Nitric oxide decreases lung injury after intestinal ischemia

Terada, Lance S., Nancy N. Mahr, and Eugene D. Jacobson.Nitric oxide decreases lung injury after intestinal ischemia. J. Appl. Physiol. 81(6):2456-2460, 1996.After injury to a primary organ, mediators arereleased into the circulation and may initiate inflammation of remoteorgans. We hypothesized that the local production of nitric oxide (NO)may act to limit the spread of inflammation to secondarily targetedorgans. In anesthetized rats, 30 min of intestinal ischemia followed by2 h of reperfusion (I/R) did not increase lung albumin leak. However,after treatment with N^G-nitro-L-arginine methyl ester(L-NAME), intestinal I/R led to increased lung leak, suggesting a protective effect of endogenous NO.The site of action of NO appeared to be the lung and not the gutbecause 1) after treatment withL-NAME, local delivery of NO tothe lung by inhalation abolished the increase in intestinal I/R-inducedlung leak; 2)L-NAME had no effect onepithelial permeability (⁵¹Cr-labeled EDTA clearance) ofreperfused small bowel; and 3) after treatment with L-NAME, localdelivery of NO to the gut by luminal perfusion did not improveepithelial permeability of reperfused intestines. Furthermore,L-NAME increased, and inhaled NOde- creased, the density of lung neutrophils in rats subjected to intestinal I/R, and treatment with the selectin antagonist fucoidan abolished L-NAME-induced lungleak in rats subjected to intestinal I/R. We conclude thatendogenous lung NO limits secondary lung injury after intestinal I/R bydecreasing pulmonary neutrophil retention.

     

Lung liquid production rates and volumes do not decrease before labor in healthy fetal sheep

Lines, A., S. B. Hooper, and R. Harding. Lung liquidproduction rates and volumes do not decrease before labor in healthy fetal sheep. J. Appl. Physiol. 82(3):927-932, 1997.Previous studies have suggested that the volumeand production rate of fetal lung liquid decrease late in gestation,before the onset of labor, in preparation for the clearance of lungliquid at birth. In contrast, our earlier studies have not shown adecrease in lung liquid volume near term, although these studies werenot continued to the onset of labor. Our aim was to determine the changes in lung liquid volume and production rate in fetal sheep duringthe last 2 wk of gestation up to the onset of labor at term (~147days). In eight chronically catheterized fetal sheep, the volume andproduction rate of fetal lung liquid were measured at 130, 135, and 140 days of gestation and then on every 2nd day until the onset oflabor. Labor was detected by monitoring uterine muscleactivity and intrauterine pressure changes. On the day of labor onset,which occurred at 147 ± 1 days of gestation, fetuses weighed 5.0 ± 0.2 kg. The volume of fetal lung liquid was 40.4 ± 2.7 ml/kgat 19 ± 1 days before labor onset and had not significantly changedby 0.7 ± 0.2 days (44.8 ± 5.1 ml/kg) before labor. Similarly, lung liquid production rates at 19 ± 1 days before labor (5.1 ± 1.8 ml ^· h^{1 ·} kg¹)were not significantly different from those at 0.7 ± 0.2 days before labor (3.4 ± 0.7 ml ^· h^{1 ·} kg¹).We conclude that, in healthy ovine fetuses, lung liquid volumes andproduction rates do not decrease before the onset of labor. Our resultsindicate that the entire volume of fetal lung liquid (~222.5 ± 36.6 ml) must be cleared after the onset of labor.

     

Nitric oxide and endothelial permeability

Hinder, Frank, Michael Booke, Lillian D. Traber, and DanielL. Traber. Nitric oxide and endothelial permeability.J. Appl. Physiol. 83(6):1941-1946, 1997.Nitric oxide synthase inhibition reversessystemic vasodilation during sepsis but may increase endothelialpermeability. To assess adverse effects on the pulmonary vasculature,12 sheep were chronically instrumented with lung lymph fistulas andhydraulic pulmonary venous occluders. Escherichia coli endotoxin (lipopolysaccharide; 10 ng · kg¹ · min¹)was continuously infused for 32 h. After 24 h, six animals received 25 mg/kg of N-nitro-L-argininemethyl ester (L-NAME), and sixreceived saline. All sheep developed a hyperdynamic circulatoryresponse and elevated lymph flows by 24 h of lipopolysaccharideinfusion. L-NAME reversed systemic vasodilation, increased pre- and postcapillary pulmonary vascular resistance index, pulmonary arterial pressure, and,transiently, effective pulmonary capillary pressure. Lung lymph flowswere not different between groups at 24 h or thereafter. Calculated aschanges from baseline, however, lung lymph flow was higher in theL-NAME group than in the controlanimals, with a trend toward lower lymph-to-plasma proteinconcentration ratio at 25 h. Permeability analysis at 32 h by thevenous occlusion technique showed normal reflection coefficients andelevated filtration coefficients without differences between groups.Reversal by L-NAME of thesystemic vasodilation during endotoxemia was associated with highpulmonary vascular resistance without evidence of impaired pulmonaryendothelial barrier function.

     

Chronic hypoxia alters nitric oxide-dependent pulmonary vascular responses in lungs of newborn pigs

Fike, Candice D., and Mark R. Kaplowitz. Chronichypoxia alters nitric oxide-dependent pulmonary vascular responses inlungs of newborn pigs. J. Appl.Physiol. 81(5): 2078-2087, 1996.Almost all ofthe studies evaluating the effect of chronic hypoxia on lung nitricoxide production have been performed in adult animals. Because resultsof studies in adult lungs should not be extrapolated to represent thenewborn lung, we performed studies to determine whether decreasednitric oxide production might be involved in the pathogenesis ofchronic hypoxia-induced pulmonary hypertension in newborns. We keptnewborn pigs in chambers filled with room air (control) or 11-12%O₂ for either 3-5 (short) or10-12 (long) days. Using isolated lungs, we measured pulmonary vascular responses to agents that either stimulate or inhibit thesynthesis of nitric oxide. To define the vascular sites of alteredproduction of nitric oxide, we applied the micropuncture technique andmeasured small venular pressures before and after treatment with anitric oxide synthesis inhibitor. Pulmonary vascular responses toacetylcholine were blunted in chronically hypoxic piglets of both theshort and long groups. The nitric oxide synthesis inhibitor had adifferent effect in the lungs of control piglets than in those ofchronically hypoxic piglets of the long but not of the short group. Forthe long group, the nitric oxide synthesis inhibitors causedconstriction of both arteries and veins in lungs of control but not ofchronically hypoxic piglets. These findings support the idea thatdecreased pulmonary vascular nitric oxide production occurs withchronic hypoxia in newborn pigs and might therefore contribute to thepathogenesis of pulmonary hypertension in newborns.

     

Evidence that nitric oxide increases glucose transport in skeletal muscle

Balon, Thomas W., and Jerry L. Nadler. Evidence thatnitric oxide increases glucose transport in skeletal muscle.J. Appl. Physiol. 82(1): 359-363, 1997.Nitric oxide synthase (NOS) is expressed in skeletal muscle.However, the role of nitric oxide (NO) in glucose transport in thistissue remains unclear. To determine the role of NO in modulatingglucose transport, 2-deoxyglucose (2-DG) transport was measured in ratextensor digitorum longus (EDL) muscles that were exposed to either amaximally stimulating concentration of insulin or to an electricalstimulation protocol, in the presence ofN^G-monomethyl-L-arginine,a NOS inhibitor. In addition, EDL preparations were exposed to sodiumnitroprusside (SNP), an NO donor, in the presence of submaximal andmaximally stimulating concentrations of insulin. NOS inhibition reducedboth basal and exercise-enhanced 2-DG transport but had no effect oninsulin-stimulated 2-DG transport. Furthermore, SNP increased 2-DGtransport in a dose-responsive manner. The effects of SNP and insulinon 2-DG transport were additive when insulin was present inphysiological but not in pharmacological concentrations. Chronictreadmill training increased protein expression of both type I and typeIII NOS in soleus muscle homogenates. Our results suggest that NO maybe a potential mediator of exercise-induced glucose transport.

     

Postnatal lung function and protein permeability after fetal or maternal corticosteroids in preterm lambs

Rebello, Celso M., Machiko Ikegami, M. Gore Ervin, Daniel H. Polk, and Alan H. Jobe. Postnatal lung function and protein permeability after fetal or maternal corticosteroids in preterm lambs.J. Appl. Physiol. 83(1): 213-218, 1997.We evaluated postnatal lung function andintravascular albumin loss to tissues of 123-days-gestation pretermsurfactant-treated and ventilated lambs 15 h after direct fetal(n = 8) or maternal(n = 9) betamethasone treatment orsaline placebo (n = 9). Thebetamethasone-treated groups had similar increases in dynamiccompliances, ventilatory efficiency indexes, and lung volumes relativeto controls (P < 0.05). The lossesof ¹²⁵I-labeled albumin fromblood, a marker of intravascular integrity, and the recoveries of¹²⁵I-albumin in muscle and brainwere similar for control and betamethasone-exposed lambs.Betamethasone-treated lambs had lower recoveries of¹²⁵I-albumin in lung tissues andin alveolar washes than did controls (P < 0.01). Although blood pressureswere higher for the treated groups (P < 0.05), all groups had similar blood volumes, cardiac outputs, andorgan blood flows. Maternal or fetal treatment with betamethasone 15 hbefore preterm delivery equivalently improved postnatal lung function,reduced albumin recoveries in lungs, and increased blood pressures.However, prenatal betamethasone had no effects on the systemicintravascular losses of albumin or did not change blood volumes.

     

Measurement of pulmonary blood flow by fractal analysis of flow heterogeneity in isolated canine lungs

Barman, Scott A., Laryssa L. McCloud, John D. Catravas, andIna C. Ehrhart. Measurement of pulmonary blood flow by fractalanalysis of flow heterogeneity in isolated canine lungs. J. Appl. Physiol. 81(5):2039-2045, 1996.Regional heterogeneity of lung blood flow can bemeasured by analyzing the relative dispersion (RD) of mass(weight)-flow data. Numerous studies have shown that pulmonary bloodflow is fractal in nature, a phenomenon that can be characterized bythe fractal dimension and the RD for the smallest realizable volumeelement (piece size). Although information exists for theapplicability of fractal analysis to pulmonary blood flow in wholeanimal models, little is known in isolated organs. Therefore, thepresent study was done to determine the effect of blood flow rate onthe distribution of pulmonary blood flow in the isolated blood-perfusedcanine lung lobe by using fractal analysis. Four different radiolabeledmicrospheres (¹⁴¹Ce,⁹⁵Nb,⁸⁵Sr, and⁵¹Cr), each 15 µm in diameter,were injected into the pulmonary lobar artery of isolated canine lunglobes (n = 5) perfused at fourdifferent flow rates ( flow1 = 0.42 ± 0.02 l/min;flow2 = 1.12 ± 0.07 l/min;flow 3 = 2.25 ± 0.17 l/min; flow 4 = 2.59 ± 0.17 l/min), and the pulmonary blood flow distribution was measured. Theresults of the present study indicate that under isogravimetric bloodflow conditions, all regions of horizontally perfused isolated lunglobes received blood flow that was preferentially distributed to themost distal caudal regions of the lobe. Regional pulmonary blood flowin the isolated perfused canine lobe was heterogeneous and fractal innature, as measured by the RD. As flow rates increased, fractal dimension values (averaging 1.22 ± 0.08) remained constant, whereas RD decreased, reflecting more homogeneous blood flowdistribution. At any given blood flow rate, high-flow areas of the lobereceived a proportionally larger amount of regional flow, suggestingthat the degree of pulmonary vascular recruitment may also be spatially related.

     

Nitric oxide-endothelin-1 interaction in humans

Ahlborg, Gunvor, and Jan M. Lundberg. Nitricoxide-endothelin-1 interaction in humans. J. Appl.Physiol. 82(5): 1593-1600, 1997.Healthy menreceived N^G-monomethyl-L-arginine(L-NMMA) intravenously to studycardiovascular and metabolic effects of nitric oxide synthase blockadeand whether this alters the response to endothelin-1 (ET-1) infusion.Controls only received ET-1.L-NMMA effects were that heartrate (17%), cardiac output (17%), and splanchnic and renal blood flow(both 33%) fell promptly (all P < 0.01). Mean arterial blood pressure (6%), and systemic (28%) andpulmonary (40%) vascular resistances increased(P < 0.05 to 0.001). Arterial ET-1levels (21%) increased due to a pulmonary net ET-1 release(P < 0.05 to 0.01). Splanchnic glucose output (SGO) fell (26%, P < 0.01). Arterial insulin and glucagon were unchanged. Subsequent ET-1infusion caused no change in mean arterial pressure, heart rate, orcardiac output, as found in the present controls, or in splanchnic andrenal blood flow or splanchnic glucose output as previously found withET-1 infusion (G. Ahlborg, E. Weitzberg, and J. M. Lundberg.J. Appl. Physiol. 79: 141-145,1995). In conclusion, L-NMMAlike ET-1, induces prolonged cardiovascular effects and suppresses SGO.L-NMMA causes pulmonary ET-1release and blocks responses to ET-1 infusion. The results indicatethat nitric oxide inhibits ET-1 production and thereby interacts withET-1 regarding increase in vascular tone and reduction of SGO inhumans.

     

Water transport and the distribution of aquaporin-1 in pulmonary air spaces

Effros, R. M., C. Darin, E. R. Jacobs, R. A. Rogers, G. Krenz, and E. E. Schneeberger. Water transport and thedistribution of aquaporin-1 in pulmonary air spaces.J. Appl. Physiol. 83(3): 1002-1016, 1997.Recent evidence suggests that water transport between the pulmonary vasculature and air spaces can be inhibited byHgCl₂, an agent that inhibitswater channels (aquaporin-1 and -5) of cell membranes. In the presentstudy of isolated rat lungs, clearances of labeled(³HOH) and unlabeled water werecompared after instillation of hypotonic or hypertonic solutions intothe air spaces or injection of a hypotonic bolus into the pulmonaryartery. The clearance of ³HOHbetween the air spaces and perfusate after intratracheal instillation and from the vasculature to the tissues after pulmonary arterial injections was invariably greater than that of unlabeled water, indicating that osmotically driven transport of water is limited bypermeability of the tissue barriers rather than the rate of perfusion.Exposure to 0.5 mM HgCl₂ in theperfusate and air-space solution reduced the product of the filtrationcoefficient and surface area(P_fS)of water from the air spaces to the perfusate by 28% afterinstillation of water into the trachea. In contrast, perfusion of 0.5 mM HgCl₂ in air-filled lungs reducedP_fSof the endothelium by 86% after injections into the pulmonary artery, suggesting that much of the action of this inhibitor is on the endothelial surfaces. Confocal laser scanning microscopy demonstrated that aquaporin-1 is on mouse pulmonary endothelium. No aquaporin-1 wasfound on alveolar type I cells with immunogold transmission electronmicroscopy, but small amounts were present on some type II cells.

     

Differential relaxant responses of pulmonary arteries and veins in lung explants of guinea pigs

Shi, Weibin, David H. Eidelman, and René P. Michel.Differential relaxant responses of pulmonary arteries and veins inlung explants of guinea pigs. J. Appl.Physiol. 83(5): 1476-1481, 1997.The endotheliumregulates vascular tone through release of relaxing or contractingfactors, with nitric oxide (NO) being a major endothelium-derivedrelaxing factor. In the present study, we used a lung explant techniqueto determine the differential abilities and mechanisms of pulmonaryarteries and veins of normal guinea pigs to relax after precontraction.Excised lungs of 15 guinea pigs were filled through the airways with1% agarose, cut into 1-mm-thick slices, and cultured overnight.Luminal areas of vascular cross sections were measured with animage-analysis system. Vessels were precontracted with U-46619, andresponses to histamine, acetylcholine (ACh), sodium nitroprusside, andpapaverine were examined. We also determined the effects ofN-nitro-L-arginineand of indomethacin on ACh-induced responses. We found that histaminerelaxed arteries more than veins and that ACh relaxed only arteries.N-nitro-L-arginine pretreatmentabolished ACh-induced relaxation of arteries and caused ACh-inducedcontraction of veins, whereas indomethacin markedly augmentedACh-induced relaxation of arteries (maximal relaxation: 48.5 ± 4.7 vs. 19.2 ± 5.1% without it) and induced a dose-dependentrelaxation of veins (maximal relaxation: 17.0 ± 4.1%). Sodiumnitroprusside induced a significantly greater relaxation of arteriesthan veins, whereas papaverine relaxed them equally. We conclude thatin guinea pigs endothelial NO-mediated relaxation is greater inpulmonary arteries than in veins and that ACh-induced NO-mediatedrelaxation is reduced by the simultaneous production ofcyclooxygenase-derived vasoconstrictors.

     

Developmental changes in endothelium-dependent relaxation of pulmonary arteries: role of EDNO and prostanoids

O'Donnell, Denise C., Mary L. Tod, and John B. Gordon.Developmental changes in endothelium-dependent relaxation of pulmonary arteries: role of EDNO and prostanoids. J. Appl. Physiol. 81(5): 2013-2019, 1996.Wehypothesized that maturational changes in both prostaglandin andendothelium-derived nitric oxide (EDNO) activity contribute todevelopmental changes in endothelium-dependent relaxation of newbornpulmonary arteries. Responses to endothelium-dependent vasodilatorsacetylcholine, bradykinin, and calcium ionophore A-23187 weredetermined in phenylephrine-constricted third- and fourth-generation(1- to 2-mm-diameter) pulmonary artery rings from 2-day (2d)- and 1-mo(1m)-old lambs under control conditions (Con), after inhibition of EDNOsynthesis withN-nitro-L-arginine(L-NNA), after inhibition ofprostanoid synthesis with meclofenamate (Mec), or both modulators withboth inhibitors. Endothelium-independent responses to sodiumnitroprusside (SNP) were also measured in Con rings.Endothelium-dependent relaxation was greater in 2d than 1m Con rings,particularly at high concentrations when an increase in tensionoccurred in 1m rings. L-NNAattenuated endothelium-dependent relaxation more in 2d rings, and SNPcaused greater relaxation in 2d rings. However, Mec abolished allage-related differences by attenuating relaxation in 2d rings andconstriction in 1m rings. These data suggest that developmental changesin endothelium-dependent responses of ovine pulmonary artery rings reflect both a decrease in EDNO activity and maturational differences in the relative influence of dilator and constrictor prostanoids.

     

Nitric oxide derived from sympathetic nerves regulates airway responsiveness to histamine in guinea pigs

Matsumoto, Koichiro, Hisamichi Aizawa, Shohei Takata,Hiromasa Inoue, Naotsugu Takahashi, and Nobuyuki Hara.Nitric oxide derived from sympathetic nerves regulates airwayresponsiveness to histamine in guinea pigs. J. Appl.Physiol. 83(5): 1432-1437, 1997.Nitric oxide(NO), which can be derived from the nervous system or the epithelium ofthe airway, may modulate airway responsiveness. We investigated how NOderived from the airway nervous system would affect the airwayresponsiveness to histamine and acetylcholine in mechanicallyventilated guinea pigs. An NO synthase inhibitor N^G-nitro-L-argininemethyl ester (L-NAME) (1 mmol/kgip) significantly enhanced airway responsiveness to histamine but notto acetylcholine. Its enantiomerD-NAME (1 mmol/kg ip), incontrast, had no effect. TheL-NAME-induced airwayhyperresponsiveness was still observed in animals pretreated withpropranolol (1 mg/kg iv) and atropine (1 mg/kg iv). Pretreatment withthe ganglionic blocker hexamethonium (2 mg/kg iv) completely abolishedenhancing effect of L-NAME on airway responsiveness. Bilateral cervical vagotomy did not alter theL-NAME-induced airwayhyperresponsiveness, whereas sympathetic stellatectomy completelyabolished it. Results suggest that NO that was presumably derived fromthe sympathetic nervous system regulates airway responsiveness tohistamine in guinea pigs.

     

Intratracheal instillation of a novel NO/nucleophile adduct selectively reduces pulmonary hypertension

Brilli, Richard J., Brian Krafte-Jacobs, Daniel J. Smith,Dominick Roselle, Daniel Passerini, Amos Vromen, Lori Moore, CsabaSzabó, and Andrew L. Salzman. Intratracheal instillation ofa novel NO/nucleophile adduct selectively reduces pulmonary hypertension. J. Appl. Physiol. 83(6):1968-1975, 1997.We examined the pulmonary and systemichemodynamic effects of administering soluble nitric oxide (NO) donorcompounds (NO/nucleophile adducts, i.e., NONOates) directly into thetrachea of animals with experimentally induced pulmonary hypertension.Steady-state pulmonary hypertension was created by using thethromboxane agonist U-46619. Yorkshire pigs were randomly assigned toone of four groups: group 1,intratracheal saline (control; n = 8);group 2, intratracheal sodiumnitroprusside (n = 6);group 3, intratracheal ethylputreanineNONOate (n = 6); andgroup 4, intratracheal2-(dimethylamino)-ethylputreanine NONOate (DMAEP/NO;n = 6). Pulmonary and systemichemodynamics were monitored after drug instillation.Group 4 had significant reductions in pulmonary vascular resistance index (PVRI) at all time points comparedwith steady state and compared with group1 (P < 0.05), whereas systemic vascular resistance index did not change. The meanchange in mean pulmonary arterial pressure in group4 was 33.1 ± 1.2% compared with +6.4 ± 1.3% in group 1 (P < 0.001), and the mean change inmean arterial pressure was 9.3 ± 0.7% compared with acontrol value of 0.9 ± 0.5%(P < 0.05). Groups 2 and 3 hadsignificant decreases in both PVRI and systemic vascular resistanceindex compared with steady state and with group1. In conclusion, intratracheal instillation of apolar-charged tertiary amine NONOate DMAEP/NO results in the selectivereduction of PVRI. Intermittent intratracheal instillation of selectiveNONOates may be an alternative to continuously inhaled NO in thetreatment of pulmonary hypertension.

     

Stop-flow studies of distribution of filtration in rat lungs

Lin, W., E. Jacobs, R. M. Schapira, K. Presberg, andR. M. Effros. Stop-flow studies of distribution offiltration in rat lungs. J. Appl.Physiol. 84(1): 47-52, 1998.The stop-flow approach was used to investigate where filtration occurs in the pulmonary vasculature after elevation of left atrial pressure andaspiration of HCl. Rat lungs were perfused for 11 min at zero leftatrial pressures, and then flow was stopped for 10 min and left atrialpressures were increased to 20 cmH₂O. Thereafter, ³HOH was instilled into the airspaces, and the pulmonary vasculature was flushed by perfusing it fromthe pulmonary artery to left atrium (anterograde flush) or in theopposite direction (retrograde flush). Increases in fluoresceinisothiocyanate (FITC)-dextran (molecular weight 2,000,000) indicatedfiltration, and these preceded increases in³HOH after anterograde but notretrograde flushes. This suggests that some filtration occurred throughvessels that were relatively venous compared with those through which³HOH exchange had occurred.Filtration increased fivefold after instillation of 0.1 N HCl inisotonic saline into the air spaces before perfusion. Increases inEvans blue-labeled albumin concentrations were <40% those ofFITC-dextran, indicating loss from the vasculature, but increases inunlabeled albumin and FITC-albumin were comparable.

     

Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension

Adrie, Christophe, Fumito Ichinose, AlexandraHolzmann, Larry Keefer, William E. Hurford, and Warren M. Zapol. Pulmonary vasodilation by nitric oxide gas and prodrugaerosols in acute pulmonary hypertension. J. Appl. Physiol. 84(2): 435-441, 1998.Sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate{DEA/NO;Et₂N[N(O)NO]Na} is a compound that spontaneously generates nitric oxide (NO). Becauseof its short half-life (2.1 min), we hypothesized that inhaling DEA/NOaerosol would selectively dilate the pulmonary circulation withoutdecreasing systemic arterial pressure. We compared the pulmonaryselectivity of this new NO donor with two other reference drugs:inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheepwith pulmonary hypertension induced by the infusion of U-46619, wecompared the hemodynamic effects of DEA/NO with those of incrementaldoses of inhaled NO gas. In seven additional awake sheep, we examinedthe hemodynamic effects of incremental doses of inhaled nitroprusside(i.e., SNP). Inhaled NO gas selectively dilated the pulmonaryvasculature. Inhaled DEA/NO produced nonselective vasodilation; bothsystemic vascular resistance (SVR) and pulmonary vascular resistance(PVR) were reduced. Inhaled SNP selectively dilated the pulmonarycirculation at low concentrations(10² M), inducing adecrease of PVR of up to 42% without any significant decrease of SVR(5%), but nonselectively dilated the systemic circulation atlarger doses (>10² M). Inconclusion, despite its short half-life, DEA/NO is not a selectivepulmonary vasodilator compared with inhaled NO. Inhaled SNP appears tobe selective to the pulmonary circulation at low doses but not athigher levels.

     

Distribution of blood flow and neutrophil kinetics in bronchial vasculature of sheep

Baile, Elisabeth M., Peter D. Paré, David Ernest, andPeter M. Dodek. Distribution of blood flow and neutrophil kinetics in bronchial vasculature of sheep. J. Appl.Physiol. 82(5): 1466-1471, 1997.The bronchialcirculation, as opposed to the pulmonary circulation, is the likelysource of the edema and inflammatory cells that contribute to airflowobstruction and airway narrowing associated with asthma and pulmonaryedema. The purpose of this study was to understand the mechanism ofedema formation and inflammation in airway walls. Therefore, we soughtfirst to determine the normal bronchial venous drainage pathways. Inanesthetized, ventilated, open-chest sheep we measured the relativedistribution of ⁵¹Cr-labeled redblood cells to the right and left ventricles after injection into thebronchial artery (n = 7).Using this information, we then studied the kinetics of leukocytes inthe bronchial vascular bed. We measured the extraction of¹¹¹In-labeled neutrophils duringtheir first pass through the microvasculature after injection into thebronchial artery or right ventricle (n = 6). In the first set of experiments, we found >85% of the systemic blood flow to the lung returns to the left ventricle. In the second setof experiments, we found that extraction of neutrophils in thebronchial vasculature (50-60%) was less(P < 0.05) than that in thepulmonary vasculature (80%). This finding may be explained bydifferences in the anatomy and/or hydrodynamic dispersal forces between the pulmonary and bronchial vascular beds or may reflect sequestration of neutrophils within the pulmonary microvasculature while traversing bronchial-to-pulmonary anastomotic pathways.

     

Nature and site of action of endogenous nitric oxide in vasculature of isolated pig lungs

Cremona, George, Tim Higenbottam, Motoshi Takao, Edward A. Bower, and Leslie W. Hall. Nature and site of action of endogenousnitric oxide in vasculature of isolated pig lungs. J. Appl. Physiol. 82(1): 23-31, 1997.The site ofaction of endogenous and exogenous nitric oxide (NO) in isolated piglungs was investigated by using arterial, double, and venous occlusion,which allowed precapillary, postcapillary, and venous segments to bepartitioned into arterial, precapillary, postcapillary, and venoussegments. N^G-nitro-L-arginine(L-NNA;10⁵ M) increased resistancein the arterial (35 ± 6.6%, P = 0.003), precapillary (39.3 ± 5.1%,P = 0.001), and venous (18.3 ± 4.8%, P = 0.01) segments,respectively. Sodium nitroprusside(10⁵ M) and NO (80 parts/million) reversed the effects ofL-NNA. Total pulmonary vascularresistance fell with increasing flow, due to a fall in precapillaryresistance and dynamic resistance, and was significantlylower than mean total resistance.L-NNA increased the resistancesbut did not alter the pattern of the pressure-flow relationships. It isconcluded that, in isolated pig lungs, the effect of endogenous NOseems to be dependent on flow in the arterial segment and independentof flow in the precapillary segment, but variation of its release doesnot appear to be fundamental to accommodation to changes in steadyflow.

     

Nitric oxide and thermoregulation during exercise in the horse

Mills, Paul C., David J. Marlin, Caroline M. Scott, andNicola C. Smith. Nitric oxide and thermoregulation during exercise in the horse. J. Appl. Physiol. 82(4):1035-1039, 1997.The effect of inhibition of nitric oxideproduction on sweating rate (SR) and on core, rectal, and tail skintemperatures was measured in five Thoroughbred horses during exerciseof variable intensity on a high-speed treadmill. A standard exercisetest consisting of three canters [~55% maximumO₂ uptake(O_{2 max})], withwalking (~9%O_{2 max}) and trotting(~22% O_{2 max})between each canter, was performed twice (control or test), in randomorder, by each horse.N^G-nitro-L-arginine methyl ester(L-NAME; 20 mg/kg), acompetitive inhibitor of nitric oxide synthase, was infused into thecentral circulation and induced a significant reduction in the SRmeasured on the neck (31.6 ± 6.4 vs. 9.7 ± 4.2 g · min¹ · m²;69%) and rump (14.7 ± 5.2 vs. 4.8 ± 1.6 g · min¹ · m²;67%) of the horses during canter (P < 0.05). Significant increases in core, rectal, and tailskin temperatures were also measured (P < 0.05).L-Arginine (200 mg/kg iv)partially reversed the inhibitory effects ofL-NAME on SR, but core, rectal,and tail skin temperatures continued to increase(P < 0.05), suggesting a cumulationof body heat. The results support the contention that nitric oxidesynthase inhibition diminishes SR, resulting in elevated core andperipheral temperatures leading to deranged thermoregulation duringexercise. The inhibition of sweating byL-NAME may be related toperipheral vasoconstriction but may also involve the neurogenic controlof sweating.

     

Mechanisms of stimulation of vagal pulmonary C fibers by pulmonary air embolism in dogs

Chen, H. F., B. P. Lee, and Y. R. Kou. Mechanisms ofstimulation of vagal pulmonary C fibers by pulmonary air embolism indogs. J. Appl. Physiol. 82(3):765-771, 1997.We investigated the involvement of thecyclooxygenase metabolites and hydroxyl radical (^· OH) in thestimulation of vagal pulmonary C fibers (PCs) by pulmonary air embolism(PAE). Impulses were recorded from PCs in 51 anesthetized, open-chest,and artificially ventilated dogs. Fifty of 59 PCs were stimulated byinfusion of air into the right atrium (0.2 ml ^· kg^{1 ·} min¹for 10 min). As a group (n = 59), PCactivity increased from a baseline of 0.4 ± 0.1 to a peak of 1.7 ± 0.2 impulses/s during the period from 1 min before to 2 min afterthe termination of PAE induction. In PCs initially stimulated by PAEinduction, PAE was repeated after the intervening treatment (iv) withsaline (n = 9), ibuprofen (acyclooxygenase inhibitor; n = 11), ordimethylthiourea (a ^· OH scavenger;n = 12). The responses of PCs to PAEwere not altered by saline vehicle but were abolished by ibuprofen and significantly attenuated by dimethylthiourea. Although hyperinflation of the lungs reversed the PAE-induced bronchomotor responses, it didnot reverse the stimulation of PCs (n = 8). These results suggest that 1)cyclooxygenase products are necessary for the stimulation of PCs byPAE, whereas changes in lung mechanics are not, and2) the functional importance ofcyclooxygenase products may be mediated in part through the formationof ^· OH.

     

Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension

Mathew, Rajamma, Elizabeth S. Gloster, T. Sundararajan, Carl I. Thompson, Guillermo A. Zeballos, andMichael H. Gewitz. Role of inhibition of nitric oxide productionin monocrotaline-induced pulmonary hypertension. J. Appl. Physiol. 82(5): 1493-1498, 1997.Monocrotaline (MCT)-induced pulmonary hypertension (PH) isassociated with impaired endothelium-dependent nitric oxide(NO)-mediated relaxation. To examine the role of NO in PH,Sprague-Dawley rats were given a single subcutaneous injection ofnormal saline [control (C)], 80 mg/kg MCT, or the same doseof MCT and a continuous subcutaneous infusion of 2 mg · kg¹ · day¹of molsidomine, a NO prodrug (MCT+MD). Two weeks later, plasma NO₃ levels, pulmonary arterialpressure (Ppa), ratio of right-to-left ventricular weights (RV/LV) toassess right ventricular hypertrophy, and pulmonary histology wereevaluated. The plasma NO₃ level inthe MCT group was reduced to 9.2 ± 1.5 µM(n = 12) vs. C level of 17.7 ± 1.8 µM (n = 8; P < 0.02). In the MCT+MD group,plasma NO₃ level was 12.3 ± 2.0 µM (n = 8). Ppa and RV/LV in theMCT group were increased compared with C [Ppa, 34 ± 3.4 mmHg(n = 6) vs. 19 ± 0.8 mmHg(n = 8) and 0.41 ± 0.01 (n = 9) vs. 0.25 ± 0.008 (n = 8), respectively;P < 0.001]. In the MCT+MDgroup, Ppa and RV/LV were not different when compared with C [19 ± 0.5 mmHg (n = 5) and 0.27 ± 0.01 (n = 9), respectively;P < 0.001 vs. MCT]. Medial wall thickness of lung vessels in the MCT group was increased comparedwith C [31 ± 1.5% (n = 9)vs. 13 ± 0.66% (n = 9);P < 0.001], and MDpartially prevented MCT-induced pulmonary vascular remodeling [22 ± 1.2% (n = 11);P < 0.001 vs. MCT and C].These results indicate that a defect in the availability of bioactive NO may play an important role in the pathogenesis of MCT-induced PH.