Effect of hypoxic hypoxia on systemic vasculature.

Effects of hypoxic hypoxia (HH) on cardiac output (CO), CO distribution, arterial and venous pressure-flow curves, vascular compliance, vascular time constant (tau), and resistance to venous return (RVR) were evaluated on six dogs. The vascular bed was isolated into four compartments depending on venous drainage: superior vena cava (SVC), splanchnic, renal and adrenal, and the remainder of the inferior vena cava (IVC). Low arterial O2 content and PO2 produced a threefold increase in CO at the same mean arterial pressure and a significant redistribution of CO to the SVC. Arterial pressure-flow curves decreased their slope (i.e., flow resistance) by a factor of two in the IVC and renal beds and by a factor of three in the splanchnic and SVC beds. Venous pressure-flow curves for the animal also decreased their slope significantly. HH causes a twofold increase in venous compliance and in mean venous pressure; tau did not change, but RVR halved. Seventy percent of the CO increase is explained by the increase in mean venous pressure and 30% by the reduction in RVR.

The effect of lung edema on pulmonary vasoactivity of furosemide.

Previous data suggest that furosemide improves gas exchange in pulmonary edema by preferential perfusion of nonedematous lung units. To test whether this is a direct effect of furosemide on the pulmonary vasculature as opposed to a secondary phenomenon resulting from the known peripheral effects of this drug, the effect of furosemide on the pressure-flow characteristics of the pulmonary vasculature was studied in six isolated perfused canine lungs with different degrees of gravimetrically determined edema. Furosemide shifted the pressure-flow curve by decreasing the mean intercept or average closing pressure of the pulmonary vascular bed from 13.8 +/- 5.3 to 9.5 +/- 5.4 cm H2O and the zero-flow critical closing pressure from 9.3 +/- 4.3 to 4.7 +/- 3.5 cm H2O (P less than 0.05). The slopes of these curves did not change between control and furosemide treatment. The decrease in intercept and the decrease in zero-flow critical closing pressures were closely correlated with the increase in edema (r = 0.895 for average closing pressure and r = -0.928 for critical closing pressure) (P less than 0.05). Furosemide doubled the pulmonary blood flow in the isolated lobe for the same driving pressure and the greater the amount of lobar edema the less pronounced was this furosemide-associated increase in blood flow. This direct effect of furosemide on the pulmonary vasculature could explain the improved gas exchange seen before a decrease in pulmonary edema, since this pulmonary vasoactivity would result in preferential perfusion of nonflooded alveolar units.

Independent influence of blood flow rate and mixed venous PO2 on shunt fraction.

We have tested the independent and combined effects of changes in mixed venous PO2 (PvO2) and blood flow (QT) on shunt fraction (Qs/QT) in isolated blood-perfused canine left lower lobes with edema. The lobes were ventilated with pure O2. Inflow (Pi) and outflow (Po) pressures always exceeded lobar alveolar pressure. PvO2 was varied by means of a clinical bubble oxygenator with appropriate mixtures of O2 and N2. QT was varied by changes in Pi and Po with care not to produce changes in lobar weight. Changes in QT did not influence Qs/QT. Increasing PvO2 from 40 +/- 6 to 88.4 +/- 40 Torr at constant QT significantly increased Qs/QT from 5.5 +/- 2.0 to 15.6 +/- 7.0%. Combined increases in QT and PvO2 from 66.4 +/- 2.7 to 135.6 +/- 21.5 ml/min and from 38.8 +/- 1.3 to 61.8 +/- 2.2 Torr, respectively, also produced a significant increase in Qs/QT from 7.33 +/- 2.27 to 15.43 +/- 4.45%. However, this combined change was explained exclusively by changes in PvO2. We therefore concluded that, under the conditions of our experiment, changes in PvO2 influence Qs/QT, and this may account for apparent dependence of Qs/QT on cardiac output in pulmonary edema.

Dopamine, dobutamine, and phentolamine effects on pulmonary vascular mechanics.

The pressure-flow (P-Q) relationship of the pulmonary vasculature, in an isolated canine lobe perfused under classical zone II conditions, can be characterized by a rectilinear segment at high flow, a curvilinear segment at low flow, and a pulmonary arterial pressure (Ppa) that exceeds alveolar pressure at zero flow. This demonstrates the presence of critical closure in the pulmonary vascular bed. Effects of drugs on pulmonary vascular resistance (PVR) must take the normal P-Q relationship into account. We examined the effect of dopamine (D) and dobutamine (DB), alone and in combination with phentolamine (P), on the slope of the rectilinear segment of the P-Q curve (equivalent to vascular conductance), the extrapolated Ppa intercept (Ppai), and the Ppa at zero flow (Ppaz). Low-dose D (0.4-0.8 mg) and DB (1.0-5.0 mg) did not significantly alter any parameter from control. Higher-dose D (1.2-6.8 mg) and DB (13-38 mg) decreased vascular conductance 32.3 +/- 12.1 (SE) to 50.45 +/- 5.6% (P less than 0.05), and P alone increased conductance 12.0 +/- 2.6% (P less than 0.01) from control with no significant effect on Ppai or Ppaz. The change in conductance with D and DB alone was abolished when either drug was given in combination with P. Ppaz and Ppai decreased significantly from control with DB in combination with P when no significant effect on vascular conductance was noted. The results suggest that lung vessels determining changes in flow resistance are pharmacologically distinct from those subserving critical closure in the pulmonary vascular bed.

Transvascular fluid flux measured from intravascular water concentration changes.

We have measured transvascular water flux in eight canine left lower lobes perfused in a zone 3 of West with indocyanine green-stained plasma. Transvascular flux of water was induced by a step change in the inflow pressure. Assuming the indocyanine green-labeled protein did not significantly cross the capillary membrane in one pass, the rate of transvascular fluid flux could be calculated from the change in outflow-to-inflow concentration of water. The method was validated against gravimetric measurements of water exchange. By comparing our direct measurements of transvascular flux with the time course of lobar weight change, we conclude that following changes in inflow pressure, vascular volume changes occur rapidly and slow changes in lung mass can be accounted for exclusively by water exchange. Our method shows transvascular flux follows a biphasic course, suggesting both a membrane and an interstitial resistance to fluid transudation.

Critical closure in the canine pulmonary vasculature.

The vascular pressure-flow (P-Q) relationships in zone II (West et al.) were studied in isolated canine left lower lobes, in order to characterize the total resistance in the pulmonary vascular bed with respect to incremental or flow resistance and critical closure. At each of five levels of static lung inflation, the P-Q relationship was curvilinear at low flow and rectilinear at higher flows. The slope of the linear portion was not significantly different at alveolar pressures (PA) = 5, 7, or 9 cm H2O, but decreased significantly at PA = 11 and 15 cm H2O ((P less than 0.05), indicating an increase in flow resistance. The pulmonary artery pressure (Ppa) fell to the same value at zero flow regardless of inflation level [10.1 +/- 1.0 (SD) cm H2O at PA = 5 cm H2O to 10.9 +/- 2.7 (SD) at PA = 15 cm H2O]. The Ppa intercept (Ppai), extrapolated from the linear portion of the P-Q curve and representing the average closing pressure for the vascular bed, increased from 16.0 +/- 1.8 (SD) cm H2O at PA = 5.0 to 26.5 +/- 4.4 (SD) cm H2O at PA = 15 (P less than 0.05) in a direct one-to-one relationship with the increase in PA. Since this results in a constant transmural gradient at the alveolar vessel level, these vessels must be the major fraction which undergo critical closure. Operationally defined vascular compliance, determined from the slope of a simultaneously obtained pressure-volume (P-V) curve, decreased significantly from 1.51 +/- 0.62 (SD) ml/cm H2O at PA = 5.0 H2O to 0.87 +/- 0.27 ml/cm H2O at PA = 15 cm H2O (P less than 0.05).

Single-breath nitrogen test in excised human lungs.

Pressure-volume curves and simulated single-breath nitrogen tests were performed on 32 excised left human lungs and the slope of phase III, and phase IV plus minimal volume, expressed as percent of the lung volume at a transpulmonary pressure of 30 cmH2O (closing capacity), was calculated. The lungs were graded as to the degree of emphysema and degree of peripheral airways disease. Peripheral airway dimensions were also measured. The closing capacity expressed as percent predicted in vivo was significantly correlated with the total pathological scores (P less than 0.01) and inflammation scores (P less than 0.01) as well as the transpulmonary pressures at the onset of phase IV (P less than 0.01). Correlations with the emphysema grade were not significant. The slopes of phase III were highly variable even among normal lungs and could not be shown to correlate with airways disease or emphysema.

Exponential analysis of lobar pressure-volume characteristics.

In 19 excised left human lungs, seven of which were emphysema-free, lobar pressure-volume (P-V) characteristics were analysed by fitting to the P-V data an exponential of the form V=A-Be-KPL (where V is the volume at a transpulmonary pressure (PL), A is the theoretical lung volume at infinite PL, B is the difference between A and the intercept of the fitted exponential on the volume axis and K is a shape constant). In the emphysema-free lungs there was no difference in the B/A ratio expressed as a percentage, indicating an identical position of the P-V curves of the upper and lower lobes. However the upper lobes had significantly (p less than 0.025) higher values for K than the lower lobes indicating greater compliance. In 10 emphysematous lungs the upper lobes were more severely involved than the lower lobes. In these lungs the difference in K between upper and lower lobes had been abolished suggesting that the less emphysematous lower lobes had increased compliance relatively more than the upper lobes.

Collateral ventilation in excised human lungs.

Pressure-volume (PV) curves and single-breath nitrogen (SBN) washout traces were obtained in 32 excised human lungs. Comparison of the volumes at the onset of phage IV of the SBN traces (V phase IV) and the volumes at the inflection points (VIP) of the PV curves revealed V phase IV to be significantly larger than VIP. We postulated that V phase IV was caused by bulk airway closure and that the difference between V phase IV and VIP was due to collateral ventilation. To test this we correlated V phas IV -- VIP with age and emphysema grades of the lungs. Significant correlations were obtained, demonstrating that with increasing age and emphysema grade V phase IV -- VIP also increased. This is consistent with the documented evidence for decreased resistance to collateral ventilation with increasing age and emphysema. In addition, in a total of 86 lungs we demonstrated that with increasing age and emphysema there is an increasing incidence of total lack of sigmoid deviation in the PV curve.

Lobar pressure-volume characteristics of excised human lungs.

The pressure-volume (P-V) characteristics were investigated in 14 excised left human lungs and their individual lobes. Comparison of the upper and lower lobar P-V curves of the emphysema-free and emphysematous lungs showed no significant difference when plotted as per cent lobar volume at a transpulmonary pressure (PL) of 30 cm H2O (V30). However, when in the emphysematous lungs the more severely involved lobes were compared with the less severely involved lobes, significant differences in the PL 60-90% V30 were found, the more severely involved lungs exhibited a higher PL. The mean linear intercepts were identical in the upper and lower lobes of the emphysema-free lungs indicating equal distension and validating expression of the P-V data as per cent V30. However, in he emphysematous lungs, in which the upper lobes were more severely involved, the linear intercepts tended to be larger in the upper lobes and the ratio of upper to lower lobe V30 tended to be larger than in the emphysema-free lungs. Thus, in the emphysematous lungs, comparison of the lobar P-V curves expressed as per cent V30 may not be valid.

Maximum volumes in excised human lungs: effects of age, emphysema, and formalin inflation.

The volume of air at a transpulmonary pressure (PL) of 25 cmH2O was measured in 28 emphysema-free and 39 emphysematous excised adult lungs and in the lungs of 53 infants and children. In the adult emphysema-free lungs, this volume (V25) was significantly correlated with body length in males but, corrected for body length, not significantly correlated with age in either males or females. V25 was on the average 20 per cent larger than predicted TLC in non-emphysematous lungs in vivo. The lungs were also inflated and fixed with formalin at a constant PL of 25 cm H2O and their volume measured (VL). Marked and variable underinflation compared to V25 occurred in the adult lungs and VL minus lung weight averaged 75% of V25 and 91% of predicted TLC. In infants and children, the ratio of VL minus lung weight to V25 averaged 1.08 with a range of 0.58 to 1.84. The larger the lungs, the smaller the ratio, suggesting that fixation played a role in producing the small VL. In the emphysematous lungs, a significant correlation between the degree of emphysema and V25 was found. However, a statistically significant increase in V25 only occurred when the emphysema grade was greater than 5.

Pressure-volume characteristics of excised human lungs: effects of sex, age, and emphysema.

Static deflationary pressure-volume curves were obtained in 28 emphysema-free (18 male and 10 female) and 39 emphysematous excised human lungs inflated to a maximum transpulmonary pressure (Pl) of 30 cmH2O. In emphysema-free lungs, the lung volumes at Pl 30 cmH2O (V30) were significantly related to body length in males and were significantly larger than predicated total lung capacity in vivo. However, corrected for stature (V30/body length), there was no significant age correlation. In both males and females, highly significant correlations between the PL at 50--90% V30 and age were obtained. There were no significant differences in these regressions between males and females. The emphysematous lungs were divided into three groups with increasing emphysema grades. Progressive decreases in the PL at 50--90% V30 and increases in the V30 were seen in the groups with increasing degrees of emphysema. Significant changes occurred in these measurements even in group 2 with mild emphysema, suggesting that the lesions of emphysema are not directly responsible for these changes.

Characterization of frog muscle mitochondria.

Studies on oxidative phosphorylation revealed that, in frog skeletal muscle mitochondria (SKMM) from the thigh, the adenosine diphosphate/oxygen ratio (ADP/O) was 2.8 +/- 0.1 SE, and the respiratory control ratio was 9.5 +/- 0.9, with pyruvate/malate as the substrate. Oxygen uptake rate (Qo2) was 225 mumol O2 per minute per gram mitochondrial protein +/- 13; phosphorylation rate (ADP/O X Qo2 X 2) was 1,230 mumol ADP phosphorylation per minute per gram mitochondrial protein +/- 77; and the phosphorylation capacity (phosphorylation rate times tissue mitochondrial protein content) was 3.6 mumol ADP phosphorylated per gram wet weight of muscle +/- 0.2. Tissue mitochondrial protein content was determined by the measurement of nicotinamide adenine dinucleotide (NADH) oxidase activity. Electron microscopy (EM) revealed intact, isolated, energized twisted mitochondria of a condensed form. Frog sartorius muscle mitochondria gave similar oxidative phosphorylation parameters when investigated independently of the rest of the thigh. These values of SKMM respiration from the frog are similar to those values obtained from pigeon and rabbit heart and rat skeletal muscles. However, because of the low NADH-oxidase activity indicating reduced mitochondrial content (this was verified in low-magnification EM pictures), phosphorylation capacity was significantly reduced in frog skeletal muscle mitochondria.