Circulating neuropeptide Y does not produce pulmonary hypertension during massive sympathetic activation

We tested the possibility that neuropeptide Y (NPY) may contribute to the pulmonary hypertension that occurs after massive sympathetic activation produced by intracisternal veratrine administration in the chloralose-anesthetized dog. In six dogs, veratrine caused arterial NPY-like immunoreactivity (NPY-LI) to rise from 873 +/- 150 (SE) pg/ml to peak values of 3,780 +/- 666 pg/ml by 60–120 min. (In 3 animals, adrenalectomy significantly reduced the increases in NPY-LI.) In five additional dogs, we infused porcine NPY for 30 min in doses that increased arterial NPY-LI to 8,354 +/- 1,514 pg/ml and observed only minor changes in pulmonary hemodynamics. In three isolated perfused canine left lower lung lobe (LLL) preparations, increasing doses of NPY were administered, producing levels of plasma NPY-LI, at the highest dose, that exceeded those observed after veratrine administration by three orders of magnitude. No changes in LLL arterial or double-occlusion capillary pressures were observed at any dose. Similarly, no changes in LLL hemodynamics were observed in three additional lobes when NPY was administered while norepinephrine was being infused. We conclude that it is unlikely that NPY plays a role as a circulating vasoactive agent in producing the pulmonary hypertension and edema that occur in this model.

Airway level at which edema liquid enters the air space of isolated dog lungs

To identify lung units associated with liquid leakage into the air space in high-pressure pulmonary edema, we perfused air-inflated dog lung lobes with albumin solution to fill the loose peribronchovascular interstitium. Next, we perfused the lobes for 90 s with fluorescent albumin solution then froze the lobes in liquid nitrogen. This procedure confined the fluorescent perfusate to the liquid flux pathway between the circulation and the air space and eliminated the previously filled peribronchovascular cuffs as a source of the fluorescence that entered the air space. We divided each frozen lobe into three horizontal layers and prepared fluorescence-microscopic sections of each layer. In the most apical layers where alveolar flooding was minimal, 10.6 +/- 21.0% (SD) of alveolar ducts were either fluorescence filled or air filled and continuous with fluorescence-filled alveoli. In the same layers, 11.0 +/- 19.0% of respiratory bronchioles were similarly labeled. No terminal bronchioles in these layers were fluorescence labeled. This suggested that the fluorescent albumin entered the air space across the epithelium of respiratory bronchioles, alveolar ducts, or their associated alveoli. To simulate an alternative explanation, i.e., that fluorescence first entered central airways then flowed into peripheral air spaces, we prepared two additional lobes that we first partially inflated with fluorescent albumin then filled to capacity with air. This pushed the fluorescent solution along the airways into the lung periphery. In these lobes the ciliary lining of bronchi and terminal bronchioles was fluorescence coated. By comparison, cilia in fluorescence-perfused lobes were not coated. We conclude that alveolar flooding in hydrostatic pulmonary edema occurs across the epithelium of alveolar ducts, respiratory bronchioles, or their associated alveoli.(ABSTRACT TRUNCATED AT 250 WORDS)

Do transvascular forces in isolated lobe preparations equilibrate?

We used the stepwise pressure elevation technique to study the relationship between rate of constant weight gain (Qf) and microvascular pressure (Pc) in eight isolated canine left lower lobes. The slope of this relationship, which is assumed to represent lobar conductance to filtration (Kf) was 0.0022 +/- 0.003 ml.min-1.cmH2O-1.g dry wt-1. The intercept when Qf = 0, Pcrit, commonly interpreted as the Pc at which the balance of forces across the microvasculature is overwhelmed, was 9.53 +/- 1.18 cmH2O, a lower Pc than commonly used in weight transient experiments. Consequently, at Pc greater than 9.53 cmH2O, isogravimetric conditions were never achieved. In 12 additional experiments, the perfusate's colloid osmotic pressure (II) was increased from 12 to 37 mmHg with albumin. On average, Pcrit increased from 12.2 to 23 cmH2O. Using the changes in Pcrit and II, we estimated the microvascular drag reflection coefficient for albumin (sigma d) to be 0.67. After the addition of albumin, Pc less than Pcrit induced constant weight loss along the same Qf-to-Pc relationship. To control for time, five additional lobes were observed at constant Pc for 100–180 min. Slight acceleration of the rate of weight gain occurred after they increased their weight by 30–40%. The low Kf and high sigma d, as well as the stability of the preparation, suggest a well-preserved microvasculature. Qf at Pc between 12 and 24 cmH2O did not influence measurements of Kf using the weight transient method. The low Pcrit may reflect obliteration of lymphatic channels.

Growth rate of perivascular cuffs in liquid-inflated dog lung lobes

In the early stages of pulmonary edema, excess liquid leaving the pulmonary exchange vessels accumulates in the peribronchovascular interstitium where it forms large peribronchovascular cuffs. The peribronchovascular interstitium therefore acts as a reservoir to protect the air spaces from alveolar flooding. The rate of liquid accumulation and the liquid storage capacity of the cuffs determine how quickly alveolar flooding is likely to follow once edema formation has begun. To measure the rate and capacity of interstitial filling we inflated 11 isolated degassed dog lung lobes with liquid to an inflation pressure of 14 cmH2O (total lung capacity) for 1–300 min, then froze the lobes in liquid N2. We made photographs of 20 randomly selected 12 X 8-mm cross sections from each lobe and measured cuff volume from the photographs by point-counting. We found that cuff volume increased from 2.2% of air-space volume after 1 min of inflation to 9.3% after 300 min. To measure the driving pressure responsible for cuff formation we used micropipettes to measure subpleural interstitial liquid pressure at the hilum of three additional lobes. With liquid inflation pressure set to 14 cmH2O interstitial pressure rose exponentially to 11.5 cmH2O. Interstitial compliance calculated from our volume and pressure measurements equaled 0.09 ml X cmH2O–1 X g wet wt-1, a value similar to that measured in air-inflated lungs. Goldberg [Am. J. Physiol. 239 (Heart Circ. Physiol. 8): H189-H198, 1980] has likened interstitial filling to the charging of a capacitor, a process that follows a monoexponential time course.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of bronchomotor tone on airway dimensions and resistance in excised dog lungs

In 10 excised dog lobes we measured total lobar resistance (Rlo) by forced oscillation at various transpulmonary pressures (Ptp) before and after bronchodilators and obtained simultaneous tantalum bronchograms in 5. Mean airway diameter increased up to a Ptp of 30 cmH2O, although the increase was greater between 0 and 10 cmH2O. In contrast, Rlo decreased between 0 and 10 cmH2O but increased again between 10 and 30 cmH2O. At a Ptp of 30 cmH2O, the mean diameter of small airways (〜 2 mm) increased 31%, that of large airways (〞 7 mm) 2% after aerosolized bronchodilators. At a Ptp of 1 cmH2O, increases were 44 and 15%, respectively. Values of Rlo were reduced at all Ptp after bronchodilator, but minimum Rlo occurred at lower Ptp than before, and the absolute increase in Rlo at greater Ptp was preserved. In four additional lobes, we partitioned Rlo using a retrograde catheter. All of the increase in Rlo at large Ptp was peripheral to the retrograde catheter. We conclude that excised lungs have bronchomotor tone that narrows airways even at high Ptp and that loss of tone magnifies the relative increase in Rlo at high Ptp, supporting suggestions that the increase is due to tissue resistance and hysteresis.

Vascular and airway pressures, and intersititial edema, affect peribronchial fluid pressure

Peribronchial-perivascular fluid pressure (Px(f) was measured relative to pleural pressure in six freshly excised dog lobes. Rapidly equilibrating saline-filled open-end catheters were inserted between lobar bronchus and artery to depths of 3 cm from the hilum. Px(f) was -4 to -8 cmH2O at resting lung volume and became more negative as transpulmonary pressure (Ptp) was increased, and less negative as vascular volume was increased. For example, at constnat Ptp = 30 cmH2O, mean Px(f) rose, respectively, from -35 to -31, -24, -16, and -4 cmH2O, as vascular pressure (Ppa/pv) was increased from -15 to 0, +10, +20, and +30 cmH2O. Lung weight rose steadily at Ppa/pv above 10, reflecting the development of edema. Px(f) had a significant hysteresis with respect to Ptp, being more negative in deflation. As lung edema developed, Px(f) became progressively less negative or slightly positive (even at high Ptp and low Ppa/pv) and hysteresis diminished. Modified wick catheters employed in four additional lobes gave similar results.These data suggest that Px(f) is strongly influenced by bronchovascular-parenchymal interdependence, and that when regions with negative Px(f) absorb fluid the negative pressure may be eliminated.