Effect of cigarette smoke extract on arteriolar dilatation in vivo

Mayhan, William G., and Glenda M. Sharpe. Effect ofcigarette smoke extract on arteriolar dilatation in vivo.J. Appl. Physiol. 81(5):1996-2003, 1996.The goal of this study was to determine whethercigarette smoke extract alters dilatation of arterioles in vivo inresponse to agonists that produce activation of ATP-sensitive potassiumchannels and activation of adenylate cyclase. By using intravitalmicroscopy, we measured diameter of arterioles contained within themicrocirculation of the hamster cheek pouch during suffusion withagonists in the absence and presence of cigarette smoke extract (0.1, 0.5, and 1.0%). Before treatment with cigarette smoke extract,activation of ATP-sensitive potassium channels with aprikalim andcromakalim produced dose-related dilatation of cheek poucharterioles. Similarly, activation of adenylate cyclasewith isoproterenol and forskolin produced dose-related dilatation ofcheek pouch arterioles before treatment with cigarette smoke extract.Superfusion of 0.1% cigarette smoke extract did not change baselinediameter of arterioles and did not alter responses of cheek poucharterioles to activation of ATP-sensitive potassium channels andadenylate cyclase. Superfusion of 0.5 and 1.0% cigarette smoke extractalso did not alter baseline diameter of arterioles but did impairdilatation of arterioles in response to activation of ATP-sensitivepotassium channels and adenylate cyclase. These findings suggest thatcigarette smoke extract impairs dilatation of resistance arterioles inresponse to activation of important cellular dilator pathways.

     

Innervation pattern of guinea pig pulmonary vasculature depends on vascular diameter

Haberberger, Rainer, Michael Schemann, Holger Sann, andWolfgang Kummer. Innervation pattern of guinea pig pulmonary vasculature depends on vascular diameter. J. Appl.Physiol. 82(2): 426-434, 1997.The pulmonaryvasculature is supplied by various neurochemically distinct types ofnerve fibers, including sensory substance P-containing and autonomicnoradrenergic, nitrergic, and cholinergic axons.Pharmacological experiments have suggested that various segments of thepulmonary vascular tree respond differently to the respectiveneuromediators. We, therefore, aimed to determine histochemically andimmunohistochemically for each of these neurochemically distinctperivascular axons their quantitative distribution along the vasculartree from the extrapulmonary trunks to the smallest intraparenchymalramifications in control guinea pigs(n = 5). Generally, arterialinnervation was more developed than that of veins. Along the arterialtree, noradrenergic and substance P-containing axons were ubiquitousfrom the pulmonary trunk to smallest intraparenchymal vessels, whereasnitrergic axons were practically restricted to large (>700-µm)extrapulmonary arteries. Cholinergic axons were regularly present atarteries down to 100 µm in diameter and innervated two-thirds ofsmall arteries (50-100 µm). The results demonstrate thatthe noradrenergic vasoconstrictor innervation extends throughout thepulmonary vascular system whereas the innervation pattern with varioustypes of vasodilator fibers changes with vascular diameter, parallel toknown pharmacological differences in cholinergic and nitrergicvasodilator effects.

     

Evaluation of estimates of alveolar gas exchange by using a tidally ventilated nonhomogenous lung model

Busso, Thierry, and Peter A. Robbins. Evaluation ofestimates of alveolar gas exchange by using a tidally ventilated nonhomogenous lung model. J. Appl.Physiol. 82(6): 1963-1971, 1997.The purposeof this study was to evaluate algorithms for estimatingO₂ andCO₂ transfer at thepulmonary capillaries by use of a nine-compartment tidallyventilated lung model that incorporated inhomogeneities inventilation-to-volume and ventilation-to-perfusion ratios.Breath-to-breath O₂ andCO₂ exchange at the capillary level and at the mouth were simulated by using realistic cyclical breathing patterns to drive the model, derived from 40-min recordings in six resting subjects. The SD of the breath-by-breath gas exchange atthe mouth around the value at the pulmonary capillaries was 59.7 ± 25.5% for O₂ and 22.3 ± 10.4% for CO₂. Algorithmsincluding corrections for changes in alveolar volume and for changes in alveolar gas composition improved the estimates of pulmonary exchange, reducing the SD to 20.8 ± 10.4% forO₂ and 15.2 ± 5.8% forCO₂. The remaining imprecision ofthe estimates arose almost entirely from using end-tidal measurementsto estimate the breath-to-breath changes in end-expiratory alveolar gasconcentration. The results led us to suggest an alternative method thatdoes not use changes in end-tidal partial pressures as explicitestimates of the changes in alveolar gas concentration. The proposedmethod yielded significant improvements in estimation for the modeldata of this study.

     

Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke in guinea pigs

Wu, Zhong-Xin, Robert F. Morton, and Lu-Yuan Lee. Roleof tachykinins in ozone-induced airway hyperresponsiveness to cigarettesmoke in guinea pigs. J. Appl.Physiol. 83(3): 958-965, 1997.Acute exposure to ozone(O₃) induces airwayhyperresponsiveness to various inhaled bronchoactive substances.Inhalation of cigarette smoke, a common inhaled irritant in humans, isknown to evoke a transient bronchoconstrictive effect. To examinewhether O₃ increases airwayresponsiveness to cigarette smoke, effects of smoke inhalationchallenge on total pulmonary resistance(RL) and dynamic lungcompliance (Cdyn) were compared before and after exposure toO₃ (1.5 ppm, 1 h) in anesthetizedguinea pigs. Before O₃ exposure,inhalation of two breaths of cigarette smoke (7 ml) at a lowconcentration (33%) induced a mild and reproduciblebronchoconstriction that slowly developed and reached its peak(RL = 67 ± 19%, Cdyn = 29 ± 6%) after a delay of >1 min. After exposure toO₃ the same cigarette smokeinhalation challenge evoked an intense bronchoconstriction thatoccurred more rapidly, reaching its peak(RL = 620 ± 224%, Cdyn = 35 ± 7%) within 20 s, and was sustained for >2min. By contrast, sham exposure to room air did not alter thebronchomotor response to cigarette smoke challenge. Pretreatment withCP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhancedresponses of RL and Cdyn tocigarette smoke challenge induced byO₃. These results show thatO₃ exposure induces airwayhyperresponsiveness to inhaled cigarette smoke and that the enhancedresponses result primarily from the bronchoconstrictive effect ofendogenous tachykinins.

     

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.

     

PAF increases vascular permeability without increasing pulmonary arterial pressure in the rat

In vivo pulmonary arterialcatheterization was used to determine the mechanism by whichplatelet-activating factor (PAF) produces pulmonary edema inrats. PAF induces pulmonary edema by increasing pulmonarymicrovascular permeability (PMP) without changing the pulmonarypressure gradient. Rats were cannulated for measurement of pulmonaryarterial pressure (Ppa) and mean arterial pressure. PMP wasdetermined by using either in vivo fluorescent videomicroscopy or theex vivo Evans blue dye technique. WEB 2086 was administeredintravenously (IV) to antagonize specific PAF effects. Threeexperiments were performed: 1) IV PAF, 2) topical PAF, and 3) Escherichia coli bacteremia. IV PAFinduced systemic hypotension with a decrease in Ppa. PMP increasedafter IV PAF in a dose-related manner. Topical PAF increased PMP butdecreased Ppa only at high doses. Both PMP (88 ± 5%) and Ppa(50 ± 3%) increased during E. coli bacteremia.PAF-receptor blockade prevents changes in Ppa and PMP after bothtopical PAF and E. coli bacteremia. PAF, which has beenshown to mediate pulmonary edema in prior studies, appears to act inthe lung by primarily increasing microvascular permeability. Thepresence of PAF might be prerequisite for pulmonary vascularconstriction during gram-negative bacteremia.

     

Thromboxane A2 mediates increased pulmonary microvascular permeability after intestinal reperfusion

Turnage, Richard H., John L. LaNoue, Kevin M. Kadesky, YanMeng, and Stuart I. Myers. ThromboxaneA₂ mediates increased pulmonarymicrovascular permeability after intestinal reperfusion. J. Appl. Physiol. 82(2): 592-598, 1997.This study examines the hypothesis that intestinal reperfusion(IR)-induced pulmonary thromboxane A₂(TxA₂) release increases localmicrovascular permeability and induces pulmonary vasoconstriction.Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 minof IR. Sham-operated animals (Sham) served as controls. After IR orSham, the pulmonary vessels were cannulated, and the lungs wereperfused in vitro with Krebs buffer. Microvascular permeability wasquantitated by determining the filtration coefficient(K_f),and pulmonary arterial (Ppa), venous (Ppv), and capillary (Ppc)pressures were measured to calculate vascular resistance (Rt). Afterbaseline measurements, imidazole(TxA₂ synthase inhibitor) orSQ-29,548 (TxA₂-receptorantagonist) was added to the perfusate; thenK_f, Ppa, Ppv, and Ppc were again measured. TheK_fof lungs from IR animals was four times greater than that of Sham(P = 0.001), and Rt was 63% greaterin the injured group (P = 0.01). Pc of IR lungs was twice that of controls (5.4 ± 1.0 vs. 2.83 ± 0.3 mmHg, IR vs. Sham, respectively; P < 0.05). Imidazole or SQ-29,548 returnedK_fto baseline measurements (P < 0.05)and reduced Rt by 23 and 17%, respectively(P < 0.05). IR-induced increases in Pc were only slightly reduced by 500 µg/ml imidazole (14%;P = 0.05) but unaffected by lowerdoses of imidazole (5 or 50 µg/ml) or SQ-29,548. These data suggestthat IR-induced pulmonary edema is caused by both increasedmicrovascular permeability and increased hydrostatic pressure and thatthese changes are due, at least in part, to the ongoing release ofTxA₂.

     

Pulmonary vasoconstriction induced by mitral valve obstruction in sheep

We hypothesizedthat left atrial hypertension results in pulmonary vasoconstriction,which is obscured by the expected passive decrease in pulmonaryvascular resistance. The objectives of this study were todemonstrate and quantify the vasoconstrictive changes that occur in thepulmonary circulation during experimental left atrial hypertension, todetermine the site of vasoconstriction, and to explore its mechanism.Sheep were instrumented for measurement of pulmonary arterial (Ppa),left atrial (Pla), and systemic arterial pressures (Psa) with a Foleyballoon catheter to variably obstruct the mitral valve. Distalpulmonary arterial wedge pressure (Ppaw) was determined by using a 5-FrSwan-Ganz catheter that was advanced until it wedged with the balloondeflated. Cardiac output (CO) was estimated by thermodilution;pulmonary vascular resistances (PVR) were calculated as mean (Ppa  Pla)/CO = total PVR, (Ppa  Ppaw)/CO = upstream PVR, and(Ppaw  Pla)/CO = downstream PVR. We studied 15 awake sheep atbaseline and during increases in Pla of 10 and 20 cmH₂O, with and without inhalationof ~36 parts per million of nitric oxide. Left atrial hypertensionresulted in elevation of Ppa. CO decreased only slightly at both levels of Pla elevation. Nitric oxide inhalation caused a significant decreasein PVR, which was greater as Pla increased. This vasodilator effect wasmost striking in downstream vessels. Experiments with phentolamine,atropine, and ibuprofen failed to reveal the mechanism of the reactivepulmonary vasoconstriction.

     

A finite-element model of oxygen diffusion in the pulmonary capillaries

Frank, Andreas O., C. J. Charles Chuong, and Robert L. Johnson. A finite-element model of oxygen diffusion in thepulmonary capillaries. J. Appl.Physiol. 82(6): 2036-2044, 1997.We determined the overall pulmonary diffusing capacity(DL) and the diffusing capacities of the alveolar membrane (Dm) and the red blood cell (RBC)segments (De) of the diffusional pathway forO₂ by using a two-dimensionalfinite-element model developed to represent the sheet-flowcharacteristics of pulmonary capillaries. An axisymmetric model wasalso considered to assess the effect of geometric configuration. Results showed the membrane segment contributing the major resistance, with the RBC segment resistance increasing asO₂ saturation(SO₂) rises during the RBC transit:RBC contributed 7% of the total resistance at the capillary inlet (SO₂ = 75%) and 30% toward thecapillary end (SO₂ = 95%) for a 45%hematocrit (Hct). Both Dm and DLincreased as the Hct increased but began approaching a plateau near anHct of 35%, due to competition between RBCs forO₂ influx. Both Dm andDL were found to be relatively insensitive (2~4%) to changes in plasma protein concentration (28~45%). Axisymmetric results showed similar trends for all Hct andprotein concentrations but consistently overestimated the diffusingcapacities (~2.2 times), primarily because of an exaggerated air-tissue barrier surface area. The two-dimensional model correlated reasonably well with experimental data and can better represent theO₂ uptake of the pulmonarycapillary bed.

     

Effects of pulmonary embolism on pulmonary vascular impedance in dogs and minipigs

Pigs have been reported to present with a stronger pulmonaryvascular reactivity than many other species, including dogs. Weinvestigated the pulmonary vascular impedance response to autologous blood clot embolic pulmonary hypertension in anesthetized and ventilated minipigs (n = 6) and dogs(n = 6). Before embolization, minipigs, compared with dogs, presented with higher mean pulmonary arterial pressure (Ppa; by an average of 9 mmHg), a steeper slope ofPpa-flow () relationships, and higher0-Hz impedance (Z₀) andfirst-harmonic impedance (Z₁),without significant differences in characteristic impedance (Zc), and alower ratio of pulsatile hydraulic power to total hydraulic power.Embolic pulmonary hypertension (mean Ppa: 40-55 mmHg) wasassociated with increased Z₀ andZ₁ in both species, but theminipigs had a steeper slope of Ppa/ plots and anincreased Zc. At identical and Ppa,minipigs still presented with higherZ₁ and Zc and a lower ratio ofpulsatile hydraulic power to total hydraulic power. The energytransmission ratio, defined as the hydraulic power in the measuredwaves divided by the hydraulic power in the forward waves, was betterpreserved after embolism in minipigs. No differences in wave reflection indexes were found before and after embolism. We conclude that minipigs, compared with dogs, present with a higher pulmonary vascularresistance and reactivity and adapt to embolic pulmonary hypertensionby an increased Zc without earlier wave reflection. These differencesallow for a reduced pulsatile component of hydraulic power and,therefore, a better energy transfer from the right ventricle to thepulmonary circulation.

     

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.

     

Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness

Colice, Gene L., Nicholas Hill, Yan-Jie Lee, Hongkai Du,James Klinger, James C. Leiter, and Lo-Chang Ou. Exaggerated pulmonary hypertension with monocrotaline in rats susceptible tochronic mountain sickness. J. Appl.Physiol. 83(1): 25-31, 1997.Hilltop (H) strainSprague-Dawley rats are more susceptible to chronic mountain sicknessthan are the Madison (M) strain rats. It is unclear what role pulmonaryvascular remodeling, polycythemia, and hypoxia-induced vasoconstrictionplay in mediating the more severe pulmonary hypertension that developsin the H rats during chronic hypoxia. It is also unclear whether theincreased sensitivity of the H rats to chronic mountain sickness isspecific for a hypoxia effect or, instead, reflects a generalpropensity toward the development of pulmonary hypertension.Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonaryhypertension. We hypothesized that the difference in the pulmonaryvascular response to chronic hypoxia between H and M rats reflects anincreased sensitivity of the H rats to any pulmonary hypertensivestimuli. Consequently, we expected the two strains to also differ intheir susceptibility to MCT-induced pulmonary hypertension. Pulmonaryarterial pressures in conscious H and M rats were measured 3 wk after asingle dose of MCT, exposure to a simulated high altitude of 18,000 ft(barometric pressure = 380 mmHg), and administration of a single doseof saline as a placebo. The H rats had significantlyhigher pulmonary arterial pressures and right ventricular weights afterMCT and chronic hypoxia than did the M rats. The H rats also had morepulmonary vascular remodeling, i.e., greater wall thickness as apercentage of vessel diameter, after MCT and chronic hypoxia than didthe M rats. The H rats had significantly lower arterialPO₂ than did the M rats after MCT,but the degree of hypoxemia was mild [arterialPO₂ of 72.5 ± 0.8 (SE) Torr for Hrats vs. 77.4 ± 0.8 Torr for M rats after MCT]. The H ratshad lower arterial PCO₂ and largerminute ventilation values than did the M rats after MCT. Theseventilatory differences suggest that MCT caused more severe pulmonaryvascular damage in the H rats than in the M rats. These data supportthe hypothesis that the H rats have a general propensity to developpulmonary hypertension and suggest that differences in pulmonaryvascular remodeling account for the increased susceptibility of H rats,compared with M rats, to both MCT and chronic hypoxia-induced pulmonaryhypertension.

     

Hypoxic vasoconstriction in pulmonary arterioles and venules

Hillier, Simon C., Jacquelyn A. Graham, Christopher C. Hanger, Patricia S. Godbey, Robb W. Glenny, and Wiltz W. Wagner, Jr.Hypoxic vasoconstriction in pulmonary arterioles and venules. J. Appl. Physiol. 82(4):1084-1090, 1997.Pulmonary microvessels (<70 µm) lack acomplete muscular media. We tested the hypothesis that thesethin-walled vessels do not participate in the hypoxic pressor response.Isolated canine lobes were pump perfused at precisely knownmicrovascular pressures. A videomicroscope, coupled to a computerizedimage-enhancement system, permitted accurate diameter measurements ofsubpleural arterioles and venules, with each vessel serving as its owncontrol. While vascular pressure was maintained constant throughout theprotocol, hypoxia caused an average reduction of 25% of microvesseldiameters. The constriction was reversed when nitric oxide was added tothe hypoxic gas mixture. The nitric oxide reversal, combined with alack of lobar blood flow redistribution as measured by fluorescentmicrospheres, shows that the constriction was active. This responsesuggests the unexpected potential for active intra-acinarventilation-perfusion matching.

     

Reflex tracheal smooth muscle contraction and bronchial vasodilation evoked by airway cooling in dogs

Pisarri, Thomas E., and Gordon G. Giesbrecht. Reflextracheal smooth muscle contraction and bronchial vasodilation evoked byairway cooling in dogs. J. Appl.Physiol. 82(5): 1566-1572, 1997.Coolingintrathoracic airways by filling the pulmonary circulation with coldblood alters pulmonary mechanoreceptor discharge. To determine whetherthis initiates reflex changes that could contribute to airwayobstruction, we measured changes in tracheal smooth muscle tension andbronchial arterial flow evoked by cooling. In ninechloralose-anesthetized open-chest dogs, the right pulmonary artery wascannulated and perfused; the left lung, ventilated separately, providedgas exchange. With the right lung phasically ventilated, filling theright pulmonary circulation with 5°C blood increased smooth muscletension in an innervated upper tracheal segment by 23 ± 6 (SE) gfrom a baseline of 75 g. Contraction began within 10 s of injection andwas maximal at ~30s. The response was abolished by cervical vagotomy.Bronchial arterial flow increased from 8 ± 1 to 13 ± 2 ml/min, withlittle effect on arterial blood pressure. The time course wassimilar to that of the tracheal response. This response was greatlyattenuated after cervical vagotomy. Blood at 20°C also increasedtracheal smooth muscle tension and bronchial flow, whereas 37°Cblood had little effect. The results suggest that alteration ofairway mechanoreceptor discharge by cooling can initiate reflexes thatcontribute to airway obstruction.

     

Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart

Exercisetraining induces coronary vascular adaptations. The goal of this studywas to contrast the effects of training on capillary and arteriolargrowth. Minipigs were trained for 1, 3, 8, and 16 wk and compared withcontrols. Maximal O₂ consumption increased continuously throughout the study. Capillary and arteriolar densities and diameters, and proliferation of vascular cells in thesevessels, were determined in perfusion-fixed tissue. The arterioles weresubdivided into five groups according to diameter: 10-19.9,20-30, 31-40, 41-70, and 71-120 µm. The totalvascular bed cross-sectional area increased by 37% at 16 wk, mainlybecause of an increase in the number of the small arterioles and anincrease in the diameter of the larger vessels. Capillary densityincreased at 3 wk and then returned to control levels by 16 wk;concomitantly, the number of arterioles (20-30 µm) increased at16 wk. We speculate that the "extra" capillaries observed at 3 wkwere the source of the new arterioles.

     

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.

     

Evidence against an increase in capillary permeability in subjects exposed to high altitude

Kleger, Gian-Reto, Peter Bärtsch, Peter Vock, BernhardHeilig, L. Jackson Roberts II, and Peter E. Ballmer. Evidence against an increase in capillary permeability in subjects exposed tohigh altitude. J. Appl. Physiol.81(5): 1917-1923, 1996.A potential pathogenetic cofactor for thedevelopment of acute mountain sickness and high-altitude pulmonaryedema is an increase in capillary permeability, which could occur as aresult of an inflammatory reaction and/or free radical-mediatedinjury to the lung. We measured the systemic albumin escape byintravenously injecting 5 µCi of ¹²⁵I-labeled albumin and theplasma concentrations of cytokines, F₂-isoprostanes (products of lipidperoxidation), and acute-phase proteins in 24 subjects exposed to 4,559 m. Ten subjects developed acute mountain sickness, and four subjectsdeveloped high-altitude pulmonary edema. The transcapillary escaperate of albumin was 6.9 ± 2.0%/h (SD) at low (550 m) and 6.3 ± 1.9%/h at high (4,559 m) altitude (P = 0.23; n = 24). The subjects withhigh-altitude pulmonary edema had a modest but insignificant increasein the transcapillary escape rate of albumin (4.6 ± 1.9%/h at lowvs. 5.7 ± 1.9%/h at high altitude;P = 0.42;n = 4). Plasma concentrations offibrinogen, ₁-acidglycoprotein, C-reactive protein, and interleukin-6 were unchanged inthe early phases and significantly increased by the end of theobservation period in the subjects with high-altitude pulmonary edema,whereas tumor necrosis factor- andF₂-isoprostanes did not change atall. This suggests that the inflammatory reaction was rather aconsequence than a causative factor of high-altitude pulmonary edema.In summary, these data argue against a dominant role for increasedsystemic capillary permeability in the development of acute mountainsickness and high-altitude pulmonary edema.

     

Effect of neuropeptide Y on hemodynamics of the rabbit lung

Lang, Sally A., and Michael B. Maron.Effect of neuropeptide Y on hemodynamics of the rabbit lung.J. Appl. Physiol. 84(2): 618-623, 1998.We evaluated the effect of neuropeptide Y (NPY) on thehemodynamics of the isolated rabbit lung perfused at constant flow andoutflow pressure. Doses of10⁸ and10 ⁷ M NPY increasedpulmonary arterial pressure (Ppa) from 11.5 ± 1.0 (SE) mmHg to,respectively, 16.4 ± 1.5 and 26.0 ± 3.8 mmHg (P < 0.05, n = 5 mmHg lungs), with 78 ± 4%of the increase at 10⁷ Mresulting from an increased arterial resistance. At the latter dose,pulmonary capillary pressure increased from 5.8 ± 0.9 to 9.4 ± 1.0 mmHg (P < 0.05). Whenadministered in the presence of norepinephrine,10⁸ and10⁷ M NPY(n = 6) produced extreme increases inPpa to 66.1 ± 20.5 and 114.7 ± 25.5 mmHg, respectively, thatwere due primarily to an increased arterial resistance. To determinethe significance of circulating NPY as a pulmonary vasoactive agent, wemeasured plasma NPY-like immunoreactivity in anesthetized rabbits after massively activating the sympathetic nervous system with veratrine. NPY-like immunoreactivity increased from 74 ± 10 to 111 ± 10 (SE) pM (P < 0.05). Thus,although NPY is a potent vasoconstrictor in the rabbit lung, it is notlikely that plasma NPY concentrations rise sufficiently, even aftermassive sympathetic nervous system activation, to produce pulmonaryvasoconstriction in the intact rabbit.

     

Stimulation of vagal pulmonary C fibers by inhaled wood smoke in rats

Lai, C. J., and Y. R. Kou. Stimulation of vagalpulmonary C fibers by inhaled wood smoke in rats. J. Appl. Physiol. 84(1): 30-36, 1998.This studyinvestigated the stimulation of vagal pulmonary C fibers (PCs) by woodsmoke. We recorded impulses from PCs in 58 anesthetized, open-chest,and artificially ventilated rats and delivered 6 ml of wood smoke intothe lungs. Within 1 or 2 s after the smoke delivery, an intense andnonphasic burst of discharge [ = +7.4 ± 0.7 (SE)impulses/s, n = 68] was evoked in 60 of the 68 PCs studied and lasted for 4-8 s. This immediate stimulation was usually followed by a delayed and more sustained increase in C-fiber activity ( = +2.0 ± 0.4 impulses/s). The overall stimulation was not influenced by removal of smoke particulates (n = 15) or by pretreatment withvehicle (n = 8) for dimethylthiourea (DMTU; a hydroxyl radical scavenger) or indomethacin (Indo; a cyclooxygenase inhibitor). The immediate-phase stimulation was notaffected by pretreatment with Indo (n = 8) but was largely attenuated by pretreatment with DMTU(n = 12) or by a combined treatmentwith DMTU and Indo (DMTU+Indo; n = 8).Conversely, the delayed-phase stimulation was partially suppressedeither by DMTU or by Indo but was totally abolished by DMTU+Indo. Theseresults suggest that 1) thestimulation of PCs is linked to the gas phase of wood smoke and2) hydroxyl radical, but notcyclooxygenase products, is involved in the immediate-phasestimulation, whereas both metabolites are responsible for evoking thedelayed-phase stimulation.

     

Anatomic distribution of pulmonary vascular compliance

Presson, Robert G., Jr., Said H. Audi, Christopher C. Hanger, Gerald M. Zenk, Richard A. Sidner, John H. Linehan, Wiltz W. Wagner, Jr., and Christopher A. Dawson. Anatomic distribution ofpulmonary vascular compliance. J. Appl.Physiol. 84(1): 303-310, 1998.Previously, thepressure changes after arterial and venous occlusion have been used tocharacterize the longitudinal distribution of pulmonary vascularresistance with respect to vascular compliance using compartmentalmodels. However, the compartments have not been defined anatomically.Using video microscopy of the subpleural microcirculation, we havemeasured the flow changes in ~40-µm arterioles and venules aftervenous, arterial, and double occlusion maneuvers. The quasi-steadyflows through these vessels after venous occlusion permitted anestimation of the compliance in three anatomic segments: arteries >40µm, veins >40 µm, and vessels <40 µm in diameter. We foundthat ~65% of the total pulmonary vascular compliance was in vessels<40 µm, presumably mostly capillaries. The transient portions ofthe pressure and flow data after venous, arterial, and double occlusionwere consistent with most of the arterial compliance being upstreamfrom most of the arterial resistance and most of the venous compliancebeing downstream from most of the venous resistance.