pressure (RVSP), right ventricle(RV) weight-to-body weight (BW) ratio (RV/BW), and percentmuscularization of peripheral pulmonary vessels (%MPPV) in rats givenan intravenous infusion of BNP, atrial natriuretic peptide (ANP), orsaline alone after 2 wk of normoxia or hypobaric hypoxia (0.5 atm).Hypoxia-adapted rats had higher hematocrits, RVSP, RV/BW, and %MPPVthan did normoxic controls. Under normoxic conditions, BNP infusion(0.2 and 1.4 µg/h) increased plasma BNP but had no effect on RVSP,RV/BW, or %MPPV. Under hypoxic conditions, low-rate BNP infusion (0.2 µg/h) had no effect on plasma BNP or on severity of pulmonaryhypertension. However, high-rate BNP infusion (1.4 µg/h) increasedplasma BNP (69 ± 8 vs. 35 ± 4 pg/ml, P < 0.05),lowered RV/BW (0.87 ± 0.05 vs. 1.02 ± 0.04, P < 0.05), and decreased %MPPV (60 vs. 74%,P < 0.05). There was also a trend towardlower RVSP (55 ± 3 vs. 64 ± 2, P = not significant).Infusion of ANP at 1.4 µg/h increased plasma ANP in hypoxic rats (759 ± 153 vs. 393 ± 54 pg/ml, P < 0.05) but had noeffect on RVSP, RV/BW, or %MPPV. We conclude that BNP may regulatepulmonary vascular responses to hypoxia and, at the doses used in thisstudy, is more effective than ANP at blunting pulmonary hypertensionduring the first 2 wk of hypoxia.

     

Angiogenesis in bronchial circulatory system after unilateral pulmonary artery obstruction

Charan, Nirmal B., and Paula Carvalho. Angiogenesis inbronchial circulatory system after unilateral pulmonary artery obstruction. J. Appl. Physiol. 82(1):284-291, 1997.We studied the effects of left pulmonary artery(LPA) ligation on the bronchial circulatory system (BCS) by using asheep model. LPA was ligated in the newborn lambs soon after birth(n = 8), and when the sheep were ~3yr of age anatomic studies revealed marked angiogenesis in BCS.Bronchial blood flow and cardiac output were studied by placing flowprobes around the bronchial and pulmonary arteries in four adult sheep.After LPA ligation, bronchial blood flow increased from 35 ± 6 to134 ± 42 ml/min in ~3 wk (P < 0.05). We also studied gas-exchange functions of BCS ~3 yr after the ligation of LPA in newborn lambs (n = 4) and used a control group (n = 12)in which LPA was ligated acutely. In the left lung,O₂ uptake after acute ligation was16 ± 3 ml/min and was similar to the chronic model, whereasCO₂ output in the control group was 27 ± 3 ml/min compared with 79 ± 12 ml/min in the chronic preparation (P < 0.05).We conclude that LPA ligation causes marked angiogenesis in BCS that iscapable of performing some gas-exchange functions.